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Background: Methamphetamine (METH) is a psychostimulant drug that remains a popular and threatening drug of abuse with high abuse liability. There is no established pharmacotherapy to treat METH dependence, but evidence suggests that stimulation of adenosine receptors reduces the reinforcing properties of METH and could be a potential pharmacological target. This study examines the effects of adenosine receptor subtype stimulation on METH seeking using both a cue-induced reinstatement and cue-craving model of relapse. Methods: Male and female rats were trained to self-administer METH during daily 2-h sessions. Cue-induced reinstatement of METH seeking was evaluated after extinction training. A systemic pretreatment of an adenosine A1 receptor (A1R) or A2A receptor (A2AR) agonist was administered prior to an extinction or cue session to evaluate the effects of adenosine receptor subtype stimulation on METH seeking. The effects of a systemic pretreatment of A1R or A2AR agonists were also evaluated in a cue-craving model where the cued-seeking test was conducted after 21 days of forced home-cage abstinence without extinction training. Results: Cue-induced reinstatement was reduced in both male and female rats that received A1R or A2AR agonist pretreatments. Similarly, an A1R or A2AR agonist pretreatment also inhibited cue craving in both male and female rats. Conclusion: Stimulation of either adenosine A1R or A2AR subtypes inhibits METH-seeking behavior elicited by METH-associated cues. These effects may be attributed to the ability of A1R and A2AR stimulation to disrupt cue-induced dopamine and glutamate signaling throughout the brain. [ABSTRACT FROM AUTHOR]

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration. [ABSTRACT FROM AUTHOR]

Background: α7 Nicotinic acetylcholine receptors are implicated in the reinstatement of drug-seeking, an important component of relapse. We showed previously that the α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, specifically attenuated morphine-primed reinstatement of conditioned place preference in rodents and this effect was mediated in the ventral hippocampus. Aims: The purpose of this study was to evaluate α7 nicotinic acetylcholine receptor antagonism in reinstatement of the conditioned place preference for the more widely abused opioid, heroin, and to compare the effect of α7 nicotinic acetylcholine receptor blockade on reinstatement of heroin-seeking and heroin self-administration in an intravenous self-administration model of addictive behaviour. Methods: Rats were trained to acquire heroin conditioned place preference or heroin self-administration; both followed by extinction of responding. Methyllycaconitine or saline was given prior to reinstatement of drug-primed conditioned place preference, or drug-prime plus cue-induced reinstatement of intravenous self-administration, using two protocols: without delivery of heroin in response to lever pressing to model heroin-seeking, or with heroin self-administration, using fixed and progressive ratio reward schedules, to model relapse. Results: Methyllycaconitine had no effect on acquisition of heroin conditioned place preference or lever-pressing for food rewards. Methyllycaconitine blocked reinstatement of heroin-primed conditioned place preference. Methyllycaconitine did not prevent drug-prime plus cue-induced reinstatement of heroin-seeking, reinstatement of heroin self-administration, or diminish the reinforcing effect of heroin. Conclusions: The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, prevented reinstatement of the opioid conditioned place preference, consistent with a role for α7 nicotinic acetylcholine receptors in the retrieval of associative memories of drug liking. The lack of effect of methyllycaconitine in heroin-dependent rats in two intravenous self-administration models suggests that α7 nicotinic acetylcholine receptors do not play a role in later stages of heroin abuse. [ABSTRACT FROM AUTHOR]

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females. [ABSTRACT FROM AUTHOR]

The US geriatric population is growing and using more opioids than ever before. The purpose of this study was to determine whether aging influenced the reinforcing efficacy of morphine in male and female rats using a rodent intravenous self-administration paradigm. Male and female aged (20–24 months) and young (2–4 months) Wistar rats were tested at 2 doses of morphine (0.75 mg/kg/infusion and 0.25 mg/kg/infusion). During 10 days of self-administration, aged rats took significantly less morphine than their younger counterparts at the 0.25 mg/kg/infusion dose. Aged males also earned significantly fewer infusions on a progressive ration reinforcement schedule at this dose, suggesting that the reinforcing efficacy of morphine is decreased for this group at this dose. These effects dissipated when a separate group of animals had access to the 0.75 mg/kg/infusion dose for both sexes. Our results indicate that morphine is less reinforcing at lower doses in aged male, but not female rats. This research has potential clinical implications for the chronic treatments involving opioids in aged individuals. • Aging reduced morphine self-administration in male and female Wistar rats. • Aged males had decreased responding on a progressive ratio at low dose of morphine. • At higher dose of morphine, self-administration is unchanged by age. • Aging decreases sensitivity to the reinforcing properties of morphine. [ABSTRACT FROM AUTHOR]

Rationale: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors. Objectives: Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine. Methods: Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors. Results: RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content. Conclusions: These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine. [ABSTRACT FROM AUTHOR]

Adolescent stress is a risk factor for the initiation of nicotine use, but whether adolescent stress can enhance nicotine reinforcement when it is initiated later in adulthood is unknown, and it is unclear whether males and females are equally impacted. Therefore, this study assessed physiological responses (body weight and blood serum corticosterone – CORT) to restraint stress (RS) during adolescence (P28–55) or during adulthood (P70–96) in male and female Sprague-Dawley rats. When all subjects reached adulthood (P69 or 110; 2 weeks after termination of stress exposure), they were tested on sucrose preference and intravenous single-dose nicotine (0.03 mg/kg/infusion) self-administration. It was found that all rats displayed a significant CORT response to RS. Importantly, stress during adolescence, but not during adulthood, enhanced subsequent acquisition of nicotine intake tested in adulthood. Although this effect was observed in both sexes, only males displayed reduced body weight gain and adult sucrose preference. Moreover, regardless of stress exposure, females were more stimulated by nicotine, consumed more nicotine overall, and displayed enhanced nicotine seeking. These results suggest that adolescence is a period of heightened sensitivity to the enhancing effect of repeated stress on the susceptibility to develop nicotine dependence later in life in both sexes. • Adolescent restraint stress augments adult nicotine reinforcement in both sexes. • Regardless of stress or age, females show enhanced vulnerability to nicotine use. • Stress, sex, and age interact to produce resilience in adult stressed females. • Adolescent stressed males also show reduced weight and adult sucrose preference. [ABSTRACT FROM AUTHOR]

Nicotine is acknowledged as the key addictive compound of tobacco. Varenicline (Champix® or Chantix®), mainly acting as a partial agonist at the α4β2 nicotinic receptor, is an approved smoking cessation pharmacotherapy, although with efficacy limited to a portion of smokers. Smokers differ in the motives that drive their drug seeking and Varenicline might be more efficient in some groups more than others. Studies in rodents revealed that nicotine-seeking is strongly supported by complex interactions between nicotine and environmental cues, and notably the ability of nicotine to enhance the reinforcing properties of salient environmental stimuli. It is not yet understood whether the decrease of nicotine-seeking by acute Varenicline in rats results from antagonism of the primary reinforcing effects of nicotine, of the reinforcement-enhancing effect of nicotine on cues, or of a combination of both. Thanks to a protocol that allows assessment of the reinforcement-enhancing effect of nicotine on cues during self-administration in rats, we showed that Varenicline targets both nicotine reinforcing effects and reinforcement-enhancing effect of nicotine on cues. Importantly, individual variations in the latter determined the amplitude of acute Varenicline-induced decrease in seeking. These results suggest that Varenicline might be more beneficial in smokers who are more sensitive to nicotine effects on surrounding stimuli.

Nicotine is acknowledged as the key addictive compound of tobacco. Varenicline (Champix® or Chantix®), mainly acting as a partial agonist at the α4β2 nicotinic receptor, is an approved smoking cessation pharmacotherapy, although with efficacy limited to a portion of smokers. Smokers differ in the motives that drive their drug seeking and Varenicline might be more efficient in some groups more than others. Studies in rodents revealed that nicotine-seeking is strongly supported by complex interactions between nicotine and environmental cues, and notably the ability of nicotine to enhance the reinforcing properties of salient environmental stimuli. It is not yet understood whether the decrease of nicotine-seeking by acute Varenicline in rats results from antagonism of the primary reinforcing effects of nicotine, of the reinforcement-enhancing effect of nicotine on cues, or of a combination of both. Thanks to a protocol that allows assessment of the reinforcement-enhancing effect of nicotine on cues during self-administration in rats, we showed that Varenicline targets both nicotine reinforcing effects and reinforcement-enhancing effect of nicotine on cues. Importantly, individual variations in the latter determined the amplitude of acute Varenicline-induced decrease in seeking. These results suggest that Varenicline might be more beneficial in smokers who are more sensitive to nicotine effects on surrounding stimuli. [ABSTRACT FROM AUTHOR]

Highlights • Rats with prenatal ethanol exposure display higher locomotor responses to novelty. • Rats with prenatal ethanol exposure show greater amphetamine conditioned place preference. • Rats with prenatal ethanol exposure self-administer more amphetamine. • No group differences are observed at higher amphetamine doses. • Rats with prenatal ethanol exposure exhibit amphetamine-induced reinstatement. Abstract Prenatal ethanol exposure (PE) causes many cognitive and behavioral deficits including increased drug addiction risk, demonstrated by enhanced ethanol intake and behavioral phenotypes associated with addiction risk. Additionally, preclinical studies show that PE persistently changes the function of dopaminergic neurons in the ventral tegmental area, a major neural substrate for addiction, and alters these neurons' responses to psychostimulants. Accordingly, PE could also lead to increased risk of addiction to drugs of abuse, other than ethanol. In the present study, addiction risk was examined utilizing paradigms of amphetamine conditioned place preference (CPP) and intravenous self-administration. Ethanol was administered to pregnant dams via intragastric gavage (6 g/kg, during gestational days 8–20). Behavioral tests were conducted in adult male offspring. Amphetamine at a low dose (0.3 mg/kg, i.p.) induced CPP in PE but not control rats, whereas at a higher dose (0.6 mg/kg, i.p.) both groups acquired CPP. There was no group difference in amphetamine-induced CPP reinstatement. Furthermore, PE rats self-administered more amphetamine at a low dose (0.02 mg/kg/infusion) than controls, while no group differences were observed at a higher dose (0.1 mg/kg/infusion). Rats with PE also exhibited greater reactivity to contextual drug cues after extended abstinence and amphetamine-induced reinstatement of drug seeking. These results support that PE persistently leads to increased psychostimulant addiction risk later in life, manifested in many elements of addictive behavior following limited psychostimulant exposure. The observations provide insights into prevention strategies for drug addiction in individuals with fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]

Rationale: Nicotine can enhance attention and attribution of incentive salience to nicotine-associated stimuli. However, it is not clear whether inter-individual differences in attentional capacities prior to any exposure could play a role in vulnerability to nicotine self-administration. We further explored this vulnerability through pre-existing inter-individual differences in attention to a reward-predictive cue in drug-free animals.Methods: A cued version of the Fixed Consecutive Number schedule (FCN16cue) of reinforcement task was used to assess attention. This task consists in completing a long chain of sequential lever presses to obtain a reward, and examines the rats’ ability to pay attention to a cue light that signals its availability. Rats were then trained to self-administer nicotine intravenously (30 μg/kg/0.1 mL). Drug-taking and seeking behaviors were investigated.Results: Our results showed important inter-individual differences in response for nicotine during the progressive ratio schedule of reinforcement. By comparing rats in the lower and upper quartiles of the mean breaking point, we showed that high-motivated rats were also more sensitive to the reinforcing properties of nicotine than low-motivated ones. We found that while both groups did not differ in premature responding in the FCN16cue task, high-motivated rats were more efficient in taking the cue light into account than low-motivated rats as shown by a higher proportion of optimal chains, indicating a higher level of attention to the reward-predictive cue. Moreover, it was positively correlated with higher motivation for nicotine, a hallmark of nicotine addiction.Conclusions: These results suggest that higher attention to reward-associated cues prior to drug taking predicts vulnerability to nicotine-reinforcing properties. [ABSTRACT FROM AUTHOR]

Each of the co-authors worked with Athina Markou, at different stages of our careers and in different capacities, to develop, optimize, and use animal models of drug addiction and, more generally, mental health disorders such as anxiety, depression, and schizophrenia. Here, we briefly summarize some of our work with Athina, primarily involving the use of the intracranial self-stimulation and intravenous drug self-administration procedures. This work established that excessive consumption of addictive drugs can induce profound dysfunction in brain reward circuits. Such drug-induced reward deficits are likely to play a key role in precipitating the emergence of compulsive drug-seeking behaviors. We also summarize findings suggesting that perturbations in glutamatergic transmission contribute to brain reward deficits in drug-dependent animals and that metabotropic glutamate receptors are potential targets for the development of novel medications to facilitate long-term drug abstinence and prevention of relapse. [ABSTRACT FROM AUTHOR]

Rationale Initial sensitivity to drugs of abuse often predicts subsequent use and abuse, but this relationship is not always observed in human studies. Moreover, studies examining the relationship between initial locomotor sensitivity and the rewarding and reinforcing effects of drugs in animal models have also been equivocal. Understanding the relationship between initial drug effects and propensity to continue use, potentially resulting in the development of a substance use disorder, may help to identify key targets for prevention and treatment. Objectives We examined intravenous cocaine self-administration in a set of mouse strains that were previously identified to be at the phenotypic extremes for cocaine-induced locomotor activation to determine if initial locomotor sensitivity predicted acquisition, extinction, dose response, or progressive ratio (PR) breakpoint. Methods We selected eight inbred mouse strains based on locomotor sensitivity to 20 mg/kg cocaine. These strains, designated as low and high responders, were tested in an intravenous self-administration paradigm that included acquisition of 0.5 mg/ (kg*inf) under a FR1 schedule, extinction, re-acquisition, dose response to 0.125, 0.25, 0.5, 1, and 2 mg/(kg*inf), and progressive ratio. Results We observed overall differences in self-administration behavior between high and low responders. Low responders selfadministered less cocaine and had lower breakpoints under the PR schedule. However, we also observed strain differences within each group. Self-administration in the low responder, LG/J, more closely resembled the behavior of the high-responding group, and the high responder, P/J, had self-administration behavior that more closely resembled the low-responding group. Conclusions We conclude that acute cocaine-induced locomotor activation does predict self-administration behavior, but in a strain-specific manner. These data support the idea that genetic background influences the relationship among addiction-related behaviors. [ABSTRACT FROM AUTHOR]

Alcohol is consumed orally by humans, and oral self-administration has been successfully modeled in laboratory animals. Over the last several years, attempts have been made to develop a procedure for the reliable intravenous (IV) self-administration of alcohol in rodents. IV self-administration would provide a better tool for investigating neurobiological mechanisms of alcohol reinforcement and dependence because confounding factors associated with oral self-administration, such as variations in orosensory sensitivity to alcohol and/or its absorption, are avoided. A review of the literature shows that rats, mice and non-human primates can initiate and maintain IV self-administration of alcohol. However, there are 50- to 100-fold interspecies differences in the reported alcohol infusion doses required. Most surprising is that the infusion dose (1-2 mg/kg) that reliably maintains IV alcohol self-administration in rats results in total alcohol intakes of only 20-25 mg/kg/hour, which are unlikely to have significant pharmacological effects. The evidence to support IV self-administration of such low doses of alcohol in rats as well as the potential biological mechanisms underlying such self-administration are discussed. The minute amounts of alcohol shown to reliably maintain IV self-administration behavior in rats challenge the relationship between their blood alcohol levels and the rewarding and reinforcing effects of alcohol. [ABSTRACT FROM AUTHOR]

Addiction is often characterized by intense motivation for a drug, which may be narrowly focused at the expense of other rewards. Here, we examined the role of amygdala-related circuitry in the amplification and narrowing of motivation focus for intravenous cocaine. We paired optogenetic channelrhodopsin (ChR2) stimulation in either central nucleus of amygdala (CeA) or basolateral amygdala (BLA) of female rats with one particular nose-poke porthole option for earning cocaine infusions (0.3 nig/kg, i.v.). A second alternative porthole earned identical cocaine but without ChR2 stimulation. Consequently, CeA rats quickly came to pursue their CeA ChR2-paired cocaine option intensely and exclusively, elevating cocaine intake while ignoring their alternative cocaine alone option. By comparison, BLA ChR2 pairing failed to enhance cocaine motivation. CeA rats also emitted consummatory bites toward their laser-paired porthole, suggesting that higher incentive salience made that cue more attractive. A separate progressive ratio test of incentive motivation confirmed that CeA ChR2 amplified rats' motivation, raising their breakpoint effort price for cocaine by 10-fold. However, CeA ChR2 laser on its own lacked any reinforcement value: laser by itself was never self-stimulated, not even by the same rats in which it amplified motivation for cocaine. Conversely, CeA inhibition by muscimol/baclofen microinjections prevented acquisition of cocaine selfadministration and laser preference, whereas CeA inhibition by optogenetic halorhodopsin suppressed cocaine intake, indicating that CeA circuitry is needed for ordinary cocaine motivation. We conclude that CeA ChR2 excitation paired with a cocaine option specifically focuses and amplifies motivation to produce intense pursuit and consumption focused on that single target. [ABSTRACT FROM AUTHOR]

Background Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated. Methods Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 hour; ShA) or long (6 hours; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. In addition, using electrophysiological techniques on in vitro slices, we investigated gamma-aminobutyric acidergic (GABAergic) neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats. Results We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose dependently decreased cocaine intake specifically in LgA rats but not in ShA rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking after intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867 (10 μmol/L). Conclusions These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking. [ABSTRACT FROM AUTHOR]

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, dark net) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society (UNODC, World Drug Report, 2014; EMCDDA, European Drug Report 2014: Trends and developments). The chemical structure (phenethylamines, piperazine, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%)(WDR, 2014). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone and MDMA analogues). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with Spice use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

Background Glucagon-like peptide 1 ( GLP-1) receptor agonists have been shown to decrease ethanol (EtOH) drinking in rodent assays. The GLP-1 system also powerfully modulates food and fluid intake, gastrointestinal functions, and metabolism. To begin to understand the neurobiological mechanisms by which GLP-1 receptor ligands may be able to control EtOH intake, it is important to ascertain whether they can modulate the direct reinforcing effects of EtOH, without the confound of effects on ingestive behaviors generally. Methods We trained experimentally naïve, free-fed C57 BL/6J mice to self-administer EtOH intravenously. Once stable EtOH intake was acquired, we tested the effect of acute pretreatment with the GLP-1 receptor agonist Exendin-4. Effect of Exendin-4 on operant behavior reinforced by a palatable liquid food was similarly evaluated as a control. Results Intravenous EtOH functioned as a positive reinforcer in over half the mice tested. In mice that acquired self-administration, EtOH intake was high, indeed, reaching toxic doses; 3.2 μg/kg Exendin-4 decreased intravenous EtOH intake by at least 70%, but had no significant effect on food-maintained operant responding. Conclusions This experiment produced 2 main conclusions. First, although technically challenging and yielding only moderate throughput, the intravenous self-administration procedure in mice is feasible, and sensitive to pharmacological manipulations. Second, GLP-1 receptor agonists can powerfully attenuate voluntary EtOH intake by directly modulating the reinforcing effects of EtOH. These findings support the potential usefulness of GLP-1 receptor ligands in the treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Rationale: The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB and CB receptors, CBRs and CBRs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CBR and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown. Objective: The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CBR, CBR, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats. Results: URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CBR antagonist rimonabant, but not by the CBR or PPARα antagonists AM630 and MK886, respectively. Conclusions: These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB receptor-dependent mechanism, and not via CBR or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction. [ABSTRACT FROM AUTHOR]

Addiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2 A ) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2 A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates; yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2 A knockout (KO) mice to assess the role of A2 A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2 A KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A2 A KO mice in a dose-related manner. METH intravenous self-administration was intact in A2 A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A2 A KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A2 A KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A2 A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2 A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards. [ABSTRACT FROM AUTHOR]

Rationale: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. Objectives: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. Methods: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. Results: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. Conclusions: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex. [ABSTRACT FROM AUTHOR]

Rationale: Rapid drug delivery to the brain might increase the risk for developing addiction. In rats, increasing the speed of intravenous cocaine delivery (5 vs. 90 s) increases drug intake and the subsequent motivation to self-administer cocaine. Increased motivation for cocaine could result not only from more extensive prior drug intake and operant responding for drug, but also from neuroplasticity evoked by rapid drug uptake. Objective: We determined the contributions of prior drug intake and operant responding to the increased motivation for cocaine evoked by rapid delivery. We also investigated the effects of cocaine delivery speed on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) mRNA. Methods: Rats self-administered cocaine (0.25 mg/kg/infusion) delivered over 5 or 90 s during short-access (1 h/session; ShA) or long-access (6 h; LgA) sessions. Motivation for cocaine was then assessed by measuring responding under a progressive ratio schedule of reinforcement. Next, BDNF and TrkB mRNA levels were measured in 5- and 90-s rats. Results: Five-second ShA and 5-s-LgA rats were more motivated for cocaine than their 90-s counterparts. This effect was dissociable from previous levels of drug intake or of operant responding for cocaine. In parallel, only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels in corticostriatal regions. Conclusions: Rapid drug delivery augments the motivation for cocaine independently of effects on the levels of drug intake or operant responding for drug. We suggest that rapid delivery might increase the motivation for drug by promoting neuroplasticity within reward pathways. This neuroplasticity could involve increased regulation of BDNF/TrkB. [ABSTRACT FROM AUTHOR]

Nicotine addiction is characterized by repetitive drug taking and drug seeking, both tightly controlled by cannabinoid CB1 receptors. The responsiveness of neurons of the bed nucleus of the stria terminalis (BNST) to infralimbic cortex (ILCx) excitatory inputs is increased in rats with active, but not passive, nicotine taking. Therefore,wehypothesize that acquisition of the learned association between nicotine infusion and a paired cue light permits the strengthening of the ILCx-BNST synapses after ILCx tetanic stimulation. We exposed rats to intravenous nicotine self-administration for 2 months. Using a combination of in vivo protocols (electrical stimulations, extracellular recordings, and pharmacological manipulations), we characterized the effects of 10 Hz stimulation of the ILCx on BNST excitatory responses, under different conditions of exposure to nicotine. In addition, we tested whether the effects of the stimulation were CB1 receptor-dependent. The results show that nicotine self-administration supports the induction of evoked spike potentiation in the BNST in response to 10 Hz stimulation of ILCx afferents. Although not altered by nicotine abstinence, this cellular adaptation was blocked by CB1 receptor antagonism. Moreover, blockade of BNST CB1 receptors prevented increases in time-out responding subsequent to ILCx stimulation and decreased cue-induced reinstatement. Thus, the synaptic potentiation within the BNST in response to ILCx stimulation seems to contribute to the cue-elicited responding associated with nicotine self-administration and is tightly controlled by CB1 receptors. [ABSTRACT FROM AUTHOR]

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as 'bath salts' or 'legal highs', have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4-methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self-administration and to lower thresholds for intracranial self-stimulation (ICSS) in rats. In the first experiment, the rats were trained to intravenously self-administer MDPV in daily 2-hour sessions for 10 days at doses of 0.05, 0.1 or 0.2 mg/kg per infusion. The rats were then allowed to self-administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, the rats self-administered MDPV for an additional 10 days under short access (ShA; 2 hours/day) or long access (LgA; 6 hours/day) conditions to assess escalation of intake. A separate group of rats underwent the same procedures, with the exception of self-administering methamphetamine (0.05 mg/kg per infusion) instead of MDPV. In the second experiment, the effects of MDPV on ICSS thresholds following acute administration (0.1, 0.5, 1 and 2 mg/kg, i.p.) were assessed. MDPV maintained self-administration across all doses tested. A positive relationship between MDPV dose and breakpoints for reinforcement under PR conditions was observed. LgA conditions led to escalation of drug intake at 0.1 and 0.2 mg/kg doses, and rats self-administering methamphetamine showed similar patterns of escalation. Finally, MDPV significantly lowered ICSS thresholds at all doses tested. Together, these findings indicate that MDPV has reinforcing properties and activates brain reward circuitry, suggesting a potential for abuse and addiction in humans. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the effect of repeated contingent opioid exposure on striatal medium spiny neurons (MSNs) in D1- and D2-GFP expressing mice. [•] Mice were trained to self-administer remifentanil, a mu opioid receptor agonist. [•] Once stable self-administration was obtained, electrophysiology recordings were done. [•] Mu receptors pre-synaptic to D1-, but not D2-, MSNs demonstrated reduced sensitivity. [•] This finding suggests a specific adaptation of D1-MSNs after opiate self-administration. [ABSTRACT FROM AUTHOR]

Cannabinoid type 1 ( CB1) receptors control the motivational properties and reinforcing effects of nicotine. Indeed, peripheral administration of a CB1 receptor antagonist dramatically decreases both nicotine taking and seeking. However, the neural substrates through which the cannabinoid CB1 receptors regulate the voluntary intake of nicotine remain to be elucidated. In the present study, we sought to determine whether central injections of a CB1 receptor antagonist delivered either into the ventral tegmental area ( VTA) or the nucleus accumbens ( NAC) may alter nicotine intravenous self-administration ( IVSA). Rats were first trained to self-administer nicotine (30 μg/kg/0.1 ml). The effect of central infusions of the CB1 antagonist AM 251 (0, 1 and 10 μg/0.5 μl/side) on nicotine-taking behavior was then tested. Intra- VTA infusions of AM 251 dose dependently reduced IVSA with a significant decrease for the dose 10 μg/0.5 μl/side. Moreover, operant responding for water was unaltered by intra- VTA AM 251 at the same dose. Surprisingly, intra- NAC delivery of AM 251 did not alter nicotine behavior at all. These data suggest that in rats chronically exposed to nicotine IVSA, the cannabinoid CB1 receptors located in the VTA rather than in the NAC specifically control nicotine reinforcement and, subsequently, nicotine-taking behavior. [ABSTRACT FROM AUTHOR]

ABSTRACT Several lines of evidence suggest that there may be a shared vulnerability to acquire behaviors motivated by strong incentive stimuli. Non-food restricted male Sprague-Dawley rats ( n = 78) underwent place conditioning with Oreos, and were subsequently tested on cocaine self-administration (SA) on fixed and progressive ratios, as well as extinction and reinstatement by cocaine primes and by consumption of Oreos. Although there was a group preference for the Oreo-paired compartment, at the individual level some rats (69%) displayed a preference and others did not. In cocaine SA, 'preference' rats achieved higher break points on a progressive ratio, and displayed greater responding during extinction and cocaine-induced reinstatement. Within the context of this study, Oreo-cocaine cross-reinstatement was not observed. In a control study, rats ( n = 29) conditioned with a less palatable food (rice cakes) also displayed individual differences in place preference, but not on subsequent cocaine tests. These findings indicate that there is a relationship between incentive learning promoted by palatable foods and by cocaine. This supports the hypothesis that co-morbid food-drug addictions may result from a shared vulnerability to acquire behaviors motivated by strong incentives. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The modulatory activity of the orphan receptor GPR3 in the brain has been related to the control of emotional behaviours. Limbic structures that express GPR3 have been associated with the effects of drug abuse. EXPERIMENTAL APPROACH The role of GPR3 in different cocaine-elicited behaviours including locomotor activity, behavioural sensitization, conditioned place preference (CPP) and intravenous self-administration was evaluated in Gpr3-/- mice and their Gpr3+/+ littermates. Cocaine-induced dopamine release in the nucleus accumbens was also evaluated to elucidate the effect of Gpr3 deletion on extracellular levels of dopamine. KEY RESULTS Gpr3-/- mice exhibited higher rewarding responses in the CPP paradigm. Gpr3-/- mice self-administered more cocaine, especially during the first days of training. No differences were found between genotypes regarding behavioural sensitization and the maximal effort required to obtain a cocaine infusion. Non-contingent priming injections of cocaine before operant training eliminated enhanced cocaine self-administration in Gpr3-/- mice. Extracellular levels of dopamine in the nucleus accumbens induced by cocaine did not differ between genotypes. CONCLUSIONS AND IMPLICATIONS The increased responsiveness of Gpr3-/- mice to the acute locomotor effects of cocaine and the inconsistency to further increase this effect reflected an 'already maximally sensitized' basal state. Enhanced responsiveness of Gpr3-/- mice to cocaine reward and to early phases of reinforcement suggests that an initial alteration increased vulnerability to this type of drug abuse. Overall, altered signalling pathways of GPR3 could contribute to the neurobiological substrate involved in developing addiction to cocaine. [ABSTRACT FROM AUTHOR]

Considerable evidence suggests that transmission at hypocretin-1 (orexin-1) receptors (Hcrt-R1) plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV) cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg) dose-dependently decreased cocaine (0.5 mg/kg/infusion) self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg) also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg) on brain reward systems, as measured by reversal of cocaine-induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts. [ABSTRACT FROM AUTHOR]

Rationale: The antidepressant nortriptyline is a second-line pharmacotherapy for smoking cessation. Given that there is limited preclinical data available on the effects of nortriptyline on responses to nicotine, the present study sought to evaluate its effects on the reinforcing, discriminative stimulus (DS) and aversive effects of nicotine in male hooded Lister rats. Methods: The effects of nortriptyline (0, 1, 3 and 10 mg/kg, i.p.) on responding under the control of a second order schedule of nicotine (0.03 mg/kg per infusion) intravenous self-administration (IVSA; n = 7), food-maintained responding ( n = 6), discrimination of nicotine (0.2 mg/kg, s.c.) from saline in a two-lever procedure controlled by a fixed ratio and variable interval schedule of food reinforcement ( n = 12) and on the development of nicotine- and lithium-induced conditioned taste aversions (CTA) ( n = 8 per dose of nortriptyline) were examined. Results: Nortriptyline (3 mg/kg) reduced responding for nicotine in the drug-free interval in which behaviour was supported by nicotine-associated cues and subsequent intervals in which nicotine was available; however, food-maintained responding was also reduced at the same dose. Nortriptyline (3 mg/kg) blocked the development of a nicotine-induced CTA but not a lithium-induced CTA, indicating that these effects are unlikely to be due to non-specific effects of nortriptyline on taste perception or learning. Lastly, nortriptyline had no effect on the DS properties of nicotine. Conclusions: Nortriptyline appears to attenuate the reinforcing and aversive stimulus properties of nicotine, which may mediate its anti-smoking effects. However, the results should be interpreted with caution, as non-specific effects of nortriptyline may have contributed to these findings. [ABSTRACT FROM AUTHOR]

Abstract: Tobacco smoking is one of the leading causes of disease and premature death in the United States. Nicotine is considered the major reinforcing component in tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits. The α4β2 nAChRs, particularly those located in the mesoaccumbens dopamine pathway, play a key role in regulating the reinforcing properties of nicotine. Considering that twelve mammalian nAChR subunits have been cloned, it is likely that nAChRs containing subunits in addition to, or other than, α4 and β2 also play a role in the tobacco smoking habit. Consistent with this possibility, human genome-wide association studies have shown that genetic variation in the CHRNA5–CHRNA3–CHRNB4 gene cluster located in chromosome region 15q25, which encode the α5, α3 and β4 nAChR subunits, respectively, increases vulnerability to tobacco addiction and smoking-related diseases. Most recently, α5-containing nAChRs located in the habenulo-interpeduncular tract were shown to limit intravenous nicotine self-administration behavior in rats and mice, suggesting that deficits in α5-containing nAChR signaling in the habenulo-interpeduncular tract increases vulnerability to the motivational properties of nicotine. Finally, evidence suggests that nAChRs may also play a prominent role in controlling consumption of addictive drugs other than nicotine, including cocaine, alcohol, opiates and cannabinoids. The aim of the present review is to discuss recent preclinical findings concerning the identity of the nAChR subtypes that regulate self-administration of nicotine and other drugs of abuse. [Copyright &y& Elsevier]

Rationale: Exposure to intermittent episodes of social defeat stress can increase drug seeking and leads to intense drug taking in rats. Objectives: This study investigated the consequences of repeated, intermittent social defeat stress on patterns of drug self-administration in rats with access to heroin, cocaine, or a heroin-cocaine combination ('speedball'). Methods: Male Long-Evans rats were either handled (controls) or subjected to 25-min social defeat stress episodes on days 1, 4, 7, and 10 during confrontations with an aggressive resident. Ten days following the last defeat, rats were assessed for locomotor cross-sensitization in response to heroin or cocaine. Animals were then prepared with intrajugular catheters for drug self-administration. Separate groups of controls and defeated rats were examined for self-administration of heroin (experiment 1), a heroin-cocaine combination (experiment 2), or cocaine (experiment 3). Drug self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement during limited access sessions or a 24-h unlimited access binge. Results: Rats with a history of intermittent social defeat stress showed sensitized locomotor behavior when challenged with heroin or cocaine relative to controls. During the 24-h binge session, defeated rats escalated cocaine-taking behavior (ca. 110 mg/kg vs. 66 mg/kg in controls), persisted in self-administering cocaine or the heroin-cocaine mixture for more hours, and showed a tendency for increased heroin-cocaine intake, but no effects on heroin taking. Conclusions: A history of social defeat stress seems to preferentially promote escalated intake of cocaine but not heroin, unless a heroin-cocaine combination is available. [ABSTRACT FROM AUTHOR]

Rationale: The neural and psychological mechanisms underlying vulnerability to drug addiction are poorly understood. Although a number of animal models have been developed to investigate vulnerability to stimulant addiction, few have considered how vulnerability traits such as impulsivity predict hallmark features of heroin addiction including the escalation of drug intake and increased propensity for relapse following protracted abstinence. Objective: The aim of this study was to investigate whether high impulsivity in rats predicts the propensity to escalate intravenous heroin self-administration and to relapse following an extended withdrawal period from heroin. Methods: High (HI)- and low (LI)-impulsive rats, defined by the extent of premature responding on the 5-choice serial reaction time test (5-CSRTT), were catheterized and allowed to self-administer heroin (40 μg/100 μl/infusion). After 5 days of short access (1 h/day) to heroin, rats were then given extended (6 h/day) access to heroin for 18 consecutive days. Results: High impulsivity predicted neither a greater tendency to acquire heroin SA nor an increased escalation of heroin self-administration. Moreover, high impulsivity was not associated with an increased propensity to relapse after protracted withdrawal from heroin. Nevertheless, marked inter-individual differences in the escalation of heroin self-administration were observed. Conclusions: Although high impulsivity on the 5-CSRTT has been shown to predict loss of control over cocaine intake, this does not generalize to a loss of control over heroin self-administration. These findings suggest important distinctions in vulnerability mechanisms underlying cocaine and heroin addiction with trait-like impulsivity playing a role in stimulant but not opiate addiction. [ABSTRACT FROM AUTHOR]

Abstract: Maternal cigarette smoking during pregnancy can result in behavioural problems of the offspring. Although the causative agent in tobacco smoke that leads to these aberrations is not known, some studies using animal models have supported the hypothesis that nicotine may cause impairments in fatal and neonatal development. However, in many of the animal studies nicotine has been administered by subcutaneous injections, which could lead to significant fetal hypoxia; some routes of drug administration included stressful procedures to pregnant dams that could create unfavorable fetal environment. In this study, mice were exposed to nicotine via drinking solution. The effects of nicotine exposure throughout early development on behavioural measures during adolescence and adulthood were examined. Adult female dams were allowed to orally self-administer a saccharin, or nicotine plus saccharin solution during gestation and lactation. Following weaning, plasma nicotine concentrations were measured in nicotine-exposed dams, and their offspring were tested using various behavioural measures. [3H]Epibatidine binding was also measured in the cortex and hippocampus at two different time points in the nicotine-exposed adolescents. The results of the study indicate that exposure to nicotine throughout early development influenced intravenous nicotine self-administration, social interactions and performance under a forced swim test. Exposure throughout early development to nicotine however did not affect [3H]epibatidine binding in the hippocampus and cortex. [Copyright &y& Elsevier]

Corticosterone, the main glucorticoid hormone in rodents, facilitates behavioral responses to cocaine. Corticosterone is proposed to modulate cocaine intravenous self-administration (SA) and cocaine-induced locomotion through distinct receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), respectively. However, this remains debatable. On one hand, modulation of both responses by the GR was tested in different experimental conditions, i.e. light versus dark nycthemeral phase and naïve versus cocaine-experienced animals. On the other hand, modulation of both responses by the MR was never tested directly but only inferred based on the ability of low plasma corticosterone levels (those for which corticosterone almost exclusively binds the MR) to compensate the effects of adrenalectomy. Our goal here was to test the involvement of the GR and the MR in cocaine-induced locomotor and reinforcing effects in the same experimental conditions. C57Bl/6J mice were trained for cocaine (1 mg/kg/infusion) intravenous SA over 40 SA sessions. The animals were then administered with mifepristone (30 mg/kg i.p.), a GR antagonist, or with spironolactone (20 mg/kg/i.p.), an MR antagonist, 2 hours before either cocaine intravenous SA or cocaine-induced locomotion. In a comparable nycthemeral period and in similarly cocaine-experienced animals, a blockade of the GR decreased cocaine-induced reinforcing effects but not cocaine-induced locomotion. A blockade of the MR decreased both cocaine-induced reinforcing (but to a much lesser extent than the GR blockade) and locomotor effects. Altogether, our results comforted the hypothesis that the GR modulates cocaine-related operant conditioning, while the MR would modulate cocaine-related unconditioned effects. The present data also reveal mifepristone as an interesting tool for manipulating the impact of corticosterone on cocaine-induced reinforcing effects in mice. [ABSTRACT FROM AUTHOR]

The endogenous opioid system has been reported to participate in nicotine behavioural responses. The aim of the study was to determine the contribution of the endogenous peptides derived from prodynorphin in acute and chronic nicotine responses, mainly those related to its addictive properties. Locomotion and nociception were evaluated after acute nicotine administration in prodynorphin knockout mice. In addition, nicotine rewarding properties were investigated in the place-conditioning and the intravenous self-administration paradigms. The somatic signs of nicotine withdrawal were also analysed after the injection of the nicotinic antagonist mecamylamine in nicotine-dependent mice. The hypolocomotor and antinociceptive effects induced by acute nicotine administration were not modified in knockout (KO) animals. Nicotine also produced similar conditioned place preference in both genotypes. However, a shift to the left in the percentage of acquisition of intravenous nicotine-self administration was observed in prodynorphin KO mice. Indeed, a significant increase in the number of KO mice acquiring this operant behaviour was revealed when low doses of nicotine were used. Nicotine physical dependence was similar in wild-type and KO animals. These findings reveal a specific role of endogenous peptides derived from prodynorphin in nicotine self-administration, probably through the modulation of its aversive effects. [ABSTRACT FROM AUTHOR]

Abstract: The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been shown to reduce intravenous self-administration of ketamine and, to a limited extent, heroin in rats. We investigated whether MPEP affects the rewarding effect of ketamine and heroin as assessed in a conditioned place preference (CPP) paradigm. Sprague Dawley rats were subjected to a standard unbiased CPP protocol. Rats were conditioned with either ketamine or heroin (0.316–31.6 and 0.0125–0.5 mg/kg i.p., respectively), in combination with MPEP (10 mg/kg, i.p.) or its vehicle. The effect of MPEP (10 mg/kg) on the duration of extinction and on reinstatement of ketamine- and heroin-induced CPP was also examined. Ketamine and heroin induced CPP with a minimal effective dose (MED) of 10 mg/kg and 0.25 mg/kg, respectively. MPEP (1–31.6 mg/kg) did not induce CPP by itself; however, co-treatment with MPEP resulted in a 10-fold and 5-fold leftward shift in the MED of ketamine and heroin for inducing CPP, respectively. MPEP slowed extinction of ketamine-induced CPP, but not of heroin-induced CPP, and once extinction was achieved, was able to reinstate CPP in both groups. These findings indicate that a moderate dose of MPEP (10 mg/kg i.p.) potentiates, rather than attenuates, the rewarding effect of ketamine and heroin. Moreover, these data suggest that the attenuating effect of MPEP on ketamine and heroin intravenous self-administration is due to an increase, rather than a decrease, of the rewarding/reinforcing effect of these compounds. [Copyright &y& Elsevier]

The adenosine A2A receptor is specifically enriched in the medium spiny neurons that make up the ‘indirect’ output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A2A receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine self-administration and breakpoint in A2A knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A2A knockout mice. In support of this finding, a place preference to morphine was not observed in A2A knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A2A knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A2A knockout was similar to wild-type mice, yet A2A knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A2A receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A2A receptors in opiate reinforcement compared to opiate-seeking.Neuropsychopharmacology (2009) 34, 844–856; doi:10.1038/npp.2008.72; published online 4 June 2008 [ABSTRACT FROM AUTHOR]

Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5–2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 μM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1–10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.Neuropsychopharmacology (2009) 34, 266–281; doi:10.1038/npp.2008.58; published online 16 April 2008 [ABSTRACT FROM AUTHOR]

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different subunit partners of β2 (i.e., α4 and α6), the homo-pentameric α7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 μ μg free base/kg/inf) selfadministration was investigated with drug-naive mice deleted (KO) for the β2, α4, α6 and α7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice,β2-VEC mice with the ,β2 subunit re-expressed exclusively in the VTA, α4-VEC mice with selective α4 re-expression in the VTA, α6-VEC mice with selective α6 re-expression in the VTA, and α7-KO mice promptly self-administer nicotine intravenously, whereas ,β2-KO, ,β2-VEC in the substantia nigra, α4-KO and α6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of α4,β2- and α6,β2-subunit containing nicotinic receptors (α4,β2*- and α6,β2*-nAChRs), but not α7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice. [ABSTRACT FROM AUTHOR]

Selective antagonists of the mGluR5 receptor attenuate rewarding and reinforcing effects of various drugs of abuse, including alcohol, nicotine, and cocaine. However, the ability of mGluR5 antagonists to alter the reinforcing effects of methamphetamine has not yet been explored. In this study, male Sprague-Dawley rats were trained to perform an operant lever-pressing task in order to obtain intravenous infusions of methamphetamine (0.2 mg/kg/infusion) or presentation of food pellets on a fixed ratio (FR1) schedule of reinforcement. After stabilization of methamphetamine or food self-administration, the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]pyridine (MTEP; 0.3, 1.0, or 3.0 mg/kg i.p.) or vehicle were administered to the animals in a randomized counterbalanced cross-over design. MTEP at doses of 1.0 and 3.0 mg/kg significantly reduced methamphetamine self-administration by 26 and 36%, respectively, but did not alter food reinforcement at any dose tested. These data suggest that mGluR5 receptors are involved in the reinforcing effects of methamphetamine, and that antagonists of this receptor may serve as novel pharmacologic agents for the treatment of addiction to methamphetamine. [ABSTRACT FROM AUTHOR]

Abstract: The effect of 7-week forced oral nicotine exposure on acquisition of intravenous nicotine self-administration, nicotine place conditioning, and nicotine preference was studied in mice. The nicotine solution was given in stepwise increased concentrations as the sole source of liquid for 7 weeks. Nicotine exposed animals self-administered nicotine intravenously at lower unit dose than nicotine-naïve ones, indicating that the forced 7-week nicotine exposure, followed by 7-day withdrawal, had rendered them more sensitive to nicotine''s reinforcing effects. At the dose of 0.5 mg/kg, nicotine induced conditioned place preference both in drug-naïve and nicotine exposed mice, but the 0.3 mg/kg dose of nicotine failed to do so. The forced nicotine pre-exposure did not alter the nicotine preference in the 2-bottle free-choice paradigm. In conclusion, these results suggest that nicotine pre-exposure enhances the reinforcing effects of acutely administered nicotine only in the intravenous self-administration model. [Copyright &y& Elsevier]

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug widely abused by young people. The endocannabinoid system is involved in the addictive processes induced by different drugs of abuse. However, the role of this system in the pharmacological effects of MDMA has not yet been clarified. Methods: Locomotion, body temperature, and anxiogenic-like responses were evaluated after acute MDMA administration in CB1 cannabinoid receptor 1 knockout mice. Additionally, MDMA rewarding properties were investigated in the place conditioning and the intravenous self-administration paradigms. Extracellular levels of dopamine (DA) in the nucleus accumbens were also analyzed after a single administration of MDMA by in vivo microdialysis. Results: Acute MDMA administration increased locomotor activity, body temperature, and anxiogenic-like responses in wild-type mice, but these responses were lower or abolished in knockout animals. 3,4-Methylenedioxymethamphetamine produced similar conditioned place preference and increased dopamine extracellular levels in the nucleus accumbens in both genotypes. Nevertheless, CB1 knockout mice failed to self-administer MDMA at any of the doses used. Conclusions: These results indicate that CB1 cannabinoid receptors play an important role in the acute prototypical effects of MDMA and are essential in the acquisition of an operant behavior to self-administer this drug. [Copyright &y& Elsevier]

Methamphetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous methamphetamine self-administration in the rat. Mate Hooded Wistar rats were trained to self-administer intravenous methamphetamine (0.1mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 ± 1°C. They were then given their daily self-administration session at a raised ambient temperature of 30 ± 1°C. Methamphetamine self-administration was increased at 30°C under both FR1 and PR reinforcement schedules, with the tatter effect indicating that heat enhances the motivation to obtain methamphetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in methamphetamine-experienced rats suggesting some specificity in the methamphetamine effect. When rats were given access to drink isotonic saline solution during methamphetamine self-administration sessions they drank much more solution at 30°C than 23°C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of methamphetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering methamphetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of methamphetamine, or its principal metabolite amphetamine indicating that the facititatory effect of heat did not reflect altered methamphetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of methamphetamine and encourage higher levels of drug intake. [ABSTRACT FROM AUTHOR]

Individual differences in cocaine-taking behavior and liability to develop abuse are clearly observed, but underlying mechanisms are still poorly understood. A role for gene–environment interactions has been proposed but remains hypothetical. We investigated whether gene–environment interactions influence intravenous cocaine self-administration (SA) in mice. We tested the effect of a past short group housing experience on cocaine SA in two inbred strains of mice, the C57BL/6J (C57) and DBA/2J (DBA). Adult C57 and DBA mice were individually housed upon arrival in the laboratory. After 3 weeks, half of the animals of each strain were group housed for 19 days. One week after the end of group housing, cocaine SA or measurement of brain cocaine levels took place. Individually and ex-group-housed C57 mice did not differ for cocaine SA. On the contrary, the ex-group-housed DBA mice showed an upward shift in the dose-response curve as compared to individually housed DBA. Differences in brain cocaine levels could not account for the observed behavioral differences. These results demonstrate that vulnerability to cocaine reinforcing effects can be affected by gene–environment interactions. We propose a mouse model for the characterization of gene–environment interactions in the vulnerability to cocaine-taking behavior. [ABSTRACT FROM AUTHOR]

Behavioral sensitization has been proposed as a process that is important in compulsive drug use and in psychotic disorders. The present experiments examine the relationship between behavioral sensitization, induced by either social defeat or amphetamine, and intravenous cocaine self-administration in mice. Male CFW mice were exposed either to defeat experiences, amphetamine (2.5 mg/kg, i.p.) or saline (i.p.) every day for 10 days. Ten days after the last defeat or injection, mice were challenged with varying doses of amphetamine (1.0–2.5 mg/kg i.p). Mice were then trained to nose poke for intravenous cocaine (1.0 mg/kg/inf) during daily 3-h sessions. Following this acquisition phase, the animals self-administered varying doses of cocaine (0.3–1.8 mg/kg/inf) or were allowed to self-administer cocaine (0.3 mg/kg/inf) according to a progressive ratio schedule of reinforcement. Repeated social defeat produced a sensitized motor response to a single challenge of 1.5 mg/kg amphetamine and to a cumulative dosing of amphetamine. Amphetamine-pretreated mice exhibited increased cocaine self-administration during acquisition and elevated break points during performance on a progressive ratio schedule of reinforcement relative to stress-sensitized and control animals. These data extend the evidence from rats to mice for the process of sensitization leading to more cocaine taking. Contrary to what is seen in rats, increased levels of cocaine self-administration were seen only in the amphetamine-pretreated mice and not after repeated defeat stress, suggesting that the sensitized response to defeat stress may not be as robust as it is in rats in this particular strain of mice. [ABSTRACT FROM AUTHOR]