69 results on '"Marsida Kallupi"'
Search Results
2. Editorial: Opioids and opioid-use disorders
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Giordano de Guglielmo, Marsida Kallupi, Andrea Cippitelli, Daniele Caprioli, and Kabirullah Lutfy
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opioids ,opioid use disorder (OUD) ,novel opioids ,overdose ,reward ,aversion ,Therapeutics. Pharmacology ,RM1-950 - Published
- 2023
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3. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats
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Marsida Kallupi, Jenni Kononoff, Philippe A. Melas, Johanna S. Qvist, Giordano de Guglielmo, Eric R. Kandel, and Olivier George
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High-frequency stimulation ,Cocaine addiction ,Neuromodulation ,Glutamate ,Amygdala ,Withdrawal ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD). Objective: Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated. Methods: Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 μs pulse width and 130 Hz frequency) stimulation with a constant current of 150 μA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated. Results: Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions. Conclusions: These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.
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- 2022
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4. Abstinence from Escalation of Cocaine Intake Changes the microRNA Landscape in the Cortico-Accumbal Pathway
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Vidhya Kumaresan, Yolpanhchana Lim, Poorva Juneja, Allison E. Tipton, Giordano de Guglielmo, Lieselot L. G. Carrette, Marsida Kallupi, Lisa Maturin, Ying Liu, Olivier George, and Huiping Zhang
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protracted abstinence ,outbred heterogeneous stock rats ,prefrontal cortex ,nucleus accumbens ,rat brain miRNA ,small RNA sequencing ,Biology (General) ,QH301-705.5 - Abstract
Cocaine administration alters the microRNA (miRNA) landscape in the cortico-accumbal pathway. These changes in miRNA can play a major role in the posttranscriptional regulation of gene expression during withdrawal. This study aimed to investigate the changes in microRNA expression in the cortico-accumbal pathway during acute withdrawal and protracted abstinence following escalated cocaine intake. Small RNA sequencing (sRNA-seq) was used to profile miRNA transcriptomic changes in the cortico-accumbal pathway [infralimbic- and prelimbic-prefrontal cortex (IL and PL) and nucleus accumbens (NAc)] of rats with extended access to cocaine self-administration followed by an 18-h withdrawal or a 4-week abstinence. An 18-h withdrawal led to differential expression (fold-change > 1.5 and p < 0.05) of 21 miRNAs in the IL, 18 miRNAs in the PL, and two miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in the following pathways: gap junctions, neurotrophin signaling, MAPK signaling, and cocaine addiction. Moreover, a 4-week abstinence led to differential expression (fold-change > 1.5 and p < 0.05) of 23 miRNAs in the IL, seven in the PL, and five miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in pathways including gap junctions, cocaine addiction, MAPK signaling, glutamatergic synapse, morphine addiction, and amphetamine addiction. Additionally, the expression levels of several miRNAs differentially expressed in either the IL or the NAc were significantly correlated with addiction behaviors. Our findings highlight the impact of acute and protracted abstinence from escalated cocaine intake on miRNA expression in the cortico-accumbal pathway, a key circuit in addiction, and suggest developing novel biomarkers and therapeutic approaches to prevent relapse by targeting abstinence-associated miRNAs and their regulated mRNAs.
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- 2023
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5. Editorial: The Role of Neuropeptides in Drug Addiction and Other Psychiatric Disorders
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Kabirullah Lutfy, Lucia Hipolito, Valentina Ferretti, Leandro F. Vendruscolo, and Marsida Kallupi
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addiction ,glucagon ,leptin ,orexin ,PACAP ,MDMA ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2022
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6. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats
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Giordano de Guglielmo, Marsida Kallupi, Matthew B. Pomrenze, Elena Crawford, Sierra Simpson, Paul Schweitzer, George F. Koob, Robert O. Messing, and Olivier George
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Science - Abstract
Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.
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- 2019
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7. Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats
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Giordano de Guglielmo, Marsida Kallupi, Sharona Sedighim, Amy H. Newman, and Olivier George
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VK4-116 ,escalation ,opioid ,dependance ,withdrawal ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD.
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- 2020
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8. Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.
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Andrea Cippitelli, Giuseppe Astarita, Andrea Duranti, Giovanni Caprioli, Massimo Ubaldi, Serena Stopponi, Marsida Kallupi, Gianni Sagratini, Fernando Rodrìguez de Fonseca, Daniele Piomelli, and Roberto Ciccocioppo
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Medicine ,Science - Abstract
Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.
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- 2011
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9. Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala
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Jessica L. Zhou, Giordano de Guglielmo, Aaron J. Ho, Marsida Kallupi, Hai-Ri Li, Apurva S. Chitre, Lieselot LG Carrette, Olivier George, Abraham A. Palmer, Graham McVicker, and Francesca Telese
- Abstract
The amygdala contributes to negative emotional states associated with relapse to drug seeking, but the cell type-specific gene regulatory programs that are involved in addiction are unknown. Here we generate an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with low and high cocaine addiction-like behaviors following a prolonged period of abstinence. Between rats with different addiction indexes, there are thousands of cell type-specific differentially expressed genes and these are enriched for molecular pathways including GABAergic synapse in astrocytes, excitatory, and somatostatin neurons. We find that rats with higher addiction severity have excessive GABAergic inhibition in the amygdala, and that hyperpolarizing GABAergic transmission and relapse-like behavior are reversed by pharmacological manipulation of the metabolite methylglyoxal, a GABAA receptor agonist. By analyzing chromatin accessibility, we identify thousands of cell type-specific chromatin sites and transcription factor (TF) motifs where accessibility is associated with addiction-like behaviors, most notably at motifs for pioneer TFs in the FOX, SOX, and helix-loop-helix families.
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- 2022
10. Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats
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Marsida Kallupi, Giordano de Guglielmo, Lieselot LG Carrette, Sierra Simpson, Jenni Kononoff, Adam Kimbrough, Lauren C Smith, Kokila Shankar, Alicia Avelar, Dana Conlisk, Molly Brennan, Lani Tieu, Sharona Sedighim, Brent Boomhower, Lisa Maturin, McKenzie J Fannon, Angelica Martinez, Caitlin Crook, Selen Dirik, Nathan Velarde, Paul Schweitzer, Selene Bonnet-Zahedi, Dyar N. Othman, Benjamin Sichel, Kwynn Guess, Beverly Peng, Andrew S. Hu, Lucas E. Chun, Kristel Milan, Justin Lau, Yicen Zheng, Ashley Vang, Leah C. Solberg Woods, Abraham A. Palmer, and Olivier George
- Abstract
Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.
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- 2022
11. Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder
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Marsida Kallupi, Giordano de Guglielmo, Dana Conlisk, Molly Brennan, Lani Tieu, Sharona Sedighim, Brent Boomhower, Lauren C Smith, Kokila Shankar, Lieselot LG Carrette, Sierra Simpson, Alicia Avelar, Lisa Maturin, Angelica Martinez, Ran Qiao, Selen Dirik, Caitlin Crook, Selene Bonnet-Zahedi, Mohini R. Iyer, Corrine E. Blucher, McKenzie J Fannon, Leah C. Solberg Woods, Abraham A. Palmer, and Olivier George
- Abstract
RationaleCurrent medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known.ObjectivesHere, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder.MethodsOver 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement.ResultsWe found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index.ConclusionsThese results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.
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- 2022
12. Identification of pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration and identification of a causal role of short-chain fatty acids in addiction-like behaviors
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Sierra Simpson, Adam Kimbrough, Gregory Peters, Emma Wellmeyer, Rio Mclellan, Natalie Walker, Haoyu Jia, Sharon Hu, Mohini Iyer, Varshini Sathish, Sharona Sedighim, Marsida Kallupi, Molly Brennan, Lisa Maturin, Talyn Hughes, Tristin Xie, Veronika Espinoza, Lieselot Carrette, Lauren C. Smith, Jonathan Seaman, Leah C. Solberg Woods, Abraham A. Palmer, Giordano DeGuglielmo, and Olivier George
- Abstract
The gut brain axis is thought to play a role in behavior and physiological responses through chemical, immunological, and metabolite signaling. Antibiotics, diet, and drugs can alter the transit time of gut contents as well as the makeup of the microbiome. Heterogeneity in genetics and environment are also well-known factors involved in the initiation and perpetuation of substance use disorders. Few viable genetic or biological markers are available to identify individuals who are at risk of escalating opioid intake. Primarily, the addiction field has focused on the nervous system, limiting the discovery of peripheral factors that contribute to addiction. To address this gap, we characterized the microbiome before and after drug exposure, and after antibiotics depletion in male and female heterogenous stock rats to determine if microbiome constituents are protective of escalation. We hypothesized that individuals that are prone to escalation of opioid self-administration will have distinct microbial and metabolic profiles. The fecal microbiome and behavioral responses were measured over several weeks of oxycodone self-administration and after antibiotic treatment. Antibiotic treatment reduces circulating short-chain fatty acids (SCFA) by depleting microbes that ferment fiber into these essential signaling molecules for the gut-brain axis. Depletion of the microbiome increased oxycodone self-administration in a subpopulation of animals (Responders). Supplementation of SCFAs in antibiotic depleted animals decreased elevated oxycodone self-administration. Phylogenetic functional analysis reveals distinct metabolic differences in the subpopulations of animals that are sensitive to antibiotic depletion and animals rescued by SCFA supplementation. In conclusion, this study identifies pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration, demonstrates that escalation of oxycodone self-administration dysregulates the microbiome and metabolic landscape, and identifies a causal role of short-chain fatty acids in addiction-like behaviors.
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- 2022
13. Longitudinal assessment of the effects of cannabidiol over the different stages of addiction in rat models of alcohol use disorder
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Michelle R. Doyle, Angelica Martinez, Selen Dirik, Marsida Kallupi, and Giordano de Guglielmo
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Behavioral Neuroscience ,Health (social science) ,Neurology ,General Medicine ,Toxicology ,Biochemistry - Published
- 2023
14. Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats
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Jeremiah D. Momper, Lauren C. Smith, Raymond T. Suhandynata, Melissa A Hoffman, Robert L. Fitzgerald, Kate Hanham, Yadira Sepulveda, Olivier George, Lieselot L. G. Carrette, Joseph Dowling, Lani Tieu, Marsida Kallupi, and Brent Boomhower
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Male ,Nicotine ,medicine.medical_treatment ,media_common.quotation_subject ,Craving ,Pharmacology ,digestive system ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Cannabidiol ,Rats, Wistar ,Saline ,Infusion Pumps ,media_common ,business.industry ,Tobacco Use Disorder ,Abstinence ,medicine.disease ,digestive system diseases ,Rats ,Substance Withdrawal Syndrome ,030227 psychiatry ,surgical procedures, operative ,Nicotine withdrawal ,Nicotinic agonist ,Hyperalgesia ,Anticonvulsants ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
RATIONALE: Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking. OBJECTIVES: The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence. METHODS: Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for two weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for two weeks, starting one week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps that received sesame oil injections (double vehicle) or the highest dose of CBD 30mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded. RESULTS: CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30mg/kg/day) did not alter these results. CONCLUSIONS: This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine-cessation may be beneficial.
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- 2021
15. Voluntary and forced exposure to ethanol vapor produces similar escalation of alcohol drinking but differential recruitment of brain regions related to stress, habit, and reward in male rats
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Giordano de Guglielmo, Sierra Simpson, Adam Kimbrough, Dana Conlisk, Robert Baker, Maxwell Cantor, Marsida Kallupi, and Olivier George
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Male ,Alcohol Drinking ,Basic Behavioral and Social Science ,Oral and gastrointestinal ,Article ,Alcohol Use and Health ,Substance Misuse ,Habits ,Cellular and Molecular Neuroscience ,Reward ,Behavioral and Social Science ,Psychology ,Animals ,Pharmacology ,Neurology & Neurosurgery ,Ethanol ,Animal ,Central Amygdaloid Nucleus ,Neurosciences ,Pharmacology and Pharmaceutical Sciences ,Brain Disorders ,Rats ,Stroke ,Alcoholism ,Disease Models, Animal ,Good Health and Well Being ,Disease Models ,Mental health ,Blood Alcohol Content - Abstract
A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). In this model, naive outbred rats given intermittent access to alcohol vapor self-administration exhibit BAL in the 150-300 mg% range and develop somatic signs of withdrawal during acute abstinence. However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in the central nucleus of the amygdala (CeA), dorsomedial striatum (DMS), dorsolateral striatum (DLS), nucleus accumbens core (Nacc), periaqueducal grey area (PAG), lateral Habenula (HbL), and the paraventricular nucleus of the thalamus (PVT). The rats were first trained to orally self-administer alcohol in standard operant chambers and then divided in 4 groups (CIE, CI-Air, EVSA and Air-SA) and exposed to intermittent ethanol vapor (passive or active) or intermittent air (passive or active) for 8 h/day, 3 days a week. CIE and EVSA rats exhibited similar BAL (150-300 mg% range) and similar escalation of alcohol drinking during withdrawal, while no changes in terms of drinking were observed in the air exposed rats. CIE and EVSA also increased the motivation for alcohol compared to their respective air control groups under a progressive ratio schedule of reinforcement. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the CeA, however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. Moreover, acute withdrawal from EVSA specifically recruited the DMS and PVT, a pattern not observed in CIE rats.In summary, these results demonstrate that EVSA produces similar escalation of alcohol drinking, motivation to drink, and blood-alcohol levels than the CIE model, while letting animals voluntary initiate alcohol exposure and maintain alcohol dependence. Moreover, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model was similar, the recruitment of neuronal ensembles during acute withdrawal was very different with a higher recruitment of Fos+ neurons in key brain regions important for stress, reward and habit-related processes. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model with better face validity for alcohol use disorder.
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- 2023
16. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats
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Olivier George, Johanna S. Qvist, Eric R. Kandel, Philippe A. Melas, Giordano de Guglielmo, Jenni Kononoff, and Marsida Kallupi
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Male ,medicine.medical_treatment ,Deep Brain Stimulation ,Craving ,Stimulation ,Self Administration ,Pharmacology ,Medical and Health Sciences ,Nucleus Accumbens ,Substance Misuse ,Cocaine ,Cocaine addiction ,Medicine ,media_common ,Assistive Technology ,Neuromodulation ,General Neuroscience ,Central nucleus of the amygdala ,Rehabilitation ,Amygdala ,medicine.anatomical_structure ,Withdrawal ,Mental health ,medicine.symptom ,Glutamate ,Self-administration ,Locomotion ,RC321-571 ,Deep brain stimulation ,media_common.quotation_subject ,Biophysics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Bioengineering ,Nucleus accumbens ,Basic Behavioral and Social Science ,Article ,Cocaine-Related Disorders ,High-frequency stimulation ,Behavioral and Social Science ,Animals ,Neurology & Neurosurgery ,business.industry ,Addiction ,Central Amygdaloid Nucleus ,Neurosciences ,Rats ,Brain Disorders ,Good Health and Well Being ,nervous system ,Neurology (clinical) ,business ,Drug Abuse (NIDA only) - Abstract
Background Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD). Objective Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated. Methods Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 μs pulse width and 130 Hz frequency) stimulation with a constant current of 150 μA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated. Results Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions. Conclusions These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.
- Published
- 2022
17. Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use
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Lauren C. Smith, Xin Sun, Yujuan Su, Mike Klodnicki, Marsida Kallupi, Sharona Sedighim, Nathan Velarde, Kokila Shankar, Lani Tieu, Jamie Barr, Abigail A Jaquish, Giordano de Guglielmo, Olivier George, and Lieselot L. G. Carrette
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Agonist ,Nicotine ,medicine.drug_class ,media_common.quotation_subject ,Self Administration ,Electronic Nicotine Delivery Systems ,Receptors, Nicotinic ,Pharmacology ,Nucleus accumbens ,Partial agonist ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Reward ,medicine ,Animals ,Nicotinic Agonists ,Varenicline ,media_common ,business.industry ,Vaping ,Addiction ,Rats ,030227 psychiatry ,Psychiatry and Mental health ,Nicotinic acetylcholine receptor ,chemistry ,Conditioning, Operant ,Self-administration ,business ,Stress and resilience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.
- Published
- 2020
18. Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA–GABA transmission in highly addicted rats
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Jenni Kononoff, Abraham A. Palmer, Marsida Kallupi, Paul Schweitzer, Leah C. Solberg Woods, Giordano de Guglielmo, Olivier George, and Lieselot L. G. Carrette
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Male ,Population ,Self Administration ,Pharmacology ,Amygdala ,GABA ,Substance Misuse ,nociceptin ,medicine ,Animals ,Humans ,education ,gamma-Aminobutyric Acid ,hyperalgesia ,education.field_of_study ,Multidisciplinary ,business.industry ,Central nucleus of the amygdala ,Pain Research ,Neurosciences ,Opioid use disorder ,amygdala ,Biological Sciences ,Opioid-Related Disorders ,medicine.disease ,Rats ,Brain Disorders ,Nociceptin receptor ,Good Health and Well Being ,medicine.anatomical_structure ,Opioid Peptides ,Hyperalgesia ,addiction ,Chronic Pain ,medicine.symptom ,Drug Abuse (NIDA only) ,Self-administration ,business ,Oxycodone ,medicine.drug - Abstract
Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.
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- 2020
19. Characterization of the Brain Functional Architecture of Psychostimulant Withdrawal Using Single-Cell Whole-Brain Imaging
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Sierra Simpson, Marsida Kallupi, Adam Kimbrough, Olivier George, Lauren C. Smith, and Andres Collazo
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Male ,Drug Abuse (NIDA Only) ,media_common.quotation_subject ,graph theory ,Cell ,Psychostimulant withdrawal ,Neuroimaging ,Neuronal Excitability ,Biology ,Inbred C57BL ,Methamphetamine ,Nicotine ,Substance Misuse ,Mice ,Neural activity ,Cocaine ,neural activity ,medicine ,Animals ,media_common ,Modularity (networks) ,withdrawal ,General Neuroscience ,Addiction ,functional connectivity ,Neurosciences ,Substance Abuse ,Brain ,General Medicine ,Substance Withdrawal Syndrome ,Brain Disorders ,Mice, Inbred C57BL ,Good Health and Well Being ,medicine.anatomical_structure ,Neurological ,Mental health ,addiction ,Neuroscience ,Research Article: New Research ,iDISCO ,medicine.drug - Abstract
Numerous brain regions have been identified as contributing to withdrawal behaviors, but it is unclear the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/d), cocaine (60 mg/kg/d), or methamphetamine (4 mg/kg/d) for one week in male C57BL/6J mice. After one week, the minipumps were removed and brains collected 8 h (saline, nicotine, and cocaine) or 12 h (methamphetamine) after removal. We then performed single-cell whole-brain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical-driven to subcortical-driven network, including a decrease in total hub brain regions. These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway associated with withdrawal.
- Published
- 2021
20. The Cocaine and Oxycodone Biobanks, Two Repositories from Genetically Diverse and Behaviorally Characterized Rats for the Study of Addiction
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Jenni Kononoff, Dana Conlisk, Kokila Shankar, Abraham A. Palmer, Sierra Simpson, Brent Boomhower, Francisco J. Ramirez, Giordano de Guglielmo, Bonnie Lin, Lani Tieu, Leah C. Solberg Woods, Apurva S. Chitre, Olivier George, Lieselot L. G. Carrette, McKenzie J. Fannon, Lisa Maturin, Nathan Velarde, Molly Brennan, Adam Kimbrough, Angelica R Martinez, Sharona Sedighim, Lauren C. Smith, Oksana Polesskaya, and Marsida Kallupi
- Subjects
psychostimulant ,outbred strains ,Physiology ,Self Administration ,Proteomics ,Rats, Sprague-Dawley ,Substance Misuse ,Cocaine ,Addictive ,2.1 Biological and endogenous factors ,Medicine ,Aetiology ,Biomarker discovery ,media_common ,Epigenomics ,education.field_of_study ,General Neuroscience ,General Medicine ,Oxycodone ,medicine.drug ,media_common.quotation_subject ,Population ,Novel Tools and Methods ,Cocaine-Related Disorders ,Behavioral and Social Science ,Genetics ,Animals ,education ,Behavior ,business.industry ,Prevention ,Addiction ,biological specimen banks ,Neurosciences ,Abstinence ,Brain Disorders ,Rats ,Behavior, Addictive ,substance-related disorders ,Good Health and Well Being ,Opioid ,opioid ,Sprague-Dawley ,Drug Abuse (NIDA only) ,business ,Open Source Tools and Methods - Abstract
Visual Abstract, The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc. Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.
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- 2021
21. Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats
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Jeremiah D. Momper, Kenia Palomino, Adam Kimbrough, Giordano de Guglielmo, Dana Conlisk, Olivier George, Jenni Kononoff, Sierra Simpson, Sharona Sedighim, and Marsida Kallupi
- Subjects
Male ,Emotions ,Wistar ,Self Administration ,Mechanical nociception ,Medical and Health Sciences ,Substance Misuse ,0302 clinical medicine ,Medicine ,Psychiatry ,Analgesics ,Sex Characteristics ,Pain Research ,Substance Abuse ,Brain ,Self-administration ,Substance Withdrawal Syndrome ,Analgesics, Opioid ,Aggression ,Mental Health ,Hyperalgesia ,Anesthesia ,Female ,Defensive ,medicine.symptom ,Chronic Pain ,von Frey test ,Oxycodone ,medicine.drug ,Pain Threshold ,Pain ,Opioid ,Irritability ,Basic Behavioral and Social Science ,Article ,03 medical and health sciences ,Sex differences ,Behavioral and Social Science ,Nociception assay ,Animals ,Rats, Wistar ,Pharmacology ,business.industry ,Psychology and Cognitive Sciences ,Neurosciences ,030227 psychiatry ,Rats ,business ,Drug Abuse (NIDA only) ,030217 neurology & neurosurgery - Abstract
RATIONALE: Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans. OBJECTIVES: We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats. RESULTS: Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed. CONCLUSIONS: The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.
- Published
- 2020
22. Exposure to passive nicotine vapor in male adolescent rats produces a withdrawal-like state and facilitates nicotine self-administration during adulthood
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Estefania Larrosa, Giordano de Guglielmo, Olivier George, and Marsida Kallupi
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Male ,Self Administration ,Locomotor activity ,Medical and Health Sciences ,Nicotine ,0302 clinical medicine ,Pharmacology (medical) ,Secondhand exposure ,media_common ,Pediatric ,Psychiatry ,Abstinence ,Pain Research ,Substance Abuse ,Age Factors ,Electronic Cigarette Use ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Neurology ,Inhalation ,Hyperalgesia ,Administration ,Administration, Intravenous ,medicine.symptom ,Self-administration ,Intravenous ,medicine.drug ,Chronic exposure ,Moderate to severe ,Drug Abuse (NIDA Only) ,Pediatric Research Initiative ,medicine.medical_specialty ,media_common.quotation_subject ,Pain ,Article ,Drug Administration Schedule ,03 medical and health sciences ,Operant ,Internal medicine ,Administration, Inhalation ,Tobacco ,medicine ,Animals ,Dependence ,Biological Psychiatry ,Pharmacology ,Tobacco Smoke and Health ,business.industry ,Psychology and Cognitive Sciences ,Brain Disorders ,030227 psychiatry ,Rats ,Endocrinology ,Conditioning, Operant ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Conditioning - Abstract
Electronic cigarette use is particularly prevalent in adolescents, but the effects of secondhand exposure to nicotine vapor in adolescents on the propensity to develop nicotine dependence and increase nicotine self-administration in adulthood are poorly known. The present study explored the effects of nicotine vapor exposure on withdrawal-like states (hyperalgesia, spontaneous withdrawal signs, and locomotor activity) in adolescent rats and the vulnerability to acquire intravenous nicotine self-administration in adulthood. Adolescent (postnatal day 38) rats were exposed to intermittent nicotine vapor (14 h/day) for 7 consecutive days in a range of doses (0, 0.4, and 7 mg/m(3)). The rats were tested for somatic, emotional, and motivational withdrawal symptoms. When the animals reached adulthood, they were allowed to self-administer nicotine (0.03 mg/kg/0.1 ml) intravenously in operant chambers for 1 h/day for 12 consecutive days. Rats that were exposed to nicotine vapor presented moderate to severe signs of spontaneous withdrawal after the cessation of nicotine vapor. No effect on anxiety-like behavior was observed. Rats that were exposed to high levels of nicotine vapor in adolescence had lower pain thresholds and exhibited faster and higher acquisition of nicotine self-administration in adulthood. Chronic exposure to nicotine vapor in adolescent rats produces a withdrawal-like state and facilitates the acquisition of intravenous nicotine self-administration in adulthood. These results suggest that exposure of adolescents to nicotine vapor may confer higher risk of developing nicotine dependence when they become adults.
- Published
- 2019
23. Vaping nicotine-containing electronic cigarettes produces addiction-like behaviors and cardiopulmonary abnormalities in rats
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Jamie Barr, Olivier George, Xin Sun, Lieselot L. G. Carrette, Giordano de Guglielmo, Sharona Sedighim, Marsida Kallupi, Lauren C. Smith, Nathan Velarde, Mike Klodnicki, Abigail Jaquish, Lani Tieu, and Yujuan Su
- Subjects
Drug ,medicine.medical_specialty ,media_common.quotation_subject ,medicine.medical_treatment ,law.invention ,Nicotine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Medicine ,Nicotine dependence ,Varenicline ,Psychiatry ,030304 developmental biology ,media_common ,0303 health sciences ,Health professionals ,business.industry ,Addiction ,medicine.disease ,3. Good health ,chemistry ,Smoking cessation ,business ,Electronic cigarette ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The debate about electronic cigarettes has divided healthcare professionals, policymakers, and communities. Central points of disagreement are whether vaping electronic cigarettes are addictive and whether they produce major pulmonary complications. We developed a novel model of nicotine vapor self-administration in rats and found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans, exhibiting both addiction-like behaviors and cardiopulmonary abnormalities. The smoking cessation drug varenicline decreased electronic cigarette self-administration. These findings confirm the addictive properties and harmful effects of nicotine vapor and identify a potential medication for the treatment of electronic cigarette addiction.One Sentence SummaryVaping nicotine-containing electronic cigarettes produces cardiopulmonary abnormalities, nicotine dependence and addiction-like behaviors, which are reduced by the smoking cessation drug varenicline.
- Published
- 2019
24. Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence
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Paul Schweitzer, Alessandra Matzeu, Olivier George, Marsida Kallupi, and Rémi Martin-Fardon
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Male ,0301 basic medicine ,Self Administration ,Dynorphin ,Medical and Health Sciences ,Extinction, Psychological ,Substance Misuse ,0302 clinical medicine ,Cocaine ,Addictive ,Drug Interactions ,Psychiatry ,Chemistry ,Miniature Postsynaptic Potentials ,Glutamate receptor ,Extinction ,Naltrexone ,Ventral tegmental area ,Psychiatry and Mental health ,medicine.anatomical_structure ,Excitatory postsynaptic potential ,Original Article ,Mental health ,Psychology ,Self-administration ,Microinjections ,Thalamus ,Dynorphins ,Glutamatergic ,Cocaine-Related Disorders ,03 medical and health sciences ,Slice preparation ,Reward ,Behavioral and Social Science ,medicine ,Animals ,Pharmacology ,Behavior ,Orexins ,Psychology and Cognitive Sciences ,Neurosciences ,Excitatory Postsynaptic Potentials ,Extinction (psychology) ,Rats ,Orexin ,Behavior, Addictive ,Electrophysiology ,Good Health and Well Being ,030104 developmental biology ,Psychological ,Drug Abuse (NIDA only) ,Neuroscience ,030217 neurology & neurosurgery ,Paraventricular Hypothalamic Nucleus - Abstract
The orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA±DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seekingvs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.
- Published
- 2017
25. Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption
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Roberto Ciccocioppo, Dennis Yasuda, Giordano de Guglielmo, V. Blair Journigan, Nurulain T. Zaveri, Qianwei Shen, and Marsida Kallupi
- Subjects
Pharmacology ,Agonist ,Intrinsic activity ,medicine.drug_class ,business.industry ,NOP ,Medicine (miscellaneous) ,Naltrexone ,030227 psychiatry ,3. Good health ,03 medical and health sciences ,Psychiatry and Mental health ,Nociceptin receptor ,0302 clinical medicine ,medicine ,business ,Self-administration ,Receptor ,030217 neurology & neurosurgery ,Buprenorphine ,medicine.drug - Abstract
Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.
- Published
- 2017
26. Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration
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Marsida Kallupi, Giordano de Guglielmo, Olivier George, and Maury Cole
- Subjects
Male ,Wistar ,Self Administration ,Alcohol ,Anxiety ,Medical and Health Sciences ,Alcohol Use and Health ,Substance Misuse ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,media_common ,Psychiatry ,Substance Withdrawal Syndrome ,Alcoholism ,Withdrawal ,medicine.symptom ,Self-administration ,medicine.medical_specialty ,media_common.quotation_subject ,Pharmacology toxicology ,Addiction ,Basic Behavioral and Social Science ,Article ,Operant ,03 medical and health sciences ,Behavioral and Social Science ,Animals ,Rats, Wistar ,Dependence ,Pharmacology ,Ethanol ,Animal ,business.industry ,Psychology and Cognitive Sciences ,Alcohol dependence ,Neurosciences ,Vapor ,Rats ,Brain Disorders ,030227 psychiatry ,Disease Models, Animal ,Good Health and Well Being ,chemistry ,Disease Models ,Conditioning, Operant ,business ,030217 neurology & neurosurgery ,Conditioning - Abstract
RationaleA major issue in the addiction field is the limited number of animal models of the voluntary induction and maintenance of alcohol dependence in outbred rats.ObjectivesTo address this issue, we developed a novel apparatus that vaporizes alcohol for 2-10min after an active nosepoke response.MethodsMale Wistar rats were allowed to self-administer alcohol vapor for 8h/day every other day for 24 sessions (escalated) or eight sessions (non-escalated). Escalated and non-escalated rats were then tested for progressive ratio responding. Anxiety-like behavior, somatic signs of withdrawal, and hyperalgesia were assessed during acute withdrawal.ResultsThe results showed that rats exhibited excellent discrimination between the active and inactive operanda (>85%), and the escalated rats quickly increased their blood alcohol levels from ~50 to >200mg% in ~6weeks. Compared with non-escalated rats, escalated rats exhibited severe addiction-like behavior, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and higher responding on a progressive ratio schedule of reinforcement.ConclusionsThese results demonstrate that outbred rats will voluntarily self-administer alcohol vapor to the point of dependence without the use of forced alcohol administration, sweeteners, food/water restriction, operant pretraining, or behavioral/genetic selection. This novel animal model may be particularly useful for medication development to help unveil the neuronal circuitry that underlies the voluntary induction of alcohol addiction and identify novel molecular targets that are specifically recruited after the voluntary induction and maintenance of alcohol dependence.
- Published
- 2017
27. High-Frequency Stimulation of the Subthalamic Nucleus Blocks Compulsive-Like Re-Escalation of Heroin Taking in Rats
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Emmanuel Breysse, Carrie L. Wade, Marsida Kallupi, Paul Schweitzer, Olivier George, Daniel O Hernandez, George F. Koob, Elena Crawford, Giordano de Guglielmo, and Christelle Baunez
- Subjects
Male ,0301 basic medicine ,Deep brain stimulation ,Deep Brain Stimulation ,media_common.quotation_subject ,medicine.medical_treatment ,Drug-Seeking Behavior ,Self Administration ,Substantia nigra ,Stimulation ,Nucleus accumbens ,Brain mapping ,Membrane Potentials ,Heroin ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Subthalamic Nucleus ,mental disorders ,medicine ,Animals ,Rats, Wistar ,media_common ,Pharmacology ,Heroin Dependence ,Addiction ,Analgesics, Opioid ,Disease Models, Animal ,Psychiatry and Mental health ,Subthalamic nucleus ,030104 developmental biology ,nervous system ,Compulsive Behavior ,Original Article ,Psychology ,Proto-Oncogene Proteins c-fos ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Opioid addiction, including addiction to heroin, has markedly increased in the past decade. The cost and pervasiveness of heroin addiction, including resistance to recovery from addiction, provide a compelling basis for developing novel therapeutic strategies. Deep brain stimulation may represent a viable alternative strategy for the treatment of intractable heroin addiction, particularly in individuals who are resistant to traditional therapies. Here we provide preclinical evidence of the therapeutic potential of high-frequency stimulation of the subthalamic nucleus (STN HFS) for heroin addiction. STN HFS prevented the re-escalation of heroin intake after abstinence in rats with extended access to heroin, an animal model of compulsive heroin taking. STN HFS inhibited key brain regions, including the substantia nigra, entopeduncular nucleus, and nucleus accumbens shell measured using brain mapping analyses of immediate-early gene expression and produced a robust silencing of STN neurons as measured using whole-cell recording ex vivo. These results warrant further investigation to examine the therapeutic effects that STN HFS may have on relapse in humans with heroin addiction.
- Published
- 2016
28. Characterization of the brain functional architecture of psychostimulant withdrawal using single-cell whole brain imaging
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Andres Collazo, Sierra Simpson, Lauren C. Smith, Adam Kimbrough, Olivier George, and Marsida Kallupi
- Subjects
Modularity (networks) ,business.industry ,Traumatic brain injury ,Addiction ,media_common.quotation_subject ,Methamphetamine ,medicine.disease ,Substance abuse ,Nicotine ,Neuroimaging ,medicine ,Dementia ,business ,Neuroscience ,medicine.drug ,media_common - Abstract
Numerous brain regions have been identified as contributing to addiction-like behaviors, but unclear is the way in which these brain regions as a whole lead to addiction. The search for a final common brain pathway that is involved in addiction remains elusive. To address this question, we used male C57BL/6J mice and performed single-cell whole-brain imaging of neural activity during withdrawal from cocaine, methamphetamine, and nicotine. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical- to subcortical-driven network, including a decrease in total hub brain regions. These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway that leads to addiction.Significance StatementA key aspect of treating drug abuse is understanding similarities and differences of how drugs of abuse affect the brain. In the present study we examined how the brain is altered during withdrawal from psychostimulants. We found that each drug produced a unique pattern of activity in the brain, but that brains in withdrawal from cocaine and methamphetamine shared similar features. Interestingly, we found the major common link between withdrawal from all psychostimulants, when compared to controls, was a shift in the broad organization of the brain in the form of reduced modularity. Reduced modularity has been shown in several brain disorders, including traumatic brain injury, and dementia, and may be the common link between drugs of abuse.
- Published
- 2019
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29. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats
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Paul Schweitzer, Giordano de Guglielmo, George F. Koob, Robert O. Messing, Sierra Simpson, Matthew B. Pomrenze, Marsida Kallupi, Elena Crawford, and Olivier George
- Subjects
Male ,0301 basic medicine ,Corticotropin-Releasing Hormone ,Cell ,General Physics and Astronomy ,02 engineering and technology ,Alcohol use disorder ,Cardiovascular ,Oral and gastrointestinal ,Amygdalofugal pathway ,Substance Misuse ,Alcohol Use and Health ,Neural Pathways ,Addictive ,lcsh:Science ,Cancer ,media_common ,Neurons ,Multidisciplinary ,Behavior, Animal ,Chemistry ,Central nucleus of the amygdala ,Substance Abuse ,021001 nanoscience & nanotechnology ,Substance Withdrawal Syndrome ,Alcoholism ,Mental Health ,medicine.anatomical_structure ,0210 nano-technology ,psychological phenomena and processes ,medicine.medical_specialty ,Science ,media_common.quotation_subject ,Optogenetics ,Basic Behavioral and Social Science ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,Behavioral and Social Science ,medicine ,Animals ,Humans ,Behavior ,Animal ,Addiction ,Central Amygdaloid Nucleus ,Neurosciences ,General Chemistry ,medicine.disease ,Rats ,Brain Disorders ,Behavior, Addictive ,Disease Models, Animal ,Stria terminalis ,Good Health and Well Being ,030104 developmental biology ,Endocrinology ,nervous system ,Disease Models ,lcsh:Q ,Septal Nuclei ,Nucleus - Abstract
The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder., Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.
- Published
- 2019
30. An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse
- Author
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Marsida Kallupi, Olivier George, Kim D. Janda, Song Xue, and Bin Zhou
- Subjects
0301 basic medicine ,Male ,medicine.medical_treatment ,Wistar ,Self Administration ,Disease ,Pharmacology ,Nicotine ,0302 clinical medicine ,Research Articles ,Multidisciplinary ,Behavior, Animal ,Substance Abuse ,SciAdv r-articles ,Tobacco Use Disorder ,3. Good health ,Yohimbine ,Substance Withdrawal Syndrome ,5.1 Pharmaceuticals ,Hyperalgesia ,behavior and behavior mechanisms ,Compulsive Behavior ,Mental health ,Development of treatments and therapeutic interventions ,medicine.symptom ,Self-administration ,Oxidoreductases ,Research Article ,medicine.drug ,Drug Abuse (NIDA Only) ,03 medical and health sciences ,Operant ,Pharmacokinetics ,Bacterial Proteins ,mental disorders ,Behavioral and Social Science ,Tobacco ,medicine ,Animals ,Rats, Wistar ,Behavior ,Tobacco Smoke and Health ,business.industry ,Pseudomonas putida ,Animal ,Prevention ,Neurosciences ,Brain Disorders ,Rats ,030104 developmental biology ,Pharmacodynamics ,Conditioning, Operant ,Smoking cessation ,business ,030217 neurology & neurosurgery ,Neuroscience ,Conditioning - Abstract
A bacterial enzyme that eats nicotine reverses addiction-like behaviors and offers a new strategy to help smokers quit., Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)–induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.
- Published
- 2018
31. Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala
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Olivier George, Guglielmo Gd, Philippe A. Melas, Johanna S. Qvist, Jenni Kononoff, Marsida Kallupi, and Eric R. Kandel
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Deep brain stimulation ,medicine.medical_treatment ,media_common.quotation_subject ,Craving ,AMPA receptor ,Nucleus accumbens ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,030304 developmental biology ,media_common ,0303 health sciences ,business.industry ,Central nucleus of the amygdala ,Addiction ,Abstinence ,3. Good health ,surgical procedures, operative ,nervous system ,medicine.symptom ,Self-administration ,business ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
BackgroundCocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies of drug addiction strongly suggest that the nucleus accumbens (NAcc) is a viable target for deep brain stimulation (DBS).ObjectiveAlthough previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated.MethodsRats were made cocaine-dependent by allowing them to self-administer cocaine in long-access sessions (6 h, 0.5 mg/kg/infusion). The effects of high-frequency DBS of the NAcc shell on cocaine intake was then studied. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.ResultsContrary to our expectations, DBS of the NAcc shell induced a slight increase in both cocaine self-administration and cocaine-induced locomotor activity. In addition, 18 h into cocaine withdrawal, we found that DBS decreased irritability-like behavior. We also found that DBS-induced a robust increase in both cytosolic and synaptosomal levels of GluR1, but not GluR2, specifically in the central nucleus of the amygdala but not in other brain regions.ConclusionsThese preclinical results with cocaine-dependent animals do not support high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of cocaine addiction in active cocaine users. However, the decrease in irritability-like behavior during cocaine abstinence, together with previous findings showing that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, warrants future investigations of DBS as a treatment for negative emotional states and craving during abstinence.HighlightsHigh-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposedDBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent ratsDBS increases the level of GluR1 specifically in the central nucleus of the amygdala
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- 2018
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32. Neuropeptide S differently modulates alcohol-related behaviors in alcohol-preferring and non-preferring rats
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Roberto Ciccocioppo, Serena Stopponi, Marsida Kallupi, Nazzareno Cannella, Carlo Cifani, Hong Wu Li, and Massimo Ubaldi
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inorganic chemicals ,Male ,0301 basic medicine ,Alcohol Drinking ,medicine.drug_class ,media_common.quotation_subject ,education ,Drug-Seeking Behavior ,Self Administration ,Alcohol ,Anxiety ,Pharmacology ,Affect (psychology) ,Anxiolytic ,Article ,Arousal ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,mental disorders ,Neuropeptide S ,Animals ,Medicine ,Rats, Wistar ,health care economics and organizations ,media_common ,Motivation ,Ethanol ,Behavior, Animal ,business.industry ,Addiction ,Neuropeptides ,technology, industry, and agriculture ,Central Nervous System Depressants ,Alcohol preferring ,Rats ,3. Good health ,030104 developmental biology ,chemistry ,Conditioning, Operant ,Cues ,business ,Locomotion ,030217 neurology & neurosurgery - Abstract
Neuropeptide S (NPS) displays unique pharmacological properties and induces both anxiolytic and pro-stress/arousal activities. Previous studies performed using Wistar rats demonstrated that NPS facilitated alcohol and cocaine seeking but did not affect alcohol or cocaine consumption.Here, we investigated the effects of NPS in Marchigian Sardinian alcohol-preferring (msP) rats, a rat strain characterized by excessive alcohol consumption comorbid with heightened anxiety and depressive-like phenotypes. Specifically, we evaluated the effect of NPS on operant alcohol self-administration by msP rats compared to Wistar rats. The effect of NPS on cue-induced reinstatement of alcohol seeking in msP rats was also evaluated. Finally, using the open field test (OFT) and the elevated plus maze (EPM), we evaluated the effects of NPS on locomotor activity and anxiety.NPS reduced alcohol self-administration but did not affect cue-induced reinstatement in the msP rat. In addition, NPS induced reinstatement of extinguished alcohol seeking in Wistar rats without affecting alcohol intake. In the EPM task, NPS, in accordance with its anxiolytic activity, increased the time spent in the open arm of the arena by msP rats, although this effect was not observed in Wistar rats.These data suggest that the effect of NPS is strongly influenced by the genetic background of the animal. In Wistar rats, NPS acts as a pro-arousal agent to promote the reinstatement of alcohol seeking. However, when alcohol drinking is motivated by or associated with a state of pathological anxiety, NPS attenuates alcohol consumption and seeking due to its anxiolytic activity.
- Published
- 2016
33. Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood
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Marsida Kallupi, Eric R. Kandel, Maria Scherma, Adam Kimbrough, Paola Fadda, Olivier George, Philippe A. Melas, Jenni Kononoff, Denise B. Kandel, and Giordano de Guglielmo
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0301 basic medicine ,Male ,Cannabinoid receptor ,medicine.medical_treatment ,Physiology ,lcsh:Medicine ,Self Administration ,Rats, Sprague-Dawley ,0302 clinical medicine ,Cocaine ,Models ,Addictive ,lcsh:Science ,Sensitization ,media_common ,Psychomotor learning ,Pediatric ,Multidisciplinary ,Behavior, Animal ,Substance Abuse ,medicine.anatomical_structure ,Mental Health ,Models, Animal ,medicine.symptom ,Self-administration ,Adult ,Drug Abuse (NIDA Only) ,Adolescent ,media_common.quotation_subject ,Morpholines ,Drinking Behavior ,Naphthalenes ,Irritability ,Basic Behavioral and Social Science ,Cocaine dependence ,03 medical and health sciences ,Cocaine-Related Disorders ,Operant ,Behavioral and Social Science ,medicine ,Animals ,Humans ,Behavior ,business.industry ,Animal ,Addiction ,lcsh:R ,Body Weight ,Neurosciences ,Feeding Behavior ,medicine.disease ,Rats ,Benzoxazines ,Brain Disorders ,Behavior, Addictive ,030104 developmental biology ,Adolescent Behavior ,Conditioning, Operant ,lcsh:Q ,Cannabinoid ,Sprague-Dawley ,business ,Mind and Body ,030217 neurology & neurosurgery ,Conditioning - Abstract
Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.
- Published
- 2018
34. Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats
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Jenni Kononoff, Marsida Kallupi, Giordano de Guglielmo, Dana Conlisk, Adam Kimbrough, and Olivier George
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Male ,orphan receptor ,Wistar ,Alcohol use disorder ,Alcohol Use and Health ,0302 clinical medicine ,Receptors ,Medicine ,pain ,Receptor ,Orphan receptor ,0303 health sciences ,withdrawal ,General Neuroscience ,Substance Abuse ,General Medicine ,New Research ,Substance Withdrawal Syndrome ,1.1 ,Stroke ,Alcoholism ,Mental Health ,Habenula ,Cognition and Behavior ,Hyperalgesia ,Compulsive Behavior ,medicine.symptom ,Pain Threshold ,Agonist ,Drug Abuse (NIDA Only) ,medicine.medical_specialty ,Interpeduncular nucleus ,Alcohol Drinking ,medicine.drug_class ,Nerve Tissue Proteins ,alcohol use disorder ,Basic Behavioral and Social Science ,G-Protein-Coupled ,03 medical and health sciences ,Internal medicine ,Behavioral and Social Science ,compulsivity ,Animals ,030304 developmental biology ,business.industry ,habenula ,Alcohol dependence ,Neurosciences ,medicine.disease ,Rats ,Brain Disorders ,Endocrinology ,business ,030217 neurology & neurosurgery - Abstract
GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior.
- Published
- 2018
35. Self-administered nicotine increases fat metabolism and suppresses weight gain in male rats
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Eric P. Zorrilla, Marsida Kallupi, Giordano de Guglielmo, Alan F. Sved, Samantha R. Spierling, Eric C. Donny, Laura E. Rupprecht, Olivier George, and Alison D. Kreisler
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0301 basic medicine ,Male ,medicine.medical_specialty ,Nicotine ,Self Administration ,Indirect calorimetry ,Calorimetry ,Weight Gain ,Medical and Health Sciences ,Article ,03 medical and health sciences ,Eating ,0302 clinical medicine ,Internal medicine ,Male rats ,Tobacco ,medicine ,Animals ,Respiratory exchange ratio ,Obesity ,Metabolic and endocrine ,Nutrition ,Cancer ,Pharmacology ,Psychiatry ,Meal ,Tobacco Smoke and Health ,business.industry ,Oxymax ,Prevention ,Body Weight ,Psychology and Cognitive Sciences ,Lipid metabolism ,Metabolism ,Feeding Behavior ,Lipid Metabolism ,Rats ,030104 developmental biology ,Endocrinology ,Lean body mass ,Energy expenditure ,medicine.symptom ,business ,Weight gain ,030217 neurology & neurosurgery ,medicine.drug - Abstract
RATIONALE: The ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure. OBJECTIVE: The current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis. METHODS: Adult male rats with ad libitum access to powdered standard rodent chow self-administered intravenous infusions of nicotine (60 μg/kg/infusion or saline control) in daily 1-h sessions in the last hour of the light cycle. Indirect calorimetry measured respiratory exchange ratio (RER), energy expenditure, motor activity, and food and water consumption for 22.5 h between select self-administration sessions. RESULTS: Self-administered nicotine suppressed weight gain and reduced the percent of body fat without altering the percent of lean mass, as measured by Echo MRI. Nicotine reduced RER, indicating increased fat utilization; this effect was observed prior to weight suppression. Moreover, nicotine intake did not affect motor activity or energy expenditure. Daily food intake was not altered by nicotine self-administration; however, a trend in suppression of meal size, a transient suppression of water intake, and an increase in meal frequency was observed. CONCLUSION: These data provide evidence that self-administered nicotine suppresses body weight via increased fat metabolism, independent of significant changes in feeding, activity, or energy expenditure.
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- 2018
36. An Enzymatic Advance in Nicotine Cessation Therapy
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Pedro O. Miranda, Lauren C. Smith, Marsida Kallupi, Olivier George, Bin Zhou, Kim D. Janda, and Song Xue
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0301 basic medicine ,Nicotine ,Pharmacology ,Catalysis ,Article ,03 medical and health sciences ,Substance Misuse ,Pharmacokinetics ,Bacterial Proteins ,In vivo ,Albumins ,Tobacco ,Enzyme Stability ,Materials Chemistry ,Medicine ,Humans ,chemistry.chemical_classification ,Tobacco Smoke and Health ,business.industry ,Pseudomonas putida ,Organic Chemistry ,Metals and Alloys ,Albumin ,Brain ,General Chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Blockade ,Nicotine metabolism ,030104 developmental biology ,Enzyme ,Good Health and Well Being ,chemistry ,Chemical Sciences ,Ceramics and Composites ,Smoking Cessation ,business ,Drug Abuse (NIDA only) ,Binding domain ,medicine.drug ,Half-Life - Abstract
A nicotine-degrading enzyme termed NicA2 was altered (NicA2-J1) through fusion of an albumin binding domain to increase its half-life. Examination of NicA2-J1 in vivo demonstrated a complete blockade of brain nicotine access, which in turn blunted nicotine's psychoactive effects. These data further support development of pharmacokinetic nicotine cessation therapeutics.
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- 2018
37. CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure
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Adam Kimbrough, Olivier George, Eric P. Zorrilla, Marsida Kallupi, Giordano de Guglielmo, and Jenni Kononoff
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0301 basic medicine ,Male ,Aggressive ,Drugs of abuse ,Corticotropin-Releasing Hormone ,Wistar ,Medicine (miscellaneous) ,Self Administration ,Alcohol use disorder ,Pharmacology ,Toxicology ,chemistry.chemical_compound ,Alcohol Use and Health ,Substance Misuse ,0302 clinical medicine ,Receptors ,Medicine ,Psychology ,Receptor ,media_common ,Protracted abstinence ,Alcohol Abstinence ,Corticotropin-Releasing Factor ,Substance Abuse ,Irritable Mood ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Alcoholism ,Mental Health ,Inhalation ,Administration ,medicine.symptom ,medicine.medical_specialty ,media_common.quotation_subject ,Clinical Sciences ,Addiction ,Irritability ,Basic Behavioral and Social Science ,03 medical and health sciences ,Internal medicine ,Behavioral and Social Science ,Animals ,Ethanol ,business.industry ,Prevention ,Crf1 receptor ,Antagonist ,Neurosciences ,Abstinence ,medicine.disease ,030227 psychiatry ,Rats ,Brain Disorders ,030104 developmental biology ,Endocrinology ,Pyrimidines ,Good Health and Well Being ,chemistry ,Chronic Intermittent Ethanol ,business ,030217 neurology & neurosurgery ,Alcohol Use Disorder - Abstract
BackgroundIn humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression-like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests measuring withdrawal in animal models is they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropinreleasing factor (CRF)-CRF1 receptor system has been suggested to be critical for the emergence of anxiety-like behavior in ethanol dependence, but the role of this system in irritability-like behavior has not been characterized.MethodsThe present study compared the effects of chronic intermittent ethanol vapor exposure (CIE)-induced ethanol dependence on irritabilitylike behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naive, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 h and 2 weeks into abstinence from ethanol. A separate cohort of dependent rats was used to examine the effect of the specific CRF1 receptor antagonist R121919 on irritability-like behavior.ResultsDependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time-points of abstinence, ethanol-dependent rats exhibited increased aggressive-like responses compared with naive and nondependent rats. R121919 blocked the increased irritability-like behavior in dependent rats.ConclusionsThe effect of R121919 to block increased irritability-like behavior suggests that CRF plays an important role in this behavior, similar to other negative emotional withdrawal symptoms. Quantifying and understanding the molecular basis of irritability-like behavior may yield new insights into withdrawal from ethanol and other drugs of abuse.
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- 2017
38. Analgesic tolerance to morphine is regulated by PPARγ
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Gregory Demopulos, Serena Stopponi, Roberto Ciccocioppo, Marsida Kallupi, George Gaitanaris, Giordano de Guglielmo, and Giulia Scuppa
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Pharmacology ,chemistry.chemical_classification ,Drug ,business.industry ,Addiction ,media_common.quotation_subject ,Analgesic ,Peroxisome proliferator-activated receptor ,chemistry ,Opioid ,Drug tolerance ,Morphine ,Medicine ,business ,Pioglitazone ,media_common ,medicine.drug - Abstract
Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice.
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- 2014
39. CRF
- Author
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Adam, Kimbrough, Giordano, de Guglielmo, Jenni, Kononoff, Marsida, Kallupi, Eric P, Zorrilla, and Olivier, George
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Male ,Ethanol ,Alcohol Abstinence ,Self Administration ,Receptors, Corticotropin-Releasing Hormone ,Irritable Mood ,Article ,Rats ,Substance Withdrawal Syndrome ,Alcoholism ,Pyrimidines ,Administration, Inhalation ,Animals ,Rats, Wistar - Abstract
In humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression-like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests that measure withdrawal in animal models is that they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropin-releasing factor (CRF)-CRFThe present study compared the effects of chronic intermittent ethanol (CIE) vapor exposure-induced ethanol dependence on irritability-like behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naïve, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 hours and 2 weeks into abstinence from ethanol. Separate cohorts of dependent and nondependent rats were used to examine the effect of the specific CRFDependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time points of abstinence, ethanol-dependent rats exhibited increased aggressive-like responses compared with naïve and nondependent rats. R121919 reduced irritability-like behavior in both dependent and nondependent rats, but dependent rats were more sensitive to R121919.Irritability-like behavior is a clinically relevant and reliable measure of negative emotional states that is partially mediated by activation of the CRF-CRF
- Published
- 2017
40. Nicotine Vapor Method to Induce Nicotine Dependence in Rodents
- Author
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Marsida Kallupi and Olivier George
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Nicotine ,vapor ,media_common.quotation_subject ,Rodentia ,Electronic Nicotine Delivery Systems ,Pharmacology ,Article ,Substance Misuse ,03 medical and health sciences ,0302 clinical medicine ,Tobacco ,medicine ,Animals ,Nicotinic Agonists ,media_common ,Smoke ,Tobacco Smoke and Health ,Animal ,withdrawal ,Chemistry ,Nebulizers and Vaporizers ,Addiction ,Tobacco Use Disorder ,dependence ,General Medicine ,Nicotine replacement therapy ,Conditioned place preference ,Brain Disorders ,030227 psychiatry ,Disease Models, Animal ,Good Health and Well Being ,Nicotinic agonist ,Disease Models ,Brain stimulation reward ,Vaporizer ,Drug Abuse (NIDA only) ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Nicotine, the main addictive component of tobacco, induces potentiation of brain stimulation reward, increases locomotor activity, and induces conditioned place preference. Nicotine cessation produces a withdrawal syndrome that can be relieved by nicotine replacement therapy. In the last decade, the market for electronic cigarettes has flourished, especially among adolescents. The nicotine vaporizer or electronic nicotine delivery system is a battery-operated device that allows the user to simulate the experience of tobacco smoking without inhaling smoke. The device is designed to be an alternative to conventional cigarettes that emits vaporized nicotine inhaled by the user. This report describes a procedure to vaporize nicotine in the air to produce blood nicotine levels in rodents that are clinically relevant to those that are observed in humans and produce dependence. We also describe how to construct the apparatus to deliver nicotine vapor in a stable, reliable, and consistent manner, as well as how to analyze air for nicotine content. © 2017 by John Wiley & Sons, Inc.
- Published
- 2017
41. Kappa Opioid Receptor-Mediated Dysregulation of Gamma-Aminobutyric Acidergic Transmission in the Central Amygdala in Cocaine Addiction
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Sunmee Wee, George F. Koob, Marsida Kallupi, Scott Edwards, Brooke E. Schmeichel, Marisa Roberto, Christopher S. Oleata, Timothy W. Whitfield, and George Luu
- Subjects
Dynorphin ,Pharmacology ,κ-opioid receptor ,Amygdala ,gamma-Aminobutyric acid ,medicine.anatomical_structure ,medicine ,GABAergic ,Receptor ,Psychology ,Norbinaltorphimine ,Self-administration ,Biological Psychiatry ,medicine.drug - Abstract
Background Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA). Methods We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1-hour (short access [ShA]) or 6-hour (long access [LgA]) sessions induced plasticity at CeA gamma-aminobutyric acid (GABA)ergic synapses or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (norbinaltorphimine [norBNI]). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors. Results Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared with cocaine-naive rats. Acute cocaine (1 µmol/L) application significantly decreased GABA release in all groups (naive, ShA, and LgA rats). Application of U50488 (1 µmol/L) significantly decreased GABAergic transmission in the CeA from naive rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naive rats but decreased it in LgA rats. Norbinaltorphimine did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of norBNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm. Conclusions Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction.
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- 2013
42. Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: Alcohol and CRF effects
- Author
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Roberto Ciccocioppo, Markus Heilig, George F. Koob, Christopher S. Oleata, George Luu, Melissa A. Herman, Marisa Roberto, and Marsida Kallupi
- Subjects
Male ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Biology ,Neurotransmission ,Pharmacology ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Article ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Corticotropin-releasing hormone ,Species Specificity ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,GABAergic Neurons ,Rats, Wistar ,Ethanol ,GABAA receptor ,Central nucleus of the amygdala ,Antagonist ,Amygdala ,Receptors, GABA-A ,Rats ,Alcoholism ,Endocrinology ,Inhibitory Postsynaptic Potentials ,GABAergic - Abstract
The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF 1 ) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF 1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF 1 antagonist in msP, Sprague Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABA A -inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF 1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF 1 antagonist in msP rats, suggesting increased GABA release and decreased CRF 1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naive msP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence.
- Published
- 2013
43. Activation of PPARγ by Pioglitazone Potentiates the Effects of Naltrexone on Alcohol Drinking and Relapse in msP Rats
- Author
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Andrea Cippitelli, Nazzareno Cannella, Gregory Demopulos, Roberto Ciccocioppo, George Gaitanaris, Serena Stopponi, Markus Heilig, Giordano de Guglielmo, Lorenzo Somaini, Marsida Kallupi, and Massimo Ubaldi
- Subjects
Male ,Agonist ,Alcohol Drinking ,medicine.drug_class ,Narcotic Antagonists ,Drug Evaluation, Preclinical ,Medicine (miscellaneous) ,Pharmacology ,Toxicology ,Naltrexone ,chemistry.chemical_compound ,medicine ,Animals ,Hypoglycemic Agents ,Ethanol ,Pioglitazone ,business.industry ,Yohimbine ,medicine.disease ,Rats ,PPAR gamma ,Psychiatry and Mental health ,chemistry ,Alcohol withdrawal syndrome ,Drug Therapy, Combination ,Thiazolidinediones ,Cues ,business ,Self-administration ,Opioid antagonist ,medicine.drug - Abstract
Background Pioglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist used for the treatment of insulin resistance and type 2 diabetes. Previous studies conducted in our laboratory showed that activation of PPARγ by pioglitazone reduces alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Pioglitazone was not able to prevent relapse elicited by alcohol cues. Conversely, the nonselective opioid antagonist naltrexone has been shown to reduce alcohol drinking and cue- but not stress-induced relapse in rodents. Methods Based on these findings, this study was sought to determine the efficacy of pioglitazone and naltrexone combination on alcohol intake and relapse behavior. Genetically selected alcohol-preferring Marchigian Sardinian (msP) rats were used for the study. Results Pioglitazone (10 and 30 mg/kg) and naltrexone (0.25 and 1.0 mg/kg) each individually reduced alcohol drinking in msP rats. The combination of the 2 drugs resulted in a more potent alcohol drinking reduction than single agents. Confirming previous studies, pioglitazone (10 and 30 mg/kg) significantly reduced relapse induced by the pharmacological stressor yohimbine (1.25 mg/kg) but not by cues predictive of alcohol availability. Conversely, naltrexone reduced reinstatement of drug seeking elicited by alcohol cues but not by yohimbine. Conclusions The drug combination was effective in reducing both relapse behaviors. These findings open new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism.
- Published
- 2013
44. Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents
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George Gaitanaris, Roberto Ciccocioppo, Giordano de Guglielmo, Gregory Demopulos, Marsida Kallupi, and Giulia Scuppa
- Subjects
0301 basic medicine ,Male ,Narcotics ,media_common.quotation_subject ,Physical dependence ,Rodentia ,Self Administration ,(+)-Naloxone ,Pharmacology ,Heroin ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Recurrence ,medicine ,Animals ,Rats, Wistar ,media_common ,Morphine ,Pioglitazone ,Addiction ,Opioid-Related Disorders ,Yohimbine ,Rats ,Substance Withdrawal Syndrome ,Analgesics, Opioid ,Behavior, Addictive ,030104 developmental biology ,Opioid ,Conditioning, Operant ,Thiazolidinediones ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown. To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats. We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms. Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse. These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.
- Published
- 2016
45. Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction
- Author
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Friedbert Weiss, Marsida Kallupi, Michael A. Statnick, Giordano de Guglielmo, Linda M. Rorick-Kehn, Giulia Scuppa, Girolamo Calo, and Roberto Ciccocioppo
- Subjects
0301 basic medicine ,Narcotic Antagonists ,NOP ,Socio-culturale ,Self Administration ,Pharmacology ,Nociceptin Receptor ,03 medical and health sciences ,chemistry.chemical_compound ,Cocaine-Related Disorders ,0302 clinical medicine ,Cocaine ,Dopamine Uptake Inhibitors ,Animals ,Learning ,Rats, Wistar ,Receptor ,Saccharin ,Psychiatry and Mental Health ,Ethanol ,Behavior, Animal ,Ligand (biochemistry) ,Conditioned place preference ,3. Good health ,Rats ,Nociceptin receptor ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Receptors, Opioid ,Original Article ,Rats, Transgenic ,Self-administration ,030217 neurology & neurosurgery - Abstract
The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (−/−) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (−/−) rats self-administer less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (−/−). When NOP (−/−) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (−/−) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (−/−) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.
- Published
- 2016
46. Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption
- Author
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Marsida, Kallupi, Qianwei, Shen, Giordano, de Guglielmo, Dennis, Yasuda, V Blair, Journigan, Nurulain T, Zaveri, and Roberto, Ciccocioppo
- Subjects
Behavior, Animal ,Narcotic Antagonists ,Receptors, Opioid, mu ,Self Administration ,Naltrexone ,Nociceptin Receptor ,Article ,Buprenorphine ,Rats ,Cocaine ,Dopamine Uptake Inhibitors ,Piperidines ,Receptors, Opioid ,Animals ,Conditioning, Operant ,Cycloheptanes - Abstract
Buprenorphine’s clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa-opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine’s effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self-administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.
- Published
- 2016
47. Activation of Hypocretin-1/Orexin-A Neurons Projecting to the Bed Nucleus of the Stria Terminalis and Paraventricular Nucleus Is Critical for Reinstatement of Alcohol Seeking by Neuropeptide S
- Author
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Ilenia Severi, Nazzareno Cannella, Giordano de Guglielmo, Serena Stopponi, Hongwu Li, Barbara Ruggeri, Roberto Ciccocioppo, Massimo Ubaldi, Antonio Giordano, and Marsida Kallupi
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Alcohol Drinking ,Drug-Seeking Behavior ,Hypothalamus ,Self Administration ,Stimulation ,03 medical and health sciences ,Orexin-A ,0302 clinical medicine ,Thalamus ,Orexin Receptors ,Internal medicine ,Neuropeptide S ,medicine ,Animals ,Rats, Wistar ,Biological Psychiatry ,Neurons ,Orexins ,Ethanol ,Neuropeptides ,Retrograde tracing ,Rats ,Orexin ,Ventral tegmental area ,Disease Models, Animal ,Stria terminalis ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Locus coeruleus ,Septal Nuclei ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Paraventricular Hypothalamic Nucleus - Abstract
BACKGROUND: Environmental conditioning is a major trigger for relapse in abstinent addicts. We showed that activation of the neuropeptide S (NPS) system exacerbates reinstatement vulnerability to cocaine and alcohol via stimulation of the hypocretin-1/orexin-A (Hcrt-1/Ox-A) system. METHODS: Combining pharmacologic manipulations with immunohistochemistry techniques, we sought to determine how NPS and Hcrt-1/Ox-A systems interact to modulate reinstatement of alcohol seeking in rats. RESULTS: Intrahypothalamic injection of NPS facilitated discriminative cue-induced reinstatement of alcohol seeking. This effect was blocked by the selective Hcrt-1/Ox-A antagonist SB334867 microinjected into the hypothalamic paraventricular nucleus (PVN) or into the bed nucleus of the stria terminalis (BNST) but not into the ventral tegmental area or the locus coeruleus. Combining double labeling and confocal microscopy analyses, we found that NPScontaining axons are in close apposition to hypothalamic Hcrt-1/Ox-A positive neurons, a significant proportion of which express NPS receptors, suggesting a direct interaction between the two systems. Retrograde tracing experiments showed that intra-PVN or intra-BNST red fluorobead unilateral injection labeled bilaterally Hcrt-1/Ox-A somata, suggesting that NPS could recruit two distinct neuronal pathways. Confirming this assumption, intra-BNST or PVN Hcrt-1/Ox-A injection enhanced alcohol seeking similarly to hypothalamic NPS injection but to a lesser degree. CONCLUSIONS: Results suggest that the Hcrt-1/Ox-A neurocircuitry mediating the facilitation of cue-induced reinstatement by NPS involves structures critically involved in stress regulation such as the PVN and the BNST. These findings open to the tempting hypothesis of a role of the NPS system in modulating the interactions between stress and environmental conditioning factors in drug relapse.
- Published
- 2016
48. Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat
- Author
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Roberto Ciccocioppo, Hongwu Li, Massimo Ubaldi, Giordano de Guglielmo, Lorenzo Somaini, Gilberto Gerra, Andrea Cippitelli, Marsida Kallupi, and Serena Stopponi
- Subjects
Pharmacology ,Addiction ,media_common.quotation_subject ,Pregabalin ,Medicine (miscellaneous) ,Yohimbine ,Psychiatry and Mental health ,Oral administration ,Anesthesia ,Neuropathic pain ,medicine ,Analysis of variance ,Self-administration ,Psychology ,medicine.drug ,Cocaine seeking ,media_common - Abstract
Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction.
- Published
- 2012
49. Nociceptin/Orphanin FQ Blockade of Corticotropin-Releasing Factor-Induced Gamma-Aminobutyric Acid Release in Central Amygdala Is Enhanced After Chronic Ethanol Exposure
- Author
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Marisa Roberto, Marsida Kallupi, Melissa A. Herman, and Maureen T. Cruz
- Subjects
Male ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,GABA Agents ,Neurotransmission ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Article ,gamma-Aminobutyric acid ,Rats, Sprague-Dawley ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,gamma-Aminobutyric Acid ,Biological Psychiatry ,Ethanol ,GABAA receptor ,Chemistry ,Central nucleus of the amygdala ,Central Nervous System Depressants ,Amygdala ,Cyclic AMP-Dependent Protein Kinases ,Rats ,Alcoholism ,Nociceptin receptor ,Endocrinology ,Inhibitory Postsynaptic Potentials ,Opioid Peptides ,medicine.drug - Abstract
Background The central nucleus of the amygdala (CeA) mediates stress- and addiction-related processes. Corticotropin-releasing factor (CRF) and nociceptin/orphanin FQ (nociceptin) regulate ethanol intake and anxiety-like behavior. In the rat, CRF and ethanol significantly augment CeA gamma-aminobutyric acid (GABA) release, whereas nociceptin diminishes it. Methods Using electrophysiologic techniques in an in vitro slice preparation, we investigated the interaction of nociceptin and CRF on evoked and spontaneous GABAergic transmission in CeA slices of naive and ethanol-dependent rats and the mechanistic role of protein kinase A. Results In neurons from naive animals, nociceptin dose-dependently diminished basal-evoked GABA A receptor-mediated inhibitory postsynaptic potentials (IPSPs) by decreasing GABA release and prevented, as well as reversed, CRF-induced augmentation of IPSPs, actions that required PKA signaling. In neurons from ethanol-dependent animals, nociceptin decreased basal GABAergic transmission and blocked the CRF-induced increase in GABA release to a greater extent than in naive controls. Conclusions These data provide new evidence for an interaction between the nociceptin and CRF systems in the CeA. Nociceptin opposes CRF effects on CeA GABAergic transmission with sensitization of this effect in dependent animals. These properties of nociceptin may underlie its anti-alcohol and anxiolytic properties and identify the nociceptin receptor as a useful therapeutic target for alcoholism.
- Published
- 2012
50. Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System
- Author
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Serena Stopponi, Daina Economidou, Markus Heilig, Roberto Ciccocioppo, Nazzareno Cannella, Maurizio Massi, and Marsida Kallupi
- Subjects
Male ,Receptors, Neuropeptide ,medicine.medical_specialty ,Alcohol Drinking ,Lateral hypothalamus ,Substance-Related Disorders ,Conditioning, Classical ,Hypothalamus ,Neuropeptide ,Self Administration ,Receptors, G-Protein-Coupled ,Orexin Receptors ,Internal medicine ,Neuropeptide S ,medicine ,Animals ,Urea ,Naphthyridines ,Rats, Wistar ,Neuropeptide S receptor ,Pharmacology ,Analysis of Variance ,Benzoxazoles ,Ethanol ,Chemistry ,Neuropeptides ,Antagonist ,Central Nervous System Depressants ,Orexin receptor ,Rats ,Orexin ,Disease Models, Animal ,Psychiatry and Mental health ,Endocrinology ,Cues ,Self-administration - Abstract
The association of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat) into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment.
- Published
- 2009
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