465 results on '"NICOTINE"'
Search Results
2. Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use
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Smith, Lauren C, Kallupi, Marsida, Tieu, Lani, Shankar, Kokila, Jaquish, Abigail, Barr, Jamie, Su, Yujuan, Velarde, Nathan, Sedighim, Sharona, Carrette, Lieselot LG, Klodnicki, Mike, Sun, Xin, de Guglielmo, Giordano, and George, Olivier
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Prevention ,Behavioral and Social Science ,Brain Disorders ,Neurosciences ,Electronic Nicotine Delivery Systems ,Substance Misuse ,Drug Abuse (NIDA only) ,Tobacco ,Basic Behavioral and Social Science ,Good Health and Well Being ,Animals ,Conditioning ,Operant ,Nicotine ,Nicotinic Agonists ,Rats ,Receptors ,Nicotinic ,Self Administration ,Vaping ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological psychology - 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.
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- 2020
3. Nicotine effects on associative learning in human non-smokers
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Hahn, Britta, Wells, Ashleigh K, Lenartowicz, Agatha, and Yuille, Marie B
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Drug Abuse (NIDA only) ,Tobacco Smoke and Health ,Brain Disorders ,Behavioral and Social Science ,Prevention ,Substance Misuse ,Tobacco ,Mental Health ,Clinical Research ,Basic Behavioral and Social Science ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Mental health ,Good Health and Well Being ,Adult ,Association Learning ,Cross-Over Studies ,Double-Blind Method ,Female ,Humans ,Male ,Middle Aged ,Nicotine ,Nicotinic Agonists ,Non-Smokers ,Photic Stimulation ,Reaction Time ,Tobacco Use Cessation Devices ,Young Adult ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Neurosciences ,Biological psychology - Abstract
Tobacco smoking is the most common preventable cause of death in the US. Nicotine is considered the primary constituent responsible for tobacco addiction. Its paradoxically high abuse potential may reflect behavioral control by drug-associated stimuli, which appears to play a larger role for tobacco dependence than for other abused drugs. We tested a potential explanation, hypothesizing that nicotine enhances associative learning, the mechanism underlying the conditioning of drug-associated stimuli. Thirty-two non-smokers were exposed to transdermal nicotine (7 mg/24 h) and placebo in a double-blind cross-over study and tested with behavioral paradigms designed to isolate incidental stimulus-stimulus or stimulus-response learning. The stop signal task required speeded gender judgments of face stimuli. A tone signaled when to withhold the response. Unbeknownst to participants, some faces were always paired with stop trials. Nicotine enhanced the facilitation of stop-responses to these stimuli, and the slowing of go-responses when previously stop-associated stimuli were paired with go trials, indicating stronger associations between paired stimuli and the stop signal/stop response. Another task required feedback-based learning of associations between pairs of shape stimuli. Five pairs were made from either ten different stimuli, or from different combinations of two identical sets of five stimuli with correct associations depending on contextual information. Nicotine increased incorrect choices of stimuli that were associated in a different context, indicating stronger stimulus-stimulus associations at the expense of flexible context-adaptive behavior. The results indicate that nicotine can enhance incidental associative learning, a mechanism that may promote the formation of smoking-associated stimuli and cue-controlled drug-taking.
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- 2018
4. Ovarian Hormones and Transdermal Nicotine Administration Independently and Synergistically Suppress Tobacco Withdrawal Symptoms and Smoking Reinstatement in the Human Laboratory
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Pang, Raina D, Liautaud, Madalyn M, Kirkpatrick, Matthew G, Huh, Jimi, Monterosso, John, and Leventhal, Adam M
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Tobacco ,Estrogen ,Prevention ,Substance Misuse ,Behavioral and Social Science ,Clinical Trials and Supportive Activities ,Tobacco Smoke and Health ,Drug Abuse (NIDA only) ,Clinical Research ,Contraception/Reproduction ,Brain Disorders ,6.1 Pharmaceuticals ,Good Health and Well Being ,Administration ,Cutaneous ,Adult ,Cigarette Smoking ,Estradiol ,Female ,Humans ,Nicotine ,Ovary ,Progesterone ,Saliva ,Smoking Cessation ,Substance Withdrawal Syndrome ,Tobacco Use Cessation Devices ,Tobacco Use Disorder ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Neurosciences ,Biological psychology - Abstract
Modeling intra-individual fluctuations in estradiol and progesterone may provide unique insight into the effects of ovarian hormones on the etiology and treatment of nicotine dependence. This randomized placebo-controlled laboratory study tested the independent and interactive effects of intra-individual ovarian hormone variation and nicotine on suppression of tobacco withdrawal symptoms and smoking behavior. Female smokers randomized to 21 mg nicotine (TNP; n=37) or placebo (PBO; n=43) transdermal patch following overnight abstinence completed three sessions occurring during hormonally distinct menstrual cycle phases. At each session, participants provided saliva for hormone assays and completed repeated self-report measures (ie, tobacco withdrawal symptoms, smoking urge, and negative affect (NA)) followed by an analog smoking reinstatement task for which participants could earn money to delay smoking and subsequently purchase cigarettes to smoke. Higher (vs lower) progesterone levels were associated with greater reductions in NA. Higher (vs lower) progesterone levels and progesterone to estradiol ratios were associated with reducing smoking urges over time to a greater extent with TNP compared to PBO. There was an interaction between Patch and estradiol on NA. With TNP, higher-than-usual estradiol was associated with greater decreases in NA. However with PBO, lower-than-usual estradiol was associated with greater decreases in NA. These results suggest that the effects of TNP on mood- and smoking-related outcomes may vary depending on the ovarian hormone levels.
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- 2018
5. Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects
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Faulkner, Paul, Ghahremani, Dara G, Tyndale, Rachel F, Cox, Chelsea M, Kazanjian, Ari S, Paterson, Neil, Lotfipour, Shahrdad, Hellemann, Gerhard S, Petersen, Nicole, Vigil, Celia, and London, Edythe D
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Substance Misuse ,Drug Abuse (NIDA only) ,Tobacco ,Tobacco Smoke and Health ,Clinical Research ,Cancer ,Good Health and Well Being ,Adolescent ,Adult ,Affect ,Attention ,Consumer Behavior ,Cotinine ,Craving ,Dose-Response Relationship ,Drug ,Female ,Humans ,Male ,Nicotine ,Smoking ,Substance Withdrawal Syndrome ,Young Adult ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Neurosciences ,Biological psychology - Abstract
The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to
- Published
- 2017
6. Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study
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Brody, Arthur L, Hubert, Robert, Enoki, Ryutaro, Garcia, Lizette Y, Mamoun, Michael S, Okita, Kyoji, London, Edythe D, Nurmi, Erika L, Seaman, Lauren C, and Mandelkern, Mark A
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Prevention ,Tobacco ,Tobacco Smoke and Health ,Brain Disorders ,Cancer ,Substance Misuse ,Drug Abuse (NIDA only) ,Clinical Research ,Neurosciences ,Biomedical Imaging ,Good Health and Well Being ,Acetamides ,Adolescent ,Adult ,Aged ,Biomarkers ,Brain ,Case-Control Studies ,Cigarette Smoking ,Female ,Functional Neuroimaging ,Genotype ,Humans ,Inflammation ,Male ,Microglia ,Middle Aged ,Nicotine ,Phenyl Ethers ,Positron-Emission Tomography ,Radioligand Assay ,Radiopharmaceuticals ,Receptors ,GABA ,Young Adult ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological psychology - Abstract
In the brain, microglia continuously scan the surrounding extracellular space in order to respond to damage or infection by becoming activated and participating in neuroinflammation. When activated, microglia increase the expression of translocator protein (TSPO) 18 kDa, thereby making the TSPO expression a marker for neuroinflammation. We used the radiotracer [11C]DAA1106 (a ligand for TSPO) and positron emission tomography (PET) to determine the effect of smoking on availability of this marker for neuroinflammation. Forty-five participants (30 smokers and 15 non-smokers) completed the study and had usable data. Participants underwent a dynamic PET scanning session with bolus injection of [11C]DAA1106 (with smokers in the satiated state) and blood draws during PET scanning to determine TSPO affinity genotype and plasma nicotine levels. Whole-brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (smoker vs non-smoker) and genotype as factors, thereby controlling for genotype. Smokers and non-smokers differed in whole-brain SUVs (P=0.006) owing to smokers having 16.8% lower values than non-smokers. The groups did not differ in injected radiotracer dose or body weight, which were used to calculate SUV. An inverse association was found between whole-brain SUV and reported cigarettes per day (P
- Published
- 2017
7. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse
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Justinova, Zuzana, Panlilio, Leigh V, Moreno-Sanz, Guillermo, Redhi, Godfrey H, Auber, Alessia, Secci, Maria E, Mascia, Paola, Bandiera, Tiziano, Armirotti, Andrea, Bertorelli, Rosalia, Chefer, Svetlana I, Barnes, Chanel, Yasar, Sevil, Piomelli, Daniele, and Goldberg, Steven R
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Behavioral and Social Science ,Neurosciences ,Brain Disorders ,Prevention ,Drug Abuse (NIDA only) ,Tobacco Smoke and Health ,Tobacco ,Substance Misuse ,Basic Behavioral and Social Science ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Benzamides ,Biphenyl Compounds ,Brain ,Carbamates ,Cues ,Dopamine ,Dose-Response Relationship ,Drug ,Drug-Seeking Behavior ,Extinction ,Psychological ,Male ,Mixed Function Oxygenases ,Models ,Animal ,Nicotine ,Nicotinic Agonists ,Rats ,Rats ,Sprague-Dawley ,Recurrence ,Reward ,Saimiri ,Self Administration ,Time Factors ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.
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- 2015
8. Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats
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Costello, Matthew R, Reynaga, Daisy D, Mojica, Celina Y, Zaveri, Nurulain T, Belluzzi, James D, and Leslie, Frances M
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Prevention ,Tobacco ,Tobacco Smoke and Health ,Brain Disorders ,Behavioral and Social Science ,Substance Misuse ,Neurosciences ,Good Health and Well Being ,Animals ,Conditioning ,Operant ,Male ,Monoamine Oxidase ,Nicotine ,Nicotinic Agonists ,Rats ,Rats ,Sprague-Dawley ,Receptors ,Nicotinic ,Reinforcement ,Psychology ,Smoke ,tobacco dependence ,alpha 3 beta 4 nAChR antagonist ,self-administration ,reinstatement ,stress ,monoamine oxidase ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological psychology - Abstract
Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.
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- 2014
9. Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials
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King, David P, Paciga, Sara, Pickering, Eve, Benowitz, Neal L, Bierut, Laura J, Conti, David V, Kaprio, Jaakko, Lerman, Caryn, and Park, Peter W
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Tobacco ,Genetics ,Clinical Research ,Prevention ,Substance Misuse ,Tobacco Smoke and Health ,Drug Abuse (NIDA only) ,Brain Disorders ,Neurosciences ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Respiratory ,Good Health and Well Being ,Adult ,Aged ,Benzazepines ,Bupropion ,Dopamine Uptake Inhibitors ,Double-Blind Method ,Female ,Humans ,Male ,Middle Aged ,Nicotinic Agonists ,Pharmacogenetics ,Quinoxalines ,Research Design ,Smoking Cessation ,Tobacco Use Disorder ,Treatment Outcome ,Varenicline ,varenicline ,bupropion ,pharmacogenetics ,nicotine ,nicotinic receptor ,CYP2B6 ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological psychology - Abstract
Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9-12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23-2.52) (p
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- 2012
10. Not all smokers are alike: the hidden cost of sustained attention during nicotine abstinence
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Elliot A. Stein, Betty Jo Salmeron, John R. Fedota, Harshawardhan U. Deshpande, Thomas J. Ross, and Juan Castillo
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medicine.medical_specialty ,Nicotine ,Brain activity and meditation ,media_common.quotation_subject ,Neuroimaging ,Audiology ,Medicine ,Humans ,media_common ,Pharmacology ,Smokers ,business.industry ,Attentional control ,Cognition ,Abstinence ,medicine.disease ,Magnetic Resonance Imaging ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Nicotine withdrawal ,Endophenotype ,Smoking Cessation ,business ,Insula ,medicine.drug - Abstract
BackgroundNicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are heterogeneous, suggesting underlying endophenotypic subgroups. We identified smoker subgroups based on response accuracy during a cognitively demanding Parametric Flanker Task (PFT) and characterized their distinct neuroimaging endophenotypes using a nicotine state manipulation (sated, abstinent).MethodsForty-five smokers completed the 25-min PFT in two fMRI sessions (nicotine sated, abstinent). Task-evoked NWS-associated errors of omission (EOm), brain activity, underlying functional connectivity (FC), and brain-behavior correlations between subgroups were assessed.ResultsBased on their response accuracy in the high demand PFT condition, smokers split into high (HTP, n=21) and low task performer (LTP, n=24) subgroups. Behaviorally, HTPs showed greater response accuracy independent of nicotine state and greater vulnerability to abstinence-induced EOm. HTPs showed greater BOLD responses in attentional control brain regions for the [correct responses (–) errors of commission] PFT contrast across states. A whole-brain FC analysis with these subgroup-derived regions as seeds revealed two circuits: L Precentral : R Insula and L Insula : R Occipital, with abstinence-induced FC strength increases only in HTPs. Finally, abstinence-induced brain (FC) and behavior (EOm) differences were positively correlated for HTPs in a L Precentral : R Orbitofrontal cortical circuit.ConclusionWe used a cognitive stressor (PFT) to fractionate smokers into two subgroups (HTP/LTP). Only the HTPs demonstrated sustained attention deficits during nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this ‘dual stressor’ approach revealed distinct smoker subgroups with differential attention deficit responses to withdrawal that could be novel targets for therapeutic interventions to improve cessation outcomes.
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- 2022
11. Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes
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Paul Vezina, Hanwen Zhang, Robert R. Butler, Alena Kozlova, Stephan Steidl, Jubao Duan, Zhiping P. Pang, Alan R. Sanders, Siwei Zhang, and Thomas Ujas
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Male ,endocrine system ,Nicotine ,media_common.quotation_subject ,Addiction ,Genome-wide association study ,Biology ,Nucleus accumbens ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Allele ,Sensitization ,030304 developmental biology ,media_common ,Pharmacology ,Genetics ,0303 health sciences ,Imprinting ,Rats, Inbred F344 ,Gene expression profiling ,Rats ,Behavior, Addictive ,Ventral tegmental area ,Psychiatry and Mental health ,Phenotype ,medicine.anatomical_structure ,Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,medicine.drug - Abstract
Repeated nicotine exposure leads to sensitization (SST) and enhances self-administration (SA) in rodents. However, the molecular basis of nicotine SST and SA and their biological relevance to the mounting genome-wide association study (GWAS) loci of human addictive behaviors are poorly understood. Considering a gateway drug role of nicotine, we modeled nicotine SST and SA in F1 progeny of inbred rats (F344/BN) and conducted integrative genomics analyses. We unexpectedly observed male-specific nicotine SST and a parental effect of SA only present in paternal F344 crosses. Transcriptional profiling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) core and shell further revealed sex- and brain region-specific transcriptomic signatures of SST and SA. We found that genes associated with SST and SA were enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, SST-associated genes were often downregulated in male VTA but upregulated in female VTA, and strongly enriched for smoking GWAS risk variants, possibly explaining the male-specific SST. For SA, we found widespread region-specific allelic imbalance of expression (AIE), of which genes showing AIE bias toward paternal F344 alleles in NAc core were strongly enriched for SA-associated genes and for GWAS risk variants of smoking initiation, likely contributing to the parental effect of SA. Our study suggests a mechanistic link between transcriptional changes underlying the NIC SST and SA and human nicotine addiction, providing a resource for understanding the neurobiology basis of the GWAS findings on human smoking and other addictive phenotypes.
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- 2021
12. 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
13. Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity
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John R. Fedota, Thomas J. Ross, Hyung Wook Nam, Brooke Schleyer, Elisabeth C. Caparelli, Michael Tennekoon, Hong Gu, Yihong Yang, Osama A. Abulseoud, Elliot A. Stein, and Juan Castillo
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medicine.medical_specialty ,Nicotine ,Addiction ,Glutamic Acid ,Craving ,behavioral disciplines and activities ,Gyrus Cinguli ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Anterior cingulate cortex ,Pharmacology ,medicine.diagnostic_test ,Resting state fMRI ,business.industry ,Glutamate receptor ,Tobacco Use Disorder ,medicine.disease ,Adenosine ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,Nicotine withdrawal ,medicine.anatomical_structure ,Endocrinology ,medicine.symptom ,Functional magnetic resonance imaging ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Most cigarette smokers who wish to quit too often relapse within the first few days of abstinence, primarily due to the aversive aspects of the nicotine withdrawal syndrome (NWS), which remains poorly understood. Considerable research has suggested that the dorsal anterior cingulate cortex (dACC) plays a key role in nicotine dependence, with its functional connections between other brain regions altered as a function of trait addiction and state withdrawal. The flow of information between dACC and fronto-striatal regions is secured through different pathways, the vast majority of which are glutamatergic. As such, we investigated dACC activity using resting state functional connectivity (rsFC) with functional magnetic resonance imaging (fMRI) and glutamate (Glu) concentration with magnetic resonance spectroscopy (MRS). We also investigated the changes in adenosine levels in plasma during withdrawal as a surrogate for brain adenosine, which plays a role in fine-tuning synaptic glutamate transmission. Using a double-blind, placebo-controlled, randomized crossover design, nontreatment seeking smoking participants (N = 30) completed two imaging sessions, one while nicotine sated and another after 36 h nicotine abstinence. We observed reduced dACC Glu (P = 0.029) along with a significant reduction in plasma adenosine (P = 0.03) and adenosine monophosphate (AMP; P
- Published
- 2020
14. Nicotine dependence (trait) and acute nicotinic stimulation (state) modulate attention but not inhibitory control: converging fMRI evidence from Go–Nogo and Flanker tasks
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Betty Jo Salmeron, Elise Lesage, Thomas J. Ross, Matthew T. Sutherland, and Elliot A. Stein
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Adult ,Male ,Nicotine ,Adolescent ,medicine.medical_treatment ,media_common.quotation_subject ,Article ,Executive Function ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,medicine ,Humans ,Attention ,Nicotinic Agonists ,Varenicline ,Anterior cingulate cortex ,media_common ,Pharmacology ,Brain Mapping ,Cross-Over Studies ,Working memory ,business.industry ,Brain ,Tobacco Use Disorder ,Middle Aged ,Abstinence ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Inhibition, Psychological ,Psychiatry and Mental health ,medicine.anatomical_structure ,Nicotine withdrawal ,Nicotinic agonist ,chemistry ,Smoking cessation ,Female ,Smoking Cessation ,business ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go–Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go–Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.
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- 2020
15. Increased subjective and reinforcing effects of initial nicotine exposure in young adults with attention deficit hyperactivity disorder (ADHD) compared to matched peers: results from an experimental model of first-time tobacco use
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Kenneth A. Perkins, F. Joseph McClernon, Maggie M. Sweitzer, and Scott H. Kollins
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Adult ,Male ,Nicotine ,Adolescent ,Psychological intervention ,Choice Behavior ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Heart rate ,Humans ,Medicine ,Attention deficit hyperactivity disorder ,Nicotinic Agonists ,Dosing ,Young adult ,Administration, Intranasal ,Pharmacology ,business.industry ,Cognition ,Non-Smokers ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Blood pressure ,Attention Deficit Disorder with Hyperactivity ,Female ,business ,Reinforcement, Psychology ,030217 neurology & neurosurgery ,medicine.drug ,Clinical psychology - Abstract
Individuals with attention deficit hyperactivity disorder (ADHD) are at increased risk for adverse cigarette smoking outcomes, and little is known about factors underlying this risk. This study sought to evaluate the effects of initial nicotine exposure in young adults with and without ADHD using a novel paradigm of exposure to model initial smoking experiences. Participants were young adult nonsmokers (n = 61 ADHD, n = 75 Control) between the ages of 18-25 years (inclusive) who reported never having smoked a full cigarette, and no tobacco use in the prior 3 years. Participants were exposed to three different blinded doses of intranasally administered nicotine (0, 0.5, 1.0 mg) across three separate fixed dose experimental sessions. In subsequent sessions, participants were given the opportunity to self-administer nicotine under two different conditions-high and low cognitive demand. Physiological, subjective, and reinforcing effects of nicotine were the main outcomes. Nicotine plasma levels, and no group differences in effects of nicotine on heart rate or blood pressure, confirmed comparable dosing exposure across groups. ADHD participants reported significantly greater dizziness following nicotine, and greater pleasant subjective effects across all conditions, compared to non-ADHD non-smokers. There were no group differences on subjective reports of bad or unpleasant effects. Subsequent nicotine self-administration was significantly higher among non-smokers with ADHD, and their choices of nicotine were not influenced by cognitive condition. There are meaningful differences between young adults with and without ADHD with respect to the initial subjective and reinforcing effects of nicotine; and interventions to prevent use should start prior to typical age of experimentation among ADHD patients.
- Published
- 2019
16. Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal
- Author
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Thomas J. Gould, Matty Zimmerman, Robert D. Cole, Anastasia Matchanova, Munir Gunes Kutlu, and Vinay Parikh
- Subjects
Male ,Nicotine ,Glutamic Acid ,Striatum ,Nucleus accumbens ,Synaptic Transmission ,Article ,03 medical and health sciences ,Cognition ,Discrimination, Psychological ,0302 clinical medicine ,Neurochemical ,medicine ,Animals ,Nicotinic Agonists ,Prefrontal cortex ,Pharmacology ,Behavior, Animal ,business.industry ,Brain-Derived Neurotrophic Factor ,Glutamate receptor ,Cognitive flexibility ,medicine.disease ,Adaptation, Physiological ,Corpus Striatum ,Frontal Lobe ,Substance Withdrawal Syndrome ,030227 psychiatry ,Mice, Inbred C57BL ,Psychiatry and Mental health ,Nicotine withdrawal ,nervous system ,Conditioning, Operant ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.
- Published
- 2019
17. Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: a randomized controlled trial
- Author
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Markus Heilig, Abraham Zangen, Michal Pietrzak, Andreas Löfberg, Hanna Karlsson, Theodor Arlestig, Irene Perini, and Robin Kämpe
- Subjects
Male ,medicine.medical_specialty ,Alcohol Drinking ,medicine.medical_treatment ,Craving ,Stimulation ,Insular cortex ,behavioral disciplines and activities ,Article ,law.invention ,Nicotine ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,Double-Blind Method ,Randomized controlled trial ,law ,mental disorders ,medicine ,Humans ,Cerebral Cortex ,Pharmacology ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Middle Aged ,Transcranial Magnetic Stimulation ,3. Good health ,030227 psychiatry ,Transcranial magnetic stimulation ,Alcoholism ,Psychiatry and Mental health ,nervous system ,Female ,medicine.symptom ,business ,Insula ,psychological phenomena and processes ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.
- Published
- 2019
18. Overexpression of corticotropin-releasing factor in the nucleus accumbens enhances the reinforcing effects of nicotine in intact female versus male and ovariectomized female rats
- Author
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Zhiying Shan, Kevin P. Uribe, Adriaan W. Bruijnzeel, Victor L. Correa, Bryan Cruz, Rodolfo J. Flores, Laura E. O'Dell, Arshad M. Khan, and Briana E Pinales
- Subjects
Male ,Nicotine ,endocrine system ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Ovariectomy ,media_common.quotation_subject ,medicine.medical_treatment ,Gene Expression ,Nucleus accumbens ,Nucleus Accumbens ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Nicotinic Agonists ,Rats, Wistar ,Receptor ,Internalization ,Saline ,media_common ,Pharmacology ,Sex Characteristics ,Rats ,030227 psychiatry ,Psychiatry and Mental health ,Endocrinology ,Ovariectomized rat ,Conditioning, Operant ,Female ,Reinforcement, Psychology ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Sex characteristics ,Hormone ,medicine.drug - Abstract
This study assessed the role of stress systems in the nucleus accumbens (NAc) in promoting sex differences in the reinforcing effects of nicotine. Intravenous self-administration (IVSA) of various doses of nicotine was compared following overexpression of corticotropin-releasing factor (CRF) in the NAc of female and male rats. Ovariectomized (OVX) females were also included to assess the role of ovarian hormones in promoting nicotine reinforcement. Rats received intra-NAc administration of an adeno-associated vector that overexpressed CRF (AAV2/5-CRF) or green fluorescent protein (AAV2/5-GFP). All rats were then given extended access (23 h/day) to an inactive and an active lever that delivered nicotine. Separate groups of rats received intra-NAc AAV2/5-CRF and saline IVSA. Rats were also allowed to nose-poke for food and water during IVSA testing. At the end of the study, the NAc was dissected and rt-qPCR methods were used to estimate CRF overexpression and changes in CRF receptors (CRFr1, CRFr2) and the CRF receptor internalizing protein, β-arrestin2 (Arrb2). Overexpression of CRF in the NAc increased nicotine IVSA to a larger extent in intact female versus male and OVX females. Food intake was increased to a larger extent in intact and OVX females as compared to males. The increase in CRF gene expression was similar across all groups; however, in females, overexpression of CRF resulted in a larger increase in CRFr1 and CRFr2 relative to males. In males, overexpression of CRF produced a larger increase in Arrb2 than females, suggesting greater CRF receptor internalization. Our results suggest that stress systems in the NAc promote the reinforcing effectiveness of nicotine in female rats in an ovarian hormone-dependent manner.
- Published
- 2019
19. Increased Functional Connectivity in an Insula-Based Network is Associated with Improved Smoking Cessation Outcomes.
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Addicott, Merideth A, Sweitzer, Maggie M, Froeliger, Brett, Rose, Jed E, and McClernon, Francis J
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NEUROBIOLOGY , *SMOKING cessation , *BRAIN imaging , *NICOTINE , *SENSORIMOTOR cortex - Abstract
Little is known regarding the underlying neurobiology of smoking cessation. Neuroimaging studies indicate a role for the insula in connecting the interoceptive awareness of tobacco craving with a larger brain network that motivates smoking. We investigated differences in insula-based functional connectivity between smokers who did not relapse during a quit attempt vs those who relapsed. Smokers (n=85) underwent a resting-state functional connectivity scan and were then randomized into two groups (either smoking usual brand cigarettes or smoking very low nicotine cigarettes plus nicotine replacement therapy) for 30 days before their target quit date. Following the quit date, all participants received nicotine replacement therapy and their smoking behavior was observed for 10 weeks. Participants were subsequently classified as nonrelapsed (n=44) or relapsed (i.e., seven consecutive days of smoking ⩾1 cigarette/day; n=41). The right and left insula, as well as insula subdivisions (posterior, ventroanterior, and dorsoanterior) were used as seed regions of interest in the connectivity analysis. Using the right and left whole-insula seed regions, the nonrelapsed group had greater functional connectivity than the relapsed group with the bilateral pre- and postcentral gyri. This effect was isolated to the right and left posterior insula seed regions. Our results suggest that relapse vulnerability is associated with weaker connectivity between the posterior insula and primary sensorimotor cortices. Perhaps greater connectivity in this network improves the ability to inhibit a motor response to cigarette cravings when those cravings conflict with a goal to remain abstinent. These results are consistent with recent studies demonstrating a positive relationship between insula-related functional connectivity and cessation likelihood among neurologically intact smokers. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
20. R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats.
- Author
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Wang, Xiao-Fei, Bi, Guo-Hua, He, Yi, Yang, Hong-Ju, Gao, Jun-Tao, Okunola-Bakare, Oluyomi M, Slack, Rachel D, Gardner, Eliot L, Xi, Zheng-Xiong, and Newman, Amy Hauck
- Subjects
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MODAFINIL , *SLEEP disorders treatment , *NICOTINE , *DRUG addiction , *MICRODIALYSIS , *LABORATORY rats - Abstract
(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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21. Sex-Specific Effects of Cigarette Mentholation on Brain Nicotine Accumulation and Smoking Behavior.
- Author
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Zuo, Yantao, Mukhin, Alexey G, Behm, Frederique M, Rose, Jed E, Garg, Sudha, Nazih, Rachid, and Garg, Pradeep K
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- *
BRAIN , *MENTHOL , *NICOTINE , *SMOKING , *WOMEN , *CIGARETTES , *SMOKE inhalation injuries - Abstract
Menthol cigarettes are likely associated with greater risks of smoking dependence than non-menthol cigarettes. We sought to test the hypothesis that menthol increases the rate of brain nicotine accumulation (BNA) during smoking and thereby enhances its addictive effects. In a counter-balanced cross-over design, 10 menthol and 9 non-menthol smokers (10 females and 9 males; mean age 44.3) underwent two study phases. In each phase, the participant smoked exclusively either menthol or non-menthol research cigarettes for approximately 1 week prior to a positron emission tomography (PET) scan session, during which the subject's head was scanned following inhalation of a single puff of smoke from a cigarette containing 11C-nicotine. No differences in initial slope, Cmax, area under curve (AUC), and T1/2 of BNA were found between menthol and non-menthol cigarettes across all subjects; however, menthol relative to non-menthol cigarettes were associated with steeper initial slopes in men (p=0.008). Unexpectedly, women had faster BNA as indicated by greater values of the initial slope, Cmax, AUC, and shorter T1/2 than men (all ps<0.04). The rates of BNA were significantly correlated with ratings of smoking motivations of getting a 'rush', getting relaxing effects and marginally with alleviation of craving. These results do not provide strong support for the putative role of menthol in enhancing BNA, although further studies should explore the apparent effect of menthol on BNA in men. Fast BNA during smoking and preference of sensory properties of menthol cigarettes may independently or jointly contribute to smoking dependence among women. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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22. Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice.
- Author
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Sanjakdar, Sarah S, Maldoon, Pretal P, Marks, Michael J, Brunzell, Darlene H, Maskos, Uwe, McIntosh, J Michael, Bowers, M Scott, and Damaj, M Imad
- Subjects
- *
ACETYLCHOLINE , *NICOTINE , *NICOTINIC receptors , *CHOLINERGIC receptors , *LABORATORY mice - Abstract
Mesolimbic α6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various α6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of α6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of α6β2* nAChRs and genetic deletion of the α6 or α4 subunits in mice. We found that α6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that α4 KO failed to show nicotine preference, suggesting that α6α4β2*-nAChRs are involved. Furthermore, α6β2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective α6β2* α-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, α6 KO failed to condition to cocaine, but cocaine CPP in the α4 KO was preserved. Intriguingly, α-conotoxin MII [H9A; L15A], blocked cocaine conditioning in α4 KO mice, implicating α6β2* nAChRs in cocaine reward. Importantly, these effects did not generalize as α6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the α6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic α6β2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
23. Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking.
- Author
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Khaled, Maram ATM, Pushparaj, Abhiram, Di Ciano, Patricia, Diaz, Jorge, and Le Foll, Bernard
- Subjects
- *
DOPAMINE receptors , *AMYGDALOID body , *NICOTINE , *AUTORADIOGRAPHY , *HISTOLOGY , *PSYCHOLOGY - Abstract
Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 μg/0.5 μl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 μg/0.5 μl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [125I]7-OH-PIPAT to D3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D2 and D3 receptors in modulating this behavior. The current study supports an important role for D3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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24. Nicotine and Non-Nicotine Smoking Factors Differentially Modulate Craving, Withdrawal and Cerebral Blood Flow as Measured with Arterial Spin Labeling.
- Author
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Addicott, Merideth A, Froeliger, Brett, Kozink, Rachel V, Van Wert, Dana M, Westman, Eric C, Rose, Jed E, and McClernon, Francis J
- Subjects
- *
NICOTINE , *SMOKING , *CEREBRAL circulation , *SMOKING cessation , *MOOD (Psychology) , *TOBACCO laws - Abstract
Smoking cessation results in withdrawal symptoms such as craving and negative mood that may contribute to lapse and relapse. Little is known regarding whether these symptoms are associated with the nicotine or non-nicotine components of cigarette smoke. Using arterial spin labeling, we measured resting-state cerebral blood flow (CBF) in 29 adult smokers across four conditions: (1) nicotine patch+denicotinized cigarette smoking, (2) nicotine patch+abstinence from smoking, (3) placebo patch+denicotinized cigarette smoking, and (4) placebo patch+abstinence from smoking. We found that changes in self-reported craving positively correlated with changes in CBF from the denicotinized cigarette smoking conditions to the abstinent conditions. These correlations were found in several regions throughout the brain. Self-reported craving also increased from the nicotine to the placebo conditions, but had a minimal relationship with changes in CBF. The results of this study suggest that the non-nicotine components of cigarette smoke significantly impact withdrawal symptoms and associated brain areas, independently of the effects of nicotine. As such, the effects of non-nicotine factors are important to consider in the design and development of smoking cessation interventions and tobacco regulation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
25. Dopamine Receptor Blockade Modulates the Rewarding and Aversive Properties of Nicotine via Dissociable Neuronal Activity Patterns in the Nucleus Accumbens.
- Author
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Sun, Ninglei and Laviolette, Steven R
- Subjects
- *
DOPAMINE receptors , *NICOTINE , *NUCLEUS accumbens , *INTERNEURONS , *AVERSION - Abstract
The mesolimbic pathway comprising the ventral tegmental area (VTA) and projection terminals in the nucleus accumbens (NAc) has been identified as a critical neural system involved in processing both the rewarding and aversive behavioral effects of nicotine. Transmission through dopamine (DA) receptors functionally modulates these effects directly within the NAc. Nevertheless, the neuronal mechanisms within the NAc responsible for these bivalent behavioral effects are presently not known. Using an unbiased conditioned place preference procedure combined with in vivo neuronal recordings, we examined the effects of nicotine reward and aversion conditioning on intra-NAc neuronal sub-population activity patterns. We report that intra-VTA doses of nicotine that differentially produce rewarding or aversive behavioral effects produce opposite effects on sub-populations of fast-spiking interneurons (FSIs) or medium spiny neurons (MSNs) within the shell region of the NAc (NAshell). Thus, while the rewarding effects of intra-VTA nicotine were associated with inhibition of FSI and activation of MSNs, the aversive effects of nicotine produced the opposite pattern of NAshell neuronal population activity. Blockade of DA transmission with a broad-spectrum DA receptor antagonist, α-flupenthixol, strongly inhibited the spontaneous activity of NAshell FSIs, and reversed the conditioning properties of intra-VTA nicotine, switching nicotine-conditioned responses from aversive to rewarding. Remarkably, DA receptor blockade switched intra-NAshell neuronal population activity from an aversion to a reward pattern, concomitant with the observed switch in behavioral conditioning effects. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
26. Current Smoking and Reduced Gray Matter Volume-a Voxel-Based Morphometry Study.
- Author
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Fritz, Hans-Christian, Wittfeld, Katrin, Schmidt, Carsten O, Domin, Martin, Grabe, Hans J, Hegenscheid, Katrin, Hosten, Norbert, and Lotze, Martin
- Subjects
- *
SMOKING , *GRAY matter (Nerve tissue) , *NICOTINE , *PREFRONTAL cortex , *BRAIN - Abstract
Nicotine modulates prefrontal processing when tested with functional imaging. Previous studies on changes in regional brain volumes in small samples, reporting different life-time exposure to nicotine, identified reduced volume in smokers in prefrontal areas but reported controversial results for other areas. We investigated the association of cigarette smoking and regional gray and white matter volume by using voxel-based morphometry (VBM) for T1-weighted high-resolution magnetic resonance imaging in 315 current-smokers and 659 never-smokers from the representative Study of Health in Pomerania (SHIP). Our study showed that in current-smokers smoking is significantly associated with gray matter volume loss in the prefrontal cortex, the anterior cingulate cortex, the insula, and the olfactory gyrus. White matter volumes were not relevantly reduced in current-smokers. In current-smokers, we found associations of gray matter loss and smoking exposure (pack-years) in the prefrontal cortex, the anterior and middle cingulate cortex, and the superior temporal and angular gyrus, which however did not stand corrections for multiple testing. We confirmed associations between smoking and gray matter differences in the prefrontal cortex, the anterior cingulate cortex and the insula in the general population of Pomerania (Germany). For the first time, we identified differences in brain volumes in the olfactory gyrus. Other cerebral regions did not show significant differences when correcting for multiple comparisons within the whole brain. The regions of structural deficits might be involved in addictive behavior and withdrawal symptoms, whereas further investigations have to show if the observed atrophies were caused by smoking itself or are preexisting differences between smoking and non-smoking individuals. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
27. How nicotine withdrawal symptoms fight each other: interpeduncular GABA neuron activity dynamically controls negative affect vs. coping behavior
- Author
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Olivier George and Alicia J. Avelar
- Subjects
Nicotine ,Interpeduncular Nucleus ,media_common.quotation_subject ,Coping behavior ,Medical and Health Sciences ,Text mining ,medicine ,Humans ,Adaptation ,GABAergic Neurons ,media_common ,Psychiatry ,Pharmacology ,business.industry ,Addiction ,Psychology and Cognitive Sciences ,medicine.disease ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Good Health and Well Being ,medicine.anatomical_structure ,Nicotine withdrawal ,Psychological ,Neuron ,business ,Neuroscience - Published
- 2021
28. Dopamine Function in Cigarette Smokers: An [18F]-DOPA PET Study.
- Author
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Bloomfield, Michael AP, Pepper, Fiona, Egerton, Alice, Demjaha, Arsime, Tomasi, Gianpaolo, Mouchlianitis, Elias, Maximen, Levi, Veronese, Mattia, Turkheimer, Federico, Selvaraj, Sudhakar, and Howes, Oliver D
- Subjects
- *
DOPAMINE , *SMOKING , *PUBLIC health , *NICOTINE , *POSITRON emission tomography - Abstract
Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex- and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant Kicer) was measured with positron emission tomography and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t28=0.64, p=0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r=−0.23, p=0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
29. Subjective, Physiological, and Cognitive Responses to Intravenous Nicotine: Effects of Sex and Menstrual Cycle Phase.
- Author
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DeVito, Elise E, Herman, Aryeh I, Waters, Andrew J, Valentine, Gerald W, and Sofuoglu, Mehmet
- Subjects
- *
NICOTINE , *COGNITIVE development , *MENSTRUAL cycle , *DRUG administration , *PUBLIC health , *PSYCHOLOGY - Abstract
Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18-50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects. Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
30. Repeated Transcranial Direct Current Stimulation Prevents Abnormal Behaviors Associated with Abstinence from Chronic Nicotine Consumption.
- Author
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Pedron, Solène, Monnin, Julie, Haffen, Emmanuel, Sechter, Daniel, and Van Waes, Vincent
- Subjects
- *
DIRECT currents , *ANIMAL models in research , *NICOTINE , *LABORATORY mice , *ELECTRODES - Abstract
Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
31. Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans.
- Author
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Le Foll, Bernard, Guranda, Mihail, Wilson, Alan A, Houle, Sylvain, Rusjan, Pablo M, Wing, Victoria C, Zawertailo, Laurie, Busto, Usoa, Selby, Peter, Brody, Arthur L, George, Tony P, and Boileau, Isabelle
- Subjects
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DOPAMINE , *SMOKING , *POSITRON emission tomography , *PSYCHIATRIC drugs , *NICOTINE - Abstract
Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [11C]-(+)-PHNO ([11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [11C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [11C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [11C]-(+)-PHNO binding in D2 and D3-rich areas (−12.0 and −15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [11C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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32. Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats.
- Author
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Igari, Moe, Alexander, Jon C, Ji, Yue, Qi, Xiaoli, Papke, Roger L, and Bruijnzeel, Adrie W
- Subjects
- *
VARENICLINE , *CYTISINE , *MENTAL depression , *NICOTINE , *SMOKING cessation - Abstract
Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial α4/α6/β2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the United States for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds, very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3′-yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naive and nicotine-withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak α4β2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14 days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
33. Nicotine effects on associative learning in human non-smokers
- Author
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Ashleigh Wells, Britta Hahn, Agatha Lenartowicz, and Marie B Yuille
- Subjects
Adult ,Male ,Nicotine ,medicine.medical_specialty ,media_common.quotation_subject ,Context (language use) ,Stop signal ,Audiology ,Article ,050105 experimental psychology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Reaction Time ,medicine ,Humans ,0501 psychology and cognitive sciences ,Nicotinic Agonists ,media_common ,Pharmacology ,Cross-Over Studies ,Mechanism (biology) ,Addiction ,05 social sciences ,Association Learning ,Non-Smokers ,Middle Aged ,Tobacco Use Cessation Devices ,Associative learning ,Psychiatry and Mental health ,Facilitation ,Conditioning ,Female ,Psychology ,Photic Stimulation ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Tobacco smoking is the most common preventable cause of death in the US. Nicotine is considered the primary constituent responsible for tobacco addiction. Its paradoxically high abuse potential may reflect behavioral control by drug-associated stimuli, which appears to play a larger role for tobacco dependence than for other abused drugs. We tested a potential explanation, hypothesizing that nicotine enhances associative learning, the mechanism underlying the conditioning of drug-associated stimuli. Thirty-two non-smokers were exposed to transdermal nicotine (7 mg/24 h) and placebo in a double-blind cross-over study and tested with behavioral paradigms designed to isolate incidental stimulus–stimulus or stimulus–response learning. The stop signal task required speeded gender judgments of face stimuli. A tone signaled when to withhold the response. Unbeknownst to participants, some faces were always paired with stop trials. Nicotine enhanced the facilitation of stop-responses to these stimuli, and the slowing of go-responses when previously stop-associated stimuli were paired with go trials, indicating stronger associations between paired stimuli and the stop signal/stop response. Another task required feedback-based learning of associations between pairs of shape stimuli. Five pairs were made from either ten different stimuli, or from different combinations of two identical sets of five stimuli with correct associations depending on contextual information. Nicotine increased incorrect choices of stimuli that were associated in a different context, indicating stronger stimulus–stimulus associations at the expense of flexible context-adaptive behavior. The results indicate that nicotine can enhance incidental associative learning, a mechanism that may promote the formation of smoking-associated stimuli and cue-controlled drug-taking.
- Published
- 2018
34. Effects of alcohol dependence on discrete choice between alcohol and saccharin
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Douglas Funk, Anh D. Lê, Andrew Loughlin, Melissa Russo, and Kathleen M. Coen
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Male ,Drug ,Nicotine ,medicine.medical_specialty ,media_common.quotation_subject ,Self Administration ,Alcohol ,Choice Behavior ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Saccharin ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Rats, Long-Evans ,Nicotinic Agonists ,media_common ,Pharmacology ,Discrete choice ,Quinine ,Ethanol ,business.industry ,Alcohol dependence ,Central Nervous System Depressants ,030227 psychiatry ,Alcoholism ,Psychiatry and Mental health ,Endocrinology ,chemistry ,Self-administration ,business ,psychological phenomena and processes ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Dependence on drugs has enduring effects on drug intake and relapse. The role of choice in enhanced susceptibility to drug use in drug dependence has been little studied. Here we determine the effects of alcohol dependence on the choice between alcohol and a non-drug reward, saccharin, using the discrete choice model in food-restricted male rats. We trained rats to self-administer alcohol (12% w/v) and saccharin (0.05, 0.1%), tested their choice of alcohol vs. saccharin, and determined the effects of deprivation and intertrial interval (ITI) duration on choice. We then determined the effects of alcohol dependence, induced by repeated intermittent exposure to alcohol vapor on choice of alcohol vs. saccharin (0.1%) in discrete choice trials as well as on the effects of adulteration of alcohol with quinine on choice. We trained another group of rats to self-administer intravenous (i.v.) nicotine (0.03 mg/kg/infusion) and oral saccharin (0.1%), determined their choice, and examined the roles of ITI duration and concurrent access on choice. Rats chose equivalent amounts of 0.05% saccharin and 12% alcohol, showed a stronger choice for 0.1% saccharin, and alcohol and saccharin choice were modestly decreased and increased, respectively, by deprivation. Alcohol dependence led to profound increases in the choice of alcohol over saccharin while adulteration of alcohol with quinine did not affect choice in non-dependent or dependent rats. Rats showed marked choice for 0.1% saccharin over i.v. nicotine. The strong effect that dependence had on alcohol choice is an important validation of the discrete choice procedure.
- Published
- 2018
35. Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors
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Philip H. Smith, Dawson Stout, Marina R. Picciotto, Yann S. Mineur, Steven T. Pittenger, and Alan S. Lewis
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Male ,0301 basic medicine ,medicine.medical_specialty ,alpha7 Nicotinic Acetylcholine Receptor ,Pyridines ,Mice, Transgenic ,Hippocampal formation ,Benzylidene Compounds ,Hippocampus ,Nicotine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Nicotinic Agonists ,Genes, Immediate-Early ,Acetylcholine receptor ,Neurons ,Pharmacology ,Mice, Inbred BALB C ,biology ,Dentate gyrus ,CHRNA7 ,Granule cell ,Serenic ,Aggression ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Nicotinic agonist ,Endocrinology ,nervous system ,biology.protein ,Original Article ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.
- Published
- 2017
36. Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal.
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Turner, Jill R, Wilkinson, Derek S, Poole, Rachel LF, Gould, Thomas J, Carlson, Gregory C, and Blendy, Julie A
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- *
VARENICLINE , *NICOTINE , *NICOTINE addiction , *CAUSES of death , *SMOKING prevention , *DRUG withdrawal symptoms , *SMOKING cessation - Abstract
Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective α4β2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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37. D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers.
- Author
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Luykx, Jurjen J, Bakker, Steven C, van Boxmeer, Loes, Vinkers, Christiaan H, Smeenk, Hanne E, Visser, Wouter F, Verhoeven-Duif, Nanda M, Strengman, Eric, Buizer-Voskamp, Jacobine E, de Groene, Lizzy, van Dongen, Eric PA, Borgdorff, Paul, Bruins, Peter, de Koning, Tom J, Kahn, René S, and Ophoff, Roel A
- Subjects
- *
PROLINE , *CEREBROSPINAL fluid , *BLOOD plasma , *CIGARETTE smokers , *ALCOHOL drinking , *METHYL aspartate receptors , *NICOTINE , *BONFERRONI correction - Abstract
The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may have a role in tendencies to consume these substances. Nonetheless, little is known about concentrations of NMDAR coagonists in the cerebrospinal fluid (CSF) and plasma of individuals who smoke or consume alcohol. Glycine and L- and D-stereoisomers of alanine, serine, and proline were therefore measured using ultra-high-performance liquid chromatography-tandem mass spectrometry in 403 healthy subjects. Nicotine and alcohol consumption were quantified using questionnaires. Possible differences in NMDAR coagonist concentrations in plasma and CSF were investigated using ANCOVA with age, body mass index, and storage duration as covariates. The significance threshold was Bonferroni corrected (α=0.00625). Compared with non-smokers, smokers displayed lower levels of D-proline in plasma (p=0.0027, Cohen's d=−0.41) and D-proline in CSF (p=0.0026, Cohen's d=−0.43). D-Serine in CSF was higher in smokers than in non-smokers (p=0.0052, Cohen's d=0.41). After subdividing participants based on smoking quantity, dose-dependent decreases were demonstrated in smokers for D-proline in plasma (F=5.65, p=0.0039) and D-proline in CSF (F=5.20, p=0.0060). No differences in NMDAR coagonist levels between alcohol consumption groups were detected. To our knowledge, this is the first report to implicate D-amino acids in smoking behavior of humans. Whether such concentration differences lie at the root of or result from smoking habits may be addressed in prospective studies. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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38. Prior Exposure to THC Increases the Addictive Effects of Nicotine in Rats.
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Panlilio, Leigh V, Zanettini, Claudio, Barnes, Chanel, Solinas, Marcelo, and Goldberg, Steven R
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- *
DRUG abuse , *TOBACCO use , *CANNABIS (Genus) , *NICOTINE , *TETRAHYDROCANNABINOL - Abstract
Although it is more common for drug abuse to progress from tobacco to cannabis, in many cases cannabis use develops before tobacco use. Epidemiological evidence indicates that prior cannabis use increases the likelihood of becoming dependent on tobacco. To determine whether this effect might be due to cannabis exposure per se, in addition to any genetic, social, or environmental factors that might contribute, we extended our series of studies on 'gateway drug' effects in animal models of drug abuse. Rats were exposed to THC, the main psychoactive constituent of cannabis, for 3 days (two intraperitoneal injections/day). Then, starting 1 week later, they were allowed to self-administer nicotine intravenously. THC exposure increased the likelihood of acquiring the nicotine self-administration response from 65% in vehicle-exposed rats to 94% in THC-exposed rats. When the price of nicotine was manipulated by increasing the response requirement, THC-exposed rats maintained higher levels of intake than vehicle-exposed rats, indicating that THC exposure increased the value of nicotine reward. These results contrast sharply with our earlier findings that prior THC exposure did not increase the likelihood of rats acquiring either heroin or cocaine self-administration, nor did it increase the reward value of these drugs. The findings obtained here suggest that a history of cannabis exposure might have lasting effects that increase the risk of becoming addicted to nicotine. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. Effects of Chronic Buspirone Treatment on Nicotine and Concurrent Nicotine+Cocaine Self-Administration.
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Mello, Nancy K, Fivel, Peter A, and Kohut, Stephen J
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- *
BUSPIRONE , *NICOTINE , *COCAINE , *DRUG therapy , *DRUG abuse , *DOPAMINE - Abstract
Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal pharmacotherapy would reduce both cigarette smoking and cocaine abuse. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on serotonin and dopamine systems. In preclinical studies, it reduced cocaine self-administration following both acute and chronic treatment in rhesus monkeys. The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of intravenous (IV) nicotine and IV nicotine+cocaine combinations. Five cocaine-experienced adult rhesus monkeys (Macaca mulatta) were trained to self-administer nicotine or nicotine+cocaine combinations, and food pellets (1 g) during four 1-h daily sessions under a second-order schedule of reinforcement (FR 2 (VR16:S)). Each nicotine+cocaine combination maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Buspirone (0.032-0.56 mg/kg/h) was administered IV through one lumen of a double-lumen catheter every 20 min for 23 h each day, for 7-10 consecutive days. Each 7-10-day sequence of buspirone treatment was followed by saline-control treatment for at least 3 days until food- and drug-maintained responding returned to baseline. Buspirone dose-dependently reduced responding maintained by nicotine alone (0.001-0.1 mg/kg/inj; P<0.01) and by nicotine (0.001 or 0.0032 mg/kg/inj)+cocaine combinations (0.0032 mg/kg/inj; P<0.05-0.001) with no significant effects on food-maintained responding. We conclude that buspirone selectively attenuates the reinforcing effects of nicotine alone and nicotine+cocaine polydrug combinations in a nonhuman primate model of drug self-administration. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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40. APOE E4 Carriers Show Prospective Memory Enhancement Under Nicotine, and Evidence for Specialisation Within Medial BA10.
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Evans, Simon, Gray, Marcus A, Dowell, Nicholas G, Tabet, Naji, Tofts, Paul S, King, Sarah L, and Rusted, Jennifer M
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APOLIPOPROTEIN E , *DEMENTIA , *NICOTINE , *PROSPECTIVE memory , *PSYCHOPHARMACOLOGY , *ALZHEIMER'S disease - Abstract
There is evidence to suggest that the APOE ɛ4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ɛ4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ɛ4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ɛ4 from ɛ3 carriers. One BA10 subregion showed greater deactivation in ɛ4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ɛ4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ɛ4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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41. The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area.
- Author
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Buczynski, Matthew W, Polis, Ilham Y, and Parsons, Loren H
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- *
NICOTINE , *ANANDAMIDE , *FATTY acids , *MICRODIALYSIS , *CANNABINOID receptors , *BIOSYNTHESIS - Abstract
Cannabinoid-1 receptors (CB1) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB1 (by AEA and 2-AG) and non-CB1 (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
42. Electrical Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking Behaviors.
- Author
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Pushparaj, Abhiram, Hamani, Clement, Yu, Wilson, Shin, Damian S, Kang, Bin, Nobrega, José N, and Le Foll, Bernard
- Subjects
- *
ELECTRIC stimulation , *NICOTINE , *DRUG administration , *SUBSTANCE abuse relapse , *BRAIN stimulation , *LABORATORY rats , *NEURONS - Abstract
Pharmacological inactivation of the granular insular cortex is able to block nicotine-taking and -seeking behaviors in rats. In this study, we explored the potential of modulating activity in the insular region using electrical stimulation. Animals were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio-5 (FR-5) schedule of reinforcement followed by a progressive ratio (PR) schedule. Evaluation of the effect of stimulation in the insular region was performed on nicotine self-administration under FR-5 and PR schedules, as well on reinstatement of nicotine-seeking behavior induced by nicotine-associated cues or nicotine-priming injections. The effect of stimulation was also examined in brain slices containing insular neurons. Stimulation significantly attenuated nicotine-taking, under both schedules of reinforcement, as well as nicotine-seeking behavior induced by cues and priming. These effects appear to be specific to nicotine-associated behaviors, as stimulation did not have any effect on food-taking behavior. They appear to be anatomically specific, as stimulation surrounding the insular region had no effect on behavior. Stimulation of brain slices containing the insular region was found to inactivate insular neurons. Our results suggest that deep brain stimulation to modulate insular activity should be further explored. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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43. Occupancy of Brain Dopamine D3 Receptors and Drug Craving: A Translational Approach.
- Author
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Mugnaini, Manolo, Iavarone, Laura, Cavallini, Palmina, Griffante, Cristiana, Oliosi, Beatrice, Savoia, Chiara, Beaver, John, Rabiner, Eugenii A, Micheli, Fabrizio, Heidbreder, Christian, Andorn, Anne, Merlo Pich, Emilio, and Bani, Massimo
- Subjects
- *
DOPAMINE , *AUTORADIOGRAPHY , *PHARMACOKINETICS , *NICOTINE , *TETRAHYDRONAPHTHALENE - Abstract
Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) autoradiography and [11C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher OD3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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44. The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders.
- Author
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Grayson, Dennis R and Guidotti, Alessandro
- Subjects
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DNA methylation , *GENETICS of schizophrenia , *MENTAL illness genetics , *METHYLATION , *CHROMATIN , *NICOTINE , *ANTIPSYCHOTIC agents , *ANIMAL models in research - Abstract
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
45. Influence of δ-Opioid Receptors in the Behavioral Effects of Nicotine.
- Author
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Berrendero, Fernando, Plaza-Zabala, Ainhoa, Galeote, Lola, Flores, África, Bura, S Andreea, Kieffer, Brigitte L, and Maldonado, Rafael
- Subjects
- *
BEHAVIOR disorders , *NICOTINE , *LABORATORY mice , *OPIOID receptors , *CONDITIONED response , *DOPAMINERGIC mechanisms - Abstract
Multiple studies in animal models and humans suggest that the endogenous opioid system is an important neurobiological substrate for nicotine addictive properties. In this study, we evaluated the participation of δ-opioid receptors in different behavioral responses of nicotine by using δ-opioid receptor knockout mice. Acute nicotine administration induced hypolocomotion and antinociception in wild-type mice, which were similar in knockout animals. The development of tolerance to nicotine-induced antinociception was also similar in both genotypes. In agreement, the expression and functional activity of δ-opioid receptors were not modified in the different layers of the spinal cord and brain areas evaluated after chronic nicotine treatment. The somatic manifestation of the nicotine withdrawal syndrome precipitated by mecamylamine was also similar in wild-type and δ-opioid receptor knockout mice. In contrast, nicotine induced a conditioned place preference in wild-type animals that was abolished in knockout mice. Moreover, a lower percentage of acquisition of intravenous nicotine self-administration was observed in mice lacking δ-opioid receptors as well as in wild-type mice treated with the selective δ-opioid receptor antagonist naltrindole. Accordingly, in-vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels induced by nicotine in the nucleus accumbens was reduced in mutant mice. In summary, the present results show that δ-opioid receptors are involved in the modulation of nicotine rewarding effects. However, this opioid receptor does not participate either in several acute effects of nicotine or in the development of tolerance and physical dependence induced by chronic nicotine administration. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
46. Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia.
- Author
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Jacklin, Derek L, Goel, Amit, Clementino, Kyle J, Hall, Alexander W M, Talpos, John C, and Winters, Boyer D
- Subjects
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METHYL aspartate receptors , *LABORATORY rats , *NICOTINE , *SCHIZOPHRENIA , *COGNITION disorders , *SENSORY stimulation , *SHORT-term memory - Abstract
Schizophrenia is a complex and debilitating disorder, characterized by positive, negative, and cognitive symptoms. Among the cognitive deficits observed in patients with schizophrenia, recent work has indicated abnormalities in multisensory integration, a process that is important for the formation of comprehensive environmental percepts and for the appropriate guidance of behavior. Very little is known about the neural bases of such multisensory integration deficits, partly because of the lack of viable behavioral tasks to assess this process in animal models. In this study, we used our recently developed rodent cross-modal object recognition (CMOR) task to investigate multisensory integration functions in rats treated sub-chronically with one of two N-methyl-D-aspartate receptor (NMDAR) antagonists, MK-801, or ketamine; such treatment is known to produce schizophrenia-like symptoms. Rats treated with the NMDAR antagonists were impaired on the standard spontaneous object recognition (SOR) task, unimodal (tactile or visual only) versions of SOR, and the CMOR task with intermediate to long retention delays between acquisition and testing phases, but they displayed a selective CMOR task deficit when mnemonic demand was minimized. This selective impairment in multisensory information processing was dose-dependently reversed by acute systemic administration of nicotine. These findings suggest that persistent NMDAR hypofunction may contribute to the multisensory integration deficits observed in patients with schizophrenia and highlight the valuable potential of the CMOR task to facilitate further systematic investigation of the neural bases of, and potential treatments for, this hitherto overlooked aspect of cognitive dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]
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- 2012
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47. Previous Exposure to Nicotine Enhances the Incentive Motivational Effects of Amphetamine via Nicotine-Associated Contextual Stimuli.
- Author
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Cortright, James J, Sampedro, Georgia R, Neugebauer, Nichole M, and Vezina, Paul
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NICOTINE , *CONDITIONED response , *AMPHETAMINES , *LABORATORY rats , *EXTINCTION (Psychology) , *DISCRIMINATION learning - Abstract
The effect of nicotine exposure on the subsequent self-administration of amphetamine, extinction of this behavior, and amphetamine-induced reinstatement of drug seeking was assessed with particular attention to the contribution of contextual stimuli paired or unpaired with nicotine during exposure. Rats were exposed to five injections, one injection every third day, of either saline or nicotine (0.4 mg/kg, IP, base) in three experiments. In one, exposure injections were administered in the home cage. In another, they were administered in the self-administration chambers with the levers retracted. In a third, nicotine was administered either explicitly paired or unpaired with the self-administration chambers using a discrimination learning procedure. Starting 13-15 days later, rats were trained to self-administer amphetamine (100 μg/kg/infusion, IV), tested under a progressive ratio (PR) schedule for 6 days, subjected to up to 20 days of extinction training, and were then tested for reinstatement by non-contingent injections of amphetamine (0, 0.2, 0.4, and 0.75 mg/kg, IP). Nicotine enhanced the self-administration of amphetamine under the PR schedule and amphetamine-induced reinstatement but only when rats were tested in the chamber in which they were previously exposed to nicotine. These effects were not observed in rats exposed to nicotine in the home cage or in rats exposed to nicotine explicitly unpaired with the self-administration chambers. Exposure to nicotine also rendered rats resistant to extinction when amphetamine was withheld but this effect was observed regardless of nicotine exposure context, suggesting a separate consequence of drug exposure. Together, these results show that previous exposure to nicotine can enhance the incentive motivational effects of other psychostimulants like amphetamine and indicate a critical role for nicotine-associated contextual stimuli in the mediation of this effect. These findings have important implications for the treatment of addictions in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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48. Robust Escalation of Nicotine Intake with Extended Access to Nicotine Self-Administration and Intermittent Periods of Abstinence.
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Cohen, Ami, Koob, George F, and George, Olivier
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NICOTINE , *TOBACCO , *CIGARETTE smokers , *TOBACCO smoke , *OXIDASES - Abstract
Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hypothesized that the escalation of nicotine intake may only occur when animals are given extended-access (21 h per day) self-administration sessions after repeated periods of abstinence (24-48 h), and after chronic inhibition of monoamine oxidase using phenelzine sulfate. Intermittent access (every 24-48 h) to extended nicotine self-administration produced a robust escalation of nicotine intake, associated with increased responding under fixed- and progressive-ratio schedules of reinforcement, and increased somatic signs of withdrawal. The escalation of nicotine intake was not observed in rats with intermittent access to limited (1 h per day) nicotine self-administration or daily access to extended (21 h per day) nicotine self-administration. Moreover, inhibition of monoamine oxidase with daily administration of phenelzine increased nicotine intake by ∼50%. These results demonstrate that the escalation of nicotine intake only occurs in animals given intermittent periods of abstinence with extended access to nicotine, and that inhibition of monoamine oxidase may contribute to the escalation of smoking, thus validating both an animal model of the escalation of smoking behavior and the contribution of monoamine oxidase inhibition to compulsive nicotine-seeking. [ABSTRACT FROM AUTHOR]
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- 2012
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49. Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine.
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Sofuoglu, Mehmet, Herman, Aryeh I, Nadim, Haleh, and Jatlow, Peter
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NICOTINE , *CIGARETTE smokers , *PHARMACODYNAMICS , *SMOKING cessation , *VITAL signs - Abstract
The ratio of nicotine metabolites (trans-3′-hydroxycotinine (3HC) to cotinine) correlates with nicotine clearance. In previous studies, high nicotine metabolite ratio (NMR) predicted poor outcomes for smoking cessation treatment with nicotine patch. The underlying mechanisms that associate NMR with treatment outcomes have not been fully elucidated. A total of 100 smokers were divided into quartiles based on their baseline plasma NMR. Following overnight abstinence, smokers received saline followed by escalating intravenous doses of nicotine (0.5 and 1.0 mg/70 kg) given 30 min apart. The effects of nicotine on subjective, plasma cortisol, heart rate, and systolic and diastolic blood pressure measures were obtained. Smokers in the first NMR quartile (slower metabolizers) had lower Fagerstrom Test for Nicotine Dependence (FTND) scores, suggesting lower levels of dependence. In contrast, smokers in the fourth NMR quartile (faster metabolizers) reported greater craving for cigarettes following overnight abstinence from smoking and reported greater ratings of nicotine-induced good drug effects, drug liking, and wanting more drug. Higher NMR was also associated with greater heart rate increases in response to nicotine. These results suggest that enhanced nicotine reward and cigarette craving may contribute to the poor treatment response in smokers with high NMR. These findings warrant further investigation, especially in treatment-seeking smokers undergoing cessation treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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50. Inhibitory Inputs from Rostromedial Tegmental Neurons Regulate Spontaneous Activity of Midbrain Dopamine Cells and Their Responses to Drugs of Abuse.
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Lecca, Salvatore, Melis, Miriam, Luchicchi, Antonio, Muntoni, Anna Lisa, and Pistis, Marco
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NEURONS , *DOPAMINE , *MESENCEPHALON , *DRUGS of abuse , *NICOTINE - Abstract
The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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