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PubMed2006

A method for single-session cocaine self-administration in the mouse.

RATIONALE: Drug self-administration is a powerful method to measure the reinforcing effects of a drug, as well as to investigate behavioral, biochemical, and physiological effects of a drug specific to contingent delivery. With the spectrum of genetically modified mice available, there is a need for well-designed drug self-administration studies tailored for rapid completion of studies in mice. OBJECTIVES: We set out to develop a methodology in mice for obtaining high levels of cocaine self-administration during the first exposure to the drug. MATERIALS AND METHODS: C57Bl/6J mice were trained to lever press for liquid reinforcer on a fixed ratio 1, then a progressive ratio (PR) schedule of reinforcement before intravenous self-administration of cocaine on a PR schedule. RESULTS: Within a single 16-h session, each mouse self-administered either saline or 0.1, 0.3, 0.6, or 1.2 mg kg(-1) infusion(-1) of cocaine during four distinct 4-h subsessions. Mice showed a strong preference for cocaine vs saline, as demonstrated by higher breakpoints and greater preference for the active lever. Likewise, there was a dose-dependent increase in breakpoints obtained and in drug intake. Finally, animals receiving noncontingent cocaine pressed significantly less than mice self-administering the same dose of cocaine, indicating that a significant amount of active lever pressing is driven by drug-seeking and not the psychomotor-activating effects of cocaine alone. CONCLUSIONS: Mice will reach high breakpoints and cocaine intake during an initial exposure to cocaine. This method is well-suited to rapidly obtain progressive ratio cocaine self-administration in mice.

Animals↗

PubMed1995

Effects of response cost and unit dose on alcohol self-administration in moderate drinkers.

Alcohol self-administration by nonhumans and alcoholic humans decreases as the response requirement to obtain the drug increases. Also, increases in dose or concentration of alcohol, increase consumption up to a maximum in these populations, after which further increases in dose decrease intake. In the present study, the effects of response cost and dose on alcohol self-administration were investigated in moderate drinkers (12-45 drinks/week). Three male volunteers self-administered alcohol (commercial beer) during 2h sessions twice weekly. Alcohol was available under a fixed-ratio (FR) schedule of reinforcement. Response requirement (FR100-1600) and dose (2 and 4oz of beer) were varied separately across sessions using a within-subjects design. As response cost increased, consumption and overall rates of responding generally changed in an inverted U-shaped manner. Maximal consumption was observed at the 4oz dose. These orderly relations between response cost, dose and alcohol self-administration extend prior findings in nonhumans and alcoholics to moderate drinkers. Such consistencies support a position that a common set of variables control alcohol self-administration across these populations.

Journal Article↗

PubMed2005

Differential regulation of ionotropic glutamate receptor subunits following cocaine self-administration.

Previous examination of binge cocaine self-administration and 2 week withdrawal from cocaine self-administration on ionotropic glutamate receptor subunit (iGluRs) protein levels revealed significant alterations in iGluR protein levels that differed between the mesocorticolimbic and nigrostriatal pathways. The present study was undertaken to extend the examination of cocaine-induced alterations in iGluR protein expression by assessing the effects of acute withdrawal (15-16 h) from limited access cocaine self-administration (8 h/day, 15 days). Western blotting was used to compare levels of iGluR protein expression (NR1-3B, GluR1-7, KA2) in the mesolimbic (ventral tegmental area, VTA; nucleus accumbens, NAc; and prefrontal cortex, PFC) and nigrostriatal pathways (substantia nigra, SN and dorsal caudate-putamen, CPu). Within the mesolimbic pathway, reductions were observed in NR1 and GluR5 immunoreactivity in the VTA although no significant alterations were observed in any iGluR subunits in the NAc. In the PFC, NR1 was significantly upregulated while GluR2/3, GluR4, GluR5, GluR6/7, and KA2 were decreased. Within the nigrostriatal pathway, NR1, NR2A, NR2B, GluR1, GluR6/7 and KA2 were increased in the dorsal CPu, whereas no significant changes were observed in the SN. The results demonstrate region- and pathway-specific alterations in iGluR subunit expression following limited cocaine self-administration and suggest the importance for the activation of pathways that are substrates of the reinforcing and motoric effects of cocaine.

Animals↗

PubMed1987

Self-administration of barbiturates and benzodiazepines: a review.

Studies of barbiturate and benzodiazepine self-administration are categorized by species and route of administration. Reinforcement, defined as self-administration of drug greater than of a non-drug control, has been demonstrated most often in studies employing the IV route, and there has been greater reliability in this result for a given drug among barbiturates rather than among benzodiazepines. Most studies of PO self-administration in rodents have not demonstrated reinforcement, despite a number of behavioral manipulations to induce drug intake. Studies of PO barbiturate self-administration in monkeys have demonstrated reinforcement but recent studies of PO benzodiazepine self-administration in baboons have not, although physical dependence was demonstrated. Reinforcement via the IG route has not been reliably demonstrated. Behavioral variables, including interreinforcement interval and drug self-administration history, appear to be important determinants of whether or not reinforcement will be demonstrated, particularly among the benzodiazepines; but the range of conditions under which behavioral and pharmacological variables interact to promote or lessen the likelihood of self-administration of these drugs remains to be determined experimentally.

Animals↗

PubMed2004

Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats.

RATIONALE: Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. OBJECTIVES: To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. METHODS: The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. RESULTS: Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. CONCLUSION: There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence.

Analysis of Variance↗

PubMed1985

Oxytocin reduces intravenous heroin self-administration in heroin-tolerant rats.

Intravenous self-administration of heroin was studied in experimentally naive rats, as compared to this behavior in animals rendered tolerant to heroin by multiple injections. The tolerant rats also exhibited mild signs of spontaneous and naloxone-precipitated heroin withdrawal. Self-administration behavior developed earlier in the tolerant rats. In heroin-naive rats, oxytocin treatment did not influence the acquisition of heroin self-administration behavior. In the tolerant rats, on the other hand, oxytocin decreased the acquisition of heroin self-administration. When maintenance of heroin self-administration was studied in the tolerant rats, graded doses of oxytocin (0.05, 0.5 and 5 micrograms s.c.) decreased heroin intake. This finding, which is in agreement with previous data indicating that oxytocin attenuates the development of tolerance to and dependence on narcotic analgesics, suggests that the neuropeptide reduced the reinforcing efficacy of heroin in the tolerant organism.

Animals↗

PubMed2006

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

RATIONALE: Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. OBJECTIVES: This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of self-administered MDMA on monoamines. RESULTS: The methylenedioxy amphetamine congeners MDMA, 3,4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable self-administration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. CONCLUSIONS: Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates.

Animals↗

PubMed2005

Higher magnitude accumbal phasic firing changes among core neurons exhibiting tonic firing increases during cocaine self-administration.

Studies using i.v. cocaine self-administration in rats have documented rapid-phasic changes in the firing rate of nucleus accumbens neurons within seconds of cocaine-reinforced lever presses, as well as changes that occur over the course of the cocaine self-administration experiment, i.e. tonic changes in firing rate. During the self-administration period of the experiment, individual neurons exhibit either a tonic increase, a tonic decrease, or no tonic change in firing rate, relative to the neuron's firing rate during the pre-drug period. We evaluated whether rapid-phasic changes in firing were differentially associated with tonically reduced or tonically elevated firing of nucleus accumbens core and shell neurons in cocaine self-administering rats. Rapid-phasic firing patterns within seconds of the cocaine-reinforced lever press were exhibited predominantly by core neurons that also exhibited tonic increases in firing. Conversely, core neurons that did not exhibit such rapid-phasic firing patterns were more likely to show tonically reduced firing. Moreover, core neurons were more likely than shell neurons to exhibit: 1) tonic increases in firing and 2) rapid-phasic increases in firing preceding the cocaine-reinforced lever press. These differences between accumbens subterritories may be related to their distinct involvement in operant responding; the present findings are consistent with an emerging literature which implicates shell in contextual stimulus-induced responding, and core in processing the instrumental response via its discrete output to classic basal ganglia structures. The distinct tendency of the core to exhibit increased firing, coupled with its dichotomous firing outputs (i.e. tonic decreases without rapid phasic responses or tonic increases with rapid phasic responses), may reflect particular sensitivity of these neurons to excitatory limbic afferent signaling involved in instrumental responding. Enhanced phasic responsivity in the core may be an integral component of the mechanism inherent in normal reward processing which is subverted by chronic drug exposure.

Animals↗

PubMed1993

Naltrexone-buprenorphine interactions: effects on cocaine self-administration.

An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphine's agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphine's effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphine's suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphine's reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphine's effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.

Animals↗

PubMed1993

The effects of dose and access restrictions on the periodicity of cocaine self-administration in the rat.

Cocaine self-administration in rats was tested under various dose and frequency of access restrictions. In the continuous access condition, groups of rats were given continuous, unlimited access to one of three doses of cocaine (1.5, 0.5, and 0.2 mg/kg/infusion) for a duration of 10 days. In the discrete trials condition, a group of rats were given the opportunity to self-administer a single cocaine infusion (1.5 mg/kg) within a discrete, 10 min access trial. The rats received a continuous series of these trials for a duration of 7-10 days at one of three frequencies (1, 2 or 4 trials/h). Results suggest that when access is restricted to four access trials/h, or to a median dose range (0.5 mg/kg per infusion), rats will self-administer cocaine in a cyclical manner over extended, infradian periodicities without developing outward signs of ill health. This contrasts with previous studies where extended, unlimited access schedules have resulted in toxicity and overdose. It is suggested that dose and frequency of access restrictions may be employed in order to develop new animal models of cocaine self-administration which examine the factors underlying the reinitiation of extended periods of cocaine intake. Such models may be useful in testing interventions with the potential to disrupt cyclical patterns of cocaine self-administration.

Animals↗

PubMed1989

Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys.

The self-administration of cocaine was compared with that of bupropion, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, mazindol, methylphenidate and nomifensine, drugs that displace [3H]cocaine from its binding sites and have monoamine uptake inhibiting effects in common with those of cocaine. Squirrel monkeys responded under a second-order fixed-interval schedule of consequent i.v. drug injection, and dose-effect curves were established by determining stable rates of responding maintained by saline and a range of doses of each drug. Cocaine (0.01-0.56 mg/kg/injection), bupropion (0.1-3.0 mg/kg/injection), 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3- phenylpropyl)piperazine-(0.03-1.0 mg/kg/injection), methylphenidate (0.01-0.3 mg/kg/injection) and nomifensine (0.01-0.3 mg/kg) maintained comparable rates and patterns of responding in all subjects, whereas mazindol (0.03-0.3 mg/kg) maintained self-administration behavior in only half the monkeys studied. The present results in conjunction with those of previous studies in squirrel monkeys reveal a close correspondence between the relative potencies of cocaine and related drugs for maintaining i.v. self-administration and for increasing rates of schedule-controlled responding, suggesting that the reinforcing and psychomotor-stimulant effects of the drugs are mediated similarly. The potency relations observed in the present study also agree generally with those observed for displacement of specifically bound [3H]cocaine in monkey caudate-putamen suggesting that the reinforcing effects of cocaine involve its actions at specific recognition sites in brain.

Animals↗

PubMed1997

Flavor preference conditioning by oral self-administration of ethanol.

Oral self-administration and operant tasks have been used successfully to confirm ethanol's positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS-). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol's efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS- in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol's rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol's nutrient and pharmacological effects both contributed to the development of conditioned flavor preference.

Alcohol Drinking↗

PubMed2001

Satiety threshold during maintained cocaine self-administration in outbred mice.

Male Swiss Webster mice maintained cocaine self-administration in a regular and dose-dependent manner. These characteristics made it possible to apply the satiety threshold model of drug self-administration developed recently for cocaine self-administration in rats. Non-linear regression analysis revealed that cocaine satiety threshold was 1.3 +/- 0.6 mg/kg and the functional half-life of the cocaine was 8.1 +/- 2.2 min. Whether the self-administration of cocaine was maintained by lever presses or nose pokes did not influence the inter-injection intervals. The results are consistent with the pharmacological model of maintained cocaine self-administration. The ability to determine addiction-relevant phenotypes (the satiety threshold and functional half-life of cocaine) in inbred strains of mice may help to identify the genetic determinants of cocaine self-administration behavior.

Animals↗

PubMed2003

Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats.

Cocaine self-administration is associated with a propensity to relapse in humans and reinstatement of drug seeking in rats after prolonged withdrawal periods. These behaviors are hypothesized to be mediated by molecular neuroadaptations within the mesolimbic dopamine system. However, in most studies of drug-induced neuroadaptations, cocaine was experimenter-delivered and molecular measurements were performed after short withdrawal periods. In the present study, rats were trained to self-administer intravenous cocaine or oral sucrose (a control non-drug reward) for 10 days (6-h/day) and were killed following 1, 30, or 90 days of reward withdrawal. Tissues from the accumbens and ventral tegmental area (VTA) were assayed for candidate molecular neuroadaptations, including enzyme activities of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin-dependent kinase 5 (cdk5), tyrosine hydroxylase (TH) and glutamate receptor subunits (GluR1, GluR2 and NMDAR1). In the accumbens of cocaine-trained rats, GluR1 and NMDAR1 levels were increased on days 1 and 90, while GluR2 levels were increased on days 1 and 30, but not day 90; PKA activity levels were increased on days 1 and 30, but not day 90, while AC activity, TH and cdk5 levels were unaltered. In the VTA of cocaine-trained rats, NMDAR1 levels were increased for up to 90 days, while GluR2 levels were increased only on day 1; TH and Cdk5 levels were increased only on day 1, while PKA and AC activity levels were unaltered. Cocaine self-administration produces long-lasting molecular neuroadaptations in the VTA and accumbens that may underlie cocaine relapse during periods of abstinence.

Adaptation, Physiological↗

PubMed2003

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats.

RATIONALE AND OBJECTIVES: In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. METHODS: After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3-4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9-4", because the ninth response requirement was four lever presses). The PR9-4 schedule was also evaluated for self-administration of morphine doses of 0.001-3.2 mg/kg per injection. RESULTS: The number of ratios completed for morphine self-administration on the PR9-4 schedule, but not the PR3-4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9-4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9-4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. CONCLUSIONS: In the present study, a schedule that incremented response requirement gradually (PR9-4) supported reliable self-administration across a range of morphine doses.

Animals↗

PubMed1987

Intracranial self-administration methodologies.

Intracranial drug self-administration (ICSA) offers a relatively new approach for investigating the neurobiological mechanisms involved in brain reinforcement processes. Discrete brain regions responsible for the initiation of neuronal activity associated with the response-contingent delivery of a drug reinforcer can be identified using these procedures since the drug is infused directly into a specific brain locus. In the last decade, several papers have appeared in the literature reporting the self-administration of various substances into a number of brain regions. However, different laboratories often employ diverse methodological procedures to demonstrate ICSA, and this can lead to erroneous conclusions when comparing data from different investigations. This review presents a critical evaluation of the current status of research in this area and suggests behavioral as well as methodological guidelines for future investigations to follow.

Animals↗

PubMed1987

Effect of taste aversion learning on ethanol self-administration.

Ethanol (EtOH) oral self-administration studies using rats have had inconsistent outcomes: studies in which rats are fluid deprived report decreasing EtOH intake over trials, whereas studies not employing fluid deprivation report increasing intake over trials. The present study supports the hypothesis that differential taste aversion learning may account for some of this discrepancy. This study indicates that taste aversion learning is maximized under fluid deprivation conditions and that "latent inhibition," i.e., exposure to non-intoxicating amounts of the EtOH solution prior to conditioning, reduces taste aversion learning. It is suggested that the effect of fluid deprivation on taste aversion resulting from EtOH self-administration may be at least in part due to the development of latent inhibition in non-deprived animals during initial exposure to the EtOH solution.

Animals↗

PubMed1999

Central administration of an opiate antagonist decreases oral ethanol self-administration in rats.

BACKGROUND: Opioid peptides have been implicated in various behavioral actions of alcohol, including its reinforcing effects; however, the role of specific brain sites for these actions remains to be explored. The present study examined the effects of intracerebroventricular (ICV) or intracerebral injections of an opiate antagonist (methylnaloxonium) on ethanol self-administration. The nucleus accumbens and amygdala were selected as intracerebral sites because these regions have been implicated in the reinforcing effects of drugs of abuse. METHODS: Male Wistar rats were trained in a limited-access paradigm (30 min/day) to respond for ethanol (10% w/v) or water in a two-lever free-choice condition using a saccharin fading procedure. After the establishment of stable baseline responding for ethanol, animals were implanted stereotaxically with a guide cannula above the lateral ventricle or with bilateral guide cannulae either above the nucleus accumbens or amygdala. After postoperative recovery of stable baseline responding, the rats were tested 15 min after ICV or intracerebral microinjections of methylnaloxonium (0-2000 ng). RESULTS: Injections of methylnaloxonium into the amygdala significantly reduced responding for ethanol at doses of 250-500 ng. Injections of methylnaloxonium into the nucleus accumbens significantly reduced responding for ethanol at doses of 500-1000 ng, whereas higher doses were needed ICV. CONCLUSIONS: These results provide evidence that opioid receptors located in the amygdala and nucleus accumbens may be involved in the regulation of ethanol self-administration.

Amygdala↗