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Background: A prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self‐administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ‐8 (TARP γ‐8). This study evaluated the preclinical efficacy of JNJ‐55511118, a novel, selective, high‐affinity inhibitor of TARP γ‐8‐bound AMPARs, in reducing chronic operant alcohol self‐administration. Methods: Separate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR‐4 schedule of reinforcement. After a 40‐day baseline, JNJ‐55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self‐administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded. Results: During baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ‐55511118 decreased multiple parameters of alcohol self‐administration but did not reduce behavior‐matched sucrose‐only self‐administration. JNJ‐55511118 had no effect on sweetened alcohol or sucrose self‐administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ‐55511118 (1 mg/kg) had no effect on open‐field activity in male mice. Conclusions: This study shows for the first time that TARP γ‐8‐bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ‐55511118 in reducing alcohol self‐administration in male mice suggests that inhibition of TARP γ‐8‐bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction. [ABSTRACT FROM AUTHOR]

Background: The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon‐like‐peptide‐1 (GLP‐1) and its analogue Exendin‐4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for alcohol use disorders. However, the neural mechanisms and sites of action mediating the effects of Ex4 on alcohol intake behaviors remain to be characterized. This study examined the ventral tegmental area (VTA) as a site of action for the effects of GLP‐1 on alcohol intake. Methods: Male Long‐Evans rats were given intermittent access to 20% alcohol and trained to nose poke for 20% alcohol. Rats received intra‐VTA injections of Ex4 (vehicle, 0.01, 0.05 μg), and the effects of VTA Ex4 on alcohol self‐administration, motivation, and relapse were assessed. Results: When compared to vehicle treatment, intra‐VTA Ex4 (0.01, 0.05 μg) delivery significantly reduced alcohol self‐administration, an effect that was particularly prominent in high alcohol drinkers. However, VTA Ex4 did not reduce reacquisition of alcohol self‐administration after extinction nor the motivation to obtain alcohol. Importantly, the lower dose of Ex4 (0.01 μg) used had no effect on food intake or locomotor activity, suggesting that the reduction in alcohol self‐administration observed was not secondary to caloric intake or motor deficits. Conclusions: Together, these findings provide support for the VTA as a key site of action for GLP‐1 on alcohol self‐administration but not the reacquisition of alcohol self‐administration or motivation to work for alcohol. [ABSTRACT FROM AUTHOR]

Background: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self‐administration, is warranted. The current study is a secondary analysis examining whether alcohol cue–induced activation in the ventral striatum is predictive of subsequent alcohol self‐administration in the laboratory. Methods: Non–treatment‐seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo‐controlled, double‐blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue–reactivity task. On the following day (day 5), participants completed a 60‐minute alcohol self‐administration paradigm. Results: Multilevel Cox regressions indicated a significant effect of taste cue–elicited ventral striatum activation on latency to first drink, Wald χ2 = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self‐administration outcomes. Conclusions: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self‐administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development. [ABSTRACT FROM AUTHOR]

Background: Young adult heavy drinking is an important public health concern. Current interventions have efficacy but with only modest effects, and thus, novel interventions are needed. In prior studies, heavy drinkers, including young adults, have demonstrated stronger automatically triggered approach tendencies to alcohol‐related stimuli than lighter drinkers. Automatic action tendency retraining has been developed to correct this tendency and consequently reduce alcohol consumption. This study is the first to test multiple iterations of automatic action tendency retraining, followed by laboratory alcohol self‐administration. Methods: A total of 72 nontreatment‐seeking, heavy drinking young adults ages 21 to 25 were randomized to automatic action tendency retraining or a control condition (i.e., “sham training”). Of these, 69 (54% male) completed 4 iterations of retraining or the control condition over 5 days with an alcohol drinking session on Day 5. Self‐administration was conducted according to a human laboratory paradigm designed to model individual differences in impaired control (i.e., difficulty adhering to limits on alcohol consumption). Results: Automatic action tendency retraining was not associated with greater reduction in alcohol approach tendency or less alcohol self‐administration than the control condition. The laboratory paradigm was probably sufficiently sensitive to detect an effect of an experimental manipulation given the range of self‐administration behavior observed, both in terms of number of alcoholic and nonalcoholic drinks and measures of drinking topography. Conclusions: Automatic action tendency retraining was ineffective among heavy drinking young adults without motivation to change their drinking. Details of the retraining procedure may have contributed to the lack of a significant effect. Despite null primary findings, the impaired control laboratory paradigm is a valid laboratory‐based measure of young adult alcohol consumption that provides the opportunity to observe drinking topography and self‐administration of nonalcoholic beverages (i.e., protective behavioral strategies directly related to alcohol use). [ABSTRACT FROM AUTHOR]

Background Excessive ethanol (EtOH) consumption remains an important health concern and effective treatments are lacking. The central oxytocin system has emerged as a potentially important therapeutic target for alcohol and drug addiction. These studies tested the hypothesis that oxytocin reduces EtOH consumption. Methods Male C57 BL/6J mice were given access to EtOH (20% v/v) using a model of binge-like drinking ('drinking in the dark') that also included the use of lickometer circuits to evaluate the temporal pattern of intake as well as 2-bottle choice drinking in the home cage. In addition, EtOH (12% v/v) and sucrose (5% w/v) self-administration on fixed- and progressive-ratio schedules were also evaluated. A wide range of systemically administered oxytocin doses were tested (0 to 10 mg/kg) in these models. Results Oxytocin (0, 0.3, 1, 3, or 10 mg/kg) dose dependently reduced EtOH consumption (maximal 45% reduction) in the binge drinking model, with lower effective doses having minimal effects on general locomotor activity. Oxytocin's effect was blocked by pretreatment with an oxytocin receptor antagonist, and the pattern of contacts (licks) at the EtOH bottle suggested a reduction in motivation to drink EtOH. Oxytocin decreased 2-bottle choice drinking without altering general fluid intake. Oxytocin also reduced operant responding for EtOH and sucrose in a dose-related manner. However, oxytocin decreased responding and motivation (breakpoint values) for EtOH at doses that did not alter responding for sucrose. Conclusions These results indicate that oxytocin reduces EtOH consumption in different models of self-administration. The effects are not likely due to a general sedative effect of the neuropeptide. Further, oxytocin reduces motivation for EtOH at doses that do not alter responding for a natural reward (sucrose). While some evidence supports a role for oxytocin receptors in mediating these effects, additional studies are needed to further elucidate underlying mechanisms. Nevertheless, these results support the therapeutic potential of oxytocin as a treatment for alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background Increased levels of impulsivity are associated with increased illicit drug use and alcoholism. Previous research in our laboratory has shown that increased levels of delay discounting (a decision-making form of impulsivity) are related to appetitive processes governing alcohol self-administration as opposed to purely consummatory processes. Specifically, the high-seeking/high-drinking alcohol-preferring P rats showed increased delay discounting compared to nonselected Long Evans rats ( LE) whereas the high-drinking/moderate-seeking HAD2 rats did not. The P rats also displayed a perseverative pattern of behavior such that during operant alcohol self-administration they exhibited greater resistance to extinction. Methods One explanation for the previous findings is that P rats have a deficit in response inhibition. This study followed up on this possibility by utilizing a countermanding paradigm (stop signal reaction time [ SSRT] task) followed by operant self-administration of alcohol across increasing fixed ratio requirements ( FR; 1, 2, 5, 10, and 15 responses). In separate animals, 24-hour access 2-bottle choice (10% Et OH vs. water) drinking was assessed. Results In the SSRT task, P rats exhibited an increased SSRT compared to both LE and HAD2 rats indicating a decrease in behavioral inhibition in the P rats. Also, P rats showed increased operant self-administration across all FRs and the greatest increase in responding with increasing FR requirements. Conversely, the HAD2 and LE had shorter SSRTs and lower levels of operant alcohol self-administration. However, for 2-bottle choice drinking HAD2s and P rats consumed more Et OH and had a greater preference for Et OH compared to LE. Conclusions These data extend previous findings showing the P rats to have increased delay discounting (decision-making impulsivity) and suggest that P rats also have a lack of behavioral inhibition (motor impulsivity). This supports the notion that P rats are a highly impulsive as well as 'high-seeking' model of alcoholism, and that the HAD2s' elevated levels of alcohol consumption are not mediated via appetitive processes or impulsivity. [ABSTRACT FROM AUTHOR]

Background Alcohol's ability to potentiate the activity of γ-aminobutyric acid ( GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5 GABAA receptor ligands to alter selectively the reinforcing effects of alcohol. Methods Two groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors. Results Concentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The α5 GABAA receptor agonist QH-ii-066 enhanced and the α5 GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5 GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect. Conclusions These findings suggest a prominent and specific role for α5 GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5 GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5 GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies. [ABSTRACT FROM AUTHOR]

Background: The positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, have been found to reduce alcohol self-administration in alcohol-preferring rats. The present study was designed to assess the effect of the newly synthesized positive allosteric modulator of the GABAB receptor, BHF177, on alcohol’s reinforcing and motivational properties in selectively bred Sardinian alcohol-preferring (sP) rats. Methods: sP rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (1 to 3%, w/v) in daily 30-minute sessions. Once responding reached stable levels, rats were allocated to 2 different experiments: in the first experiment, rats were exposed to sessions with the FR4 schedule of reinforcement; in the second experiment, rats were exposed to sessions with a conventional progressive ratio (PR) schedule of reinforcement. In both experiments, the effect of BHF177 (0, 12.5, 25, and 50 mg/kg; i.g.) on responding for alcohol and sucrose (FR experiment: 1%, w/v; PR experiment: 3%, w/v) was determined. Results: In the FR experiment, pretreatment with 25 and 50 mg/kg BHF177 produced a 30 and 45% reduction, respectively, in responding for alcohol. In the PR experiment, pretreatment with 50 mg/kg BHF177 resulted in a 35% reduction in breakpoint for alcohol (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol). In both experiments, the effect of BHF177 on alcohol self-administration was specific, since responding for sucrose was unaltered by BHF177 pretreatment. Conclusions: The present results extend to BHF177 the capacity of the 2 previously tested positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, to specifically suppress alcohol’s reinforcing and motivational properties in alcohol-preferring rats. [ABSTRACT FROM AUTHOR]

Background: Alcohol and nicotine, in the form of tobacco, are commonly co-abused. Nicotinic receptors also have been implicated in alcohol action. We designed the present study to examine the possible involvement of nicotinic receptors in alcohol self-administration. Methods and Results: Pretreatment with lower doses (0.1-0.4 mg/kg) of nicotine, administered acutely or chronically, did not affect alcohol consumption, whereas a higher dose (0.8 mg/kg) initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment. We observed the same pattern of nicotine effects on alcohol self-administration using an operant procedure. A dose of 0.8 mg/kg of nicotine initially suppressed operant responding for alcohol. Such suppression of alcohol self-administration was more pronounced during the first 20 min of the 60 min operant session. Responding for alcohol in the nicotine treated group, however, was significantly increased above the saline treated group by the 5th day of treatment. Mecamylamine, a noncompetitive nicotinic receptor antagonist, reduced alcohol consumption, whereas dihydro-β-erythroidine (DHβE), a competitive nicotinic receptor antagonist, did not modify alcohol consumption. Conclusions: The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self-administration. The failure of DHβE to reduce alcohol consumption, however, suggests that ethanol-nicotine interaction is mediated by other nicotinic receptor subtypes rather than α4β2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine whether reduction of dopamine (DA) innervation to the nucleus accumbens (ACB) alters the maintenance and/or acquisition of ethanol drinking in female alcohol-preferring P rats. Compared with sham-lesioned animals, bilateral microinjections of 6-OHDA (12 μg/2.4 μl/site) into the ACB did not alter the consumption of 10% ethanol in rats that had prior experience of ethanol drinking, with both sham- and 6-OHDA-lesioned groups recovering to presurgical consumption levels at similar rates. On the other hand, the identical lesion procedure disrupted the acquisition of ethanol intake in rats with no ethanol-drinking experience prior to the lesions. A sham-lesioned group attained an ethanol intake of approximately 7 g/kg/day in 1 week, which was maintained over the following 2-week period, while the ethanol intake of the 6-OHDA-lesioned group was approximately 60% lower after 1 week and 30% lower at the end of 3 weeks. DA content of the ACB was 60% lower in both groups of the 6-OHDA-treated rats compared with the controls. The results suggest that different neural mechanisms may underlie the acquisition and maintenance of ethanol drinking behavior; the ACB DA system appears to play an important role in the acquisition of ethanol drinking. [ABSTRACT FROM AUTHOR]

This study was performed to examine ethanol self-administration in rats bred for different sensitivities to the sedative effects of alcohol [the Colorado High Alcohol Sensitive (HAS) and Low Alcohol Sensitive (LAS) rats]. Four rats from each replicate line of the HAS and LAS rats ( n= 16) were obtained from the University of Colorado, and initiation to self-administer ethanol by the sucrose-substitution procedure was attempted. Before the initiation procedure was conducted, home-cage ethanol intake and preference ratio did not differ between LAS and HAS rats. During the initiation procedure, the LAS rats came to self-administer 10% ethanol (v/v) at similar levels as outbred Wistar rats initiated with the same procedure (˜0.4 g/kg/ session). The HAS rats, however, failed to initiate (˜0.08 g/kg/session after completing the sucrose-substitution procedure) and lever pressing was reduced even more in the HAS rats when the ethanol concentration presented was >10% (v/v). Three of the eight HAS rats stopped lever pressing completely when the ethanol concentration was raised to 15%. After initiation, home-cage preference ratio differed significantly between the LAS and HAS rats (LAS > HAS, p < 0.03). That the LAS rats did not consume greater amounts of ethanol compared with outbred Long-Evans or Wistar rats is contrary to our hypothesis, based on recent human data suggesting that a lower sensitivity to ethanol could result in increased alcohol intake. The finding that the HAS rats could not be initiated, while selectively bred ethanol nonpreferring rats can, is also contrary to our hypothesis. Further studies related to ethanol self-administration with the HAS line could provide important information related to the genetics of alcohol nonacceptance. [ABSTRACT FROM AUTHOR]

Rats, from the alcohol preferring (P) line, were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. During Experiment 1, the effects of changing ethanol concentration and response requirement for ethanol were examined. Ten percent and 20% ethanol (v/v) were available on two fixed ratio (FR) schedules, FR 1 and FR 4, for 2 weeks each. During Experiment 2, the effects of increasing the response requirement for ethanol were investigated. Starting with FR 4, the FR requirement for ethanol doubled during 2-week intervals until FR 32 was in effect. For the final phase of these studies, water was placed in the dipper for 1 week followed by a return to 10% ethanol in the dipper. The results from Experiment 1 indicated that when the FR requirement was decreased from FR 4 to FR 1, ethanol-reinforced responding decreased but total daily intake increased. Lowering the FR requirement did not affect the number of ethanol bouts per day but bout size increased. Ethanol concentration had no effect on bout size but the number of bouts per day decreased when the concentration was increased to 20%. Since bout size was unchanged by increasing the ethanol concentration, intake per bout increased at 20% ethanol. The results from Experiment 2 indicated that increasing the response requirement for ethanol decreases ethanol intake. When water was placed in the dipper, responding decreased to the lowest levels observed in the experiment. When ethanol was returned to the dipper, responding returned to baseline levels. Overall, the results indicate that while P rats may consume more ethanol than other lines of rats, their behavior can be modified by environmental variables in a manner somewhat similar to heterogeneous nonselected Long-Evans rats. [ABSTRACT FROM AUTHOR]