Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH-2 Inhibitor

Background: Inherited human aldehyde dehydrogenase 2 (ALDH‐2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH‐2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH‐2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH‐2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co‐crystal structure of ALDH‐2 and daidzin. We tested the efficacy of a highly selective reversible ALDH‐2 inhibitor, CVT‐10216, in models of moderate and high alcohol drinking rats. We studied 2‐bottle choice and deprivation‐induced drinking paradigms in Fawn Hooded (FH) rats, operant self‐administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue‐induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results: CVT‐10216 increases acetaldehyde after alcohol gavage and inhibits 2‐bottle choice alcohol intake in heavy drinking rodents, including deprivation‐induced drinking. Moreover, CVT‐10216 also prevents operant self‐administration and eliminates cue‐induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT‐10216 prevents alcohol‐induced increases in NAc DA without changing basal levels. CVT‐10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion: Our findings suggest that selective reversible ALDH‐2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.     

Aversive Effects of Ethanol in Adolescent Versus Adult Rats: Potential Causes and Implication for Future Drinking

Background: Many people experiment with alcohol and other drugs of abuse during their teenage years. Epidemiological evidence suggests that younger initiates into drug taking are more likely to develop problematic drug seeking behavior, including binge and other high‐intake behaviors. The level of drug intake for any individual depends on the balance of rewarding and aversive effects of the drug in that individual. Multiple rodent studies have demonstrated that aversive effects of drugs of abuse are reduced in adolescent compared to adult animals. In this study, we addressed 2 key questions: First, do reduced aversive effects of ethanol in younger rats correlate with increased ethanol consumption? Second, are the reduced aversive effects in adolescents attributable to reduced sensitivity to ethanol’s physiologic effects? Methods: Adolescent and adult rats were tested for ethanol conditioned taste aversion (CTA) followed by a voluntary drinking period, including postdeprivation consumption. Multivariate regression was used to assess correlations. In separate experiments, adolescent and adult rats were tested for their sensitivity to the hypothermic and sedative effects of ethanol, and for blood ethanol concentrations (BECs). Results: We observed that in adolescent rats but not adults, taste aversion was inversely correlated with postdeprivation consumption. Adolescents also exhibited a greater increase in consumption after deprivation than adults. Furthermore, the age difference in ethanol CTA was not attributable to differences in hypothermia, sedation, or BECs. Conclusions: These results suggest that during adolescence, individuals that are insensitive to aversive effects are most likely to develop problem drinking behaviors. These results underscore the importance of the interaction between developmental stage and individual variation in sensitivity to alcohol.     

Effects of energy drinks mixed with alcohol on behavioral control: risks for college students consuming trendy cocktails

Background: There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmED) in young people. AmED have been implicated in risky drinking practices and greater accidents and injuries have been associated with their consumption. Despite the increased popularity of these beverages (e.g., Red Bull and vodka), there is little laboratory research examining how the effects of AmED differ from alcohol alone. This experiment was designed to investigate if the consumption of AmED alters neurocognitive and subjective measures of intoxication compared with the consumption of alcohol alone. Methods: Participants (n = 56) attended 1 session where they were randomly assigned to receive one of 4 doses (0.65 g/kg alcohol, 3.57 ml/kg energy drink, AmED, or a placebo beverage). Performance on a cued go/no‐go task was used to measure the response of inhibitory and activational mechanisms of behavioral control following dose administration. Subjective ratings of stimulation, sedation, impairment, and level of intoxication were recorded. Results: Alcohol alone impaired both inhibitory and activational mechanisms of behavioral control, as evidenced by increased inhibitory failures and increased response times compared to baseline performance. Coadministration of the energy drink with alcohol counteracted some of the alcohol‐induced impairment of response activation, but not response inhibition. For subjective effects, alcohol increased ratings of stimulation, feeling the drink, liking the drink, impairment, and level of intoxication, and alcohol decreased the rating of ability to drive. Coadministration of the energy drink with alcohol increased self‐reported stimulation, but resulted in similar ratings of the other subjective effects as when alcohol was administered alone. Conclusions: An energy drink appears to alter some of the objective and subjective impairing effects of alcohol, but not others. Thus, AmED may contribute to a high‐risk scenario for the drinker. The mix of impaired behavioral inhibition and enhanced stimulation is a combination that may make AmED consumption riskier than alcohol consumption alone.     

Adolescent C57BL/6J mice show elevated alcohol intake, but reduced taste aversion, as compared to adult mice: a potential behavioral mechanism for binge drinking

Background: Binge alcohol drinking during adolescence is a serious health problem that may increase future risk of an alcohol use disorder. Although there are several different procedures by which to preclinically model binge‐like alcohol intake, limited‐access procedures offer the advantage of achieving high voluntary alcohol intake and pharmacologically relevant blood alcohol concentrations (BACs). Therefore, in the current study, developmental differences in binge‐like alcohol drinking using a limited‐access cycling procedure were examined. In addition, as alcohol drinking has been negatively correlated with sensitivity to the aversive properties of alcohol, we examined developmental differences in sensitivity to an alcohol‐induced conditioned taste aversion (CTA). Methods: Binge‐like alcohol consumption was investigated in adolescent (4 weeks) and adult (10 weeks) male C57BL/6J mice for 2 to 4 h/d for 16 days. Developmental differences in sensitivity to an alcohol‐induced CTA were examined in adolescent and adult mice, with saline or alcohol (3 or 4 g/kg) repeatedly paired with the intake of a novel tastant (NaCl). Results: Adolescent mice showed a significant increase in alcohol intake as compared to adults, with adolescents achieving higher BACs and increasing alcohol consumption over successive cycles of the binge procedure. Conversely, adolescent mice exhibited a dose‐dependent reduction in sensitivity to the aversive properties of alcohol, as compared to adult mice, with adolescent mice failing to develop a CTA to 3 g/kg alcohol. Finally, extinction of an alcohol CTA was observed following conditioning with a higher dose of alcohol in adolescent, versus adult, mice. Conclusions: These results indicate that adolescent mice consume more alcohol, per kilogram body weight, than adults in a binge‐like model of alcohol drinking and demonstrate a blunted sensitivity to the conditioned aversive effects of alcohol. Overall, this supports a behavioral framework by which heightened binge alcohol intake during adolescence occurs, in part, via a reduced sensitivity to the aversive properties of alcohol.     

Alcohol control policies and alcohol consumption by youth: a multi-national study

Aims The study examined relationships between alcohol control policies and adolescent alcohol use in 26 countries. Design Cross‐sectional analyses of alcohol policy ratings based on the Alcohol Policy Index (API), per capita consumption and national adolescent survey data. Setting Data are from 26 countries. Participants Adolescents (aged 15–17 years) who participated in the 2003 European School Survey Project on Alcohol and Other Drugs (ESPAD) or national secondary school surveys in Spain, Canada, Australia, New Zealand and the United States. Measurements Alcohol control policy ratings based on the API; prevalence of alcohol use, heavy drinking and first drink by age 13 based on national secondary school surveys; per capita alcohol consumption for each country in 2003. Analysis Correlational and linear regression analyses were conducted to examine relationships between alcohol control policy ratings and past 30‐day prevalence of adolescent alcohol use, heavy drinking and having first drink by age 13. Per capita consumption of alcohol was included as a covariate in regression analyses. Findings More comprehensive API ratings and alcohol availability and advertising control ratings were related inversely to the past 30‐day prevalence of alcohol use and prevalence rates for drinking three to five times and six or more times in the past 30 days. Alcohol advertising control was also related inversely to the prevalence of past 30‐day heavy drinking and having first drink by age 13. Most of the relationships between API, alcohol availability and advertising control and drinking prevalence rates were attenuated and no longer statistically significant when controlling for per capita consumption in regression analyses, suggesting that alcohol use in the general population may confound or mediate observed relationships between alcohol control policies and youth alcohol consumption. Several of the inverse relationships remained statistically significant when controlling for per capita consumption. Conclusions More comprehensive and stringent alcohol control policies, particularly policies affecting alcohol availability and marketing, are associated with lower prevalence and frequency of adolescent alcohol consumption and age of first alcohol use.     

Mecamylamine and ethanol preference in healthy volunteers

BACKGROUND: Recent evidence suggests that some of the behavioral effects of alcohol may be mediated through actions on nicotinic acetylcholine receptors. Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduces alcohol preference and consumption in alcohol-preferring rats, and in humans, mecamylamine dampens some of the subjective, or mood-altering, effects of alcohol. This experiment was designed to investigate the effects of mecamylamine on consumption of alcohol in healthy social drinkers. METHODS: Healthy volunteers (12 men, 12 women) participated in a choice procedure in which they chose between an alcoholic beverage and money (low, medium, or high amounts) after pretreatment with mecamylamine (7.5 or 15 mg) or placebo. Outcome measures were the number of alcoholic beverages consumed and the subjective effects of alcohol. RESULTS: Mecamylamine (15 mg) decreased blood alcohol levels (BALs) after a small fixed dose of alcohol (0.2 g/kg). Even when the lower BALs were taken into account, mecamylamine reduced ratings of stimulation after alcohol (Addiction Research Center Inventory A scale). Mecamylamine did not significantly reduce choice for alcohol versus money. However, there was a tendency for the drug to decrease alcohol choice among participants who reported the greatest stimulant-like effects from alcohol. CONCLUSION: These results provide only limited support for the idea that nicotinic acetylcholine receptors are involved in the rewarding effects of alcohol.     

Serum 6-beta-naltrexol levels are related to alcohol responses in heavy drinkers

BACKGROUND: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. METHODS: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n = 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. RESULTS: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. CONCLUSIONS: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.     

Ethanol‐Induced Conditioned Taste Avoidance: Reward or Aversion?

Background: Rats avoid intake of a palatable taste cue when paired with all drugs of abuse tested. Evidence suggests that, at least for morphine and cocaine, rats avoid the taste cue because they are anticipating the rewarding properties of the drug. Thus, the suppressive effects of a rewarding sucrose solution and cocaine, but not those of the putatively aversive agent, lithium chloride (LiCl), are exaggerated in drug‐sensitive Lewis rats. Likewise, the suppressive effects of sucrose and morphine, but not those of LiCl, are eliminated by bilateral lesions of the gustatory thalamus. Unlike morphine and cocaine, it is less clear whether rewarding or aversive drug properties are responsible for ethanol‐induced suppression of intake of a taste cue. The present set of studies tests whether, like cocaine, ethanol‐induced suppression of intake of a taste cue also is greater in the drug‐sensitive Lewis rats and whether the suppressive effects of the drug are prevented by bilateral lesions of the taste thalamus. Methods: In Experiment 1, fluid‐deprived Lewis and Fischer rats were given 5‐minute access to 0.15% saccharin and then injected with saline or a range of doses of ethanol (0.5, 0.75, 1.0, or 1.5 g/kg). There was a total of 6 such pairings. In Experiments 2 and 3, Sprague–Dawley rats received bilateral electrophysiologically guided lesions of the gustatory thalamus. After recovery, suppression of intake of the saccharin cue was evaluated following repeated daily pairings with either a high (1.5 g/kg) or a low (0.75 g/kg) dose of ethanol. Results: Ethanol‐induced suppression of intake of the saccharin conditioned stimulus (CS) did not differ between the drug‐sensitive Lewis rats relative to the less‐sensitive Fischer rats. Lesions of the taste thalamus, however, prevented the suppressive effect of the 0.75 g/kg dose of the drug, but had no impact on the suppressive effect of the 1.5 g/kg dose of ethanol. Conclusion: The results suggest that the suppressive effects of ethanol on CS intake are mediated by both rewarding and aversive consequences, varying as a function of dose.     

Inflexible and Indifferent Alcohol Drinking in Male Mice

Background: Alcoholism is characterized by compulsive alcohol intake, but this critical feature of alcoholism is seldom captured in preclinical studies. Here, we evaluated whether alcohol‐preferring C57BL/6J mice develop compulsive alcohol drinking patterns, using adulteration of the alcohol solution with quinine, in a limited access choice paradigm. We assessed 2 independent aspects of compulsive drinking: (i) inflexible alcohol intake by testing whether mice would drink bitter alcohol solutions if this was their only source of alcohol and (ii) indifferent drinking by comparing intake of aversive and nonaversive alcohol solutions. Methods: Male C57BL/6J mice consumed alcohol for 2 or 8 consecutive weeks. The alcohol solution was then adulterated with graded quinine concentrations, and the effect on alcohol intake was determined. Results: C57BL/6J mice rapidly developed compulsive alcohol drinking patterns. Adulteration of the alcohol solution with an aversive quinine concentration failed to reduce intake, indicative of inflexible drinking behavior, after only 2 weeks of alcohol experience, although quinine adulteration did suppress the acquisition of alcohol drinking in naïve mice. After 8 weeks of alcohol consumption, the mice also became indifferent to quinine. They consumed an aversive, quinine‐containing alcohol solution, despite the simultaneous availability of an unadulterated alcohol solution. Prolonged alcohol ingestion did not alter the sensitivity to the bitter taste of quinine itself. Conclusion: These findings demonstrate the staged occurrence in mice of 2 distinct behavioral characteristics of alcoholism, i.e., inflexible and indifferent alcohol drinking.     

Behavioral traits predicting alcohol drinking in outbred rats: an investigation of anxiety, novelty seeking, and cognitive flexibility

Background: Most adults in Western society consume alcohol regularly without negative consequences. For a small subpopulation, however, drinking can quickly progress to excessive and chronic intake. Given the dangers associated with alcohol abuse, it is critical to identify traits that may place an individual at risk for developing these behaviors. To that end, we used a rat model to determine whether anxiety‐related behaviors, novelty seeking, or cognitive flexibility predict excessive alcohol drinking under both limited and continuous access conditions. Methods: Adult male rats were assessed in a series of behavioral tasks (elevated plus maze [EPM], locomotor activity, and discrimination/reversal learning in a Y‐maze) followed by 6 weeks of daily, 1‐hour access to alcohol in a free‐choice, 2‐bottle paradigm (10% alcohol vs. tap water). Next, subjects were given the opportunity to consume alcohol for 72 hours in drinking chambers that permit separate measures of each drinking bout. Half of the animals experienced a 2‐week deprivation period between the limited and continuous access sessions. Results: Time spent on the open arms of the EPM, but not novelty seeking or discrimination/reversal learning, predicted alcohol consumption during limited, 1‐h/d access sessions to alcohol. Anxiety‐related behavior also predicted the escalation of intake when animals were given 72 hours of continuous access to alcohol. Bout size, but not frequency, was responsible for the increased consumption by high‐anxiety subjects during this period. Finally, intake during limited access sessions predicted intake during continuous access, but only in subjects with low intake during limited access. Conclusions: These findings confirm that preexisting anxiety‐related behavior predicts alcohol intake under several schedules of alcohol access. Moreover, when access is unlimited, the high‐anxiety‐related group exhibited an increase in bout size, but not frequency, of drinking. In addition, we show that modest intake when alcohol is restricted may or may not progress to excessive intake when the drug is freely available.     

Helplessness in the tail suspension test is associated with an increase in ethanol intake and its rewarding effect in female mice

BACKGROUND: Depression is frequently observed in drug abusers. However, depression may be a primary factor of predisposition to drug abuse or a consequence of drug abuse. The aim of this study was to analyze the influence of a preexisting depressive-like state/helplessness on subsequent alcohol responsiveness in mice. METHODS: Male and female CD1 mice were selected according to their immobility time in the tail suspension test, and only mice with "high immobility" and "low immobility" time were retained. Using a two-bottle free-choice paradigm, these mice were given continuous access to tap water or solutions of ethanol (3-20% v/v), quinine (12.5-50 mg/liter), or sucrose (1-4% w/v). In female mice, rewarding and aversive effects of ethanol (1.5 and 3 g/kg, intraperitoneally) were also investigated using the conditioned place preference and the conditioned taste aversion paradigms. RESULTS: Female mice were more immobile and drank more ethanol than male mice. No striking sex difference was observed in quinine consumption. Sucrose intake was higher in female than in male mice, whatever the solution concentration. At the 4% concentrated solution, a sucrose-induced increase in daily fluid intake was observed only in female mice. Female mice with high immobility time (HI) consumed more ethanol at the highest concentration than female mice with low immobility time (LI), whereas no difference was observed between HI and LI male mice. Moreover, whereas LI female mice failed to express place conditioning induced by the 3-g/kg dose of ethanol, HI female mice were strongly responsive to the rewarding effect of this high ethanol dose. Ethanol dose-dependently induced a conditioned taste aversion with a similar magnitude in both LI and HI female mice. CONCLUSIONS: The findings indicate that female CD1 mice tend to drink greater amounts of ethanol or sucrose solutions than male CD1 mice, suggesting that female mice may be a better model of excessive alcohol intake. Furthermore, no relationship was found between immobility scores and ethanol consumption in male mice. On the contrary, within female mice, HI mice consumed higher amounts of ethanol than LI mice probably because they experienced greater rewarding effects of ethanol. The present results support the hypothesis that depressive-like responses may predispose to ethanol abuse in female mice.     

Solitary versus social drinking: an experimental study on effects of social exposures on in situ alcohol consumption

Background: Whereas the effects of modeling and of drinking contexts on alcohol use are documented, studies are lacking regarding the effect of given social exposures on actual alcohol consumption during drinking episodes (i.e., in situ alcohol consumption, the quantity of alcohol actually ingested in given occasion, e.g., in grams). Methods: Applying the experimental paradigms, our study investigates the impact of social condition (alone vs. with others) on in situ alcohol consumption (analog measurements) of 123 young adults who participated in 2 wine‐tasting sessions (one together with others, i.e., group condition; 1 solitary, i.e., individual condition: the sequence of participation was assigned at random). Bivariate and multivariate analyses, that is, paired‐ and independent‐samples t‐tests and repeated measure analysis of variance, were applied to investigate the effects through both transversal and longitudinal perspectives. Results: In the first session, higher average amounts of alcohol were consumed in the group condition compared with the individual one. Conversely, higher average consumption was recorded in the individual compared with the group condition in the second session. Considering simultaneously data from the 2 experimental sessions demonstrated that subjects consumed higher amounts of alcohol in individual condition when this condition was organized subsequent and not prior to the group condition. Yet, alcohol consumption in group condition appeared to not vary between the 2 sessions. Conclusions: Results first highlight the effects of social condition on in situ alcohol consumption. However, they also suggest that in situ exposition to others drinking is possibly involved in shaping the perception of context‐related drinking norms, which might further influence subsequent drinking behaviors in an analogous context. Beyond the issues of imitation effects, these findings raise the issues of the development of preventive initiatives aiming to induce changes in individuals’ perception of context‐specific drinking norms.     

Modulation of Brain Endocannabinoid Levels by Voluntary Alcohol Consumption in Alcohol-Preferring AA Rats

Background: The central nervous system cannabinoid CB1 receptors have been implicated in regulation of alcohol consumption. Less data are available on the role of the endogenous ligands for these receptors, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), in alcohol‐related behaviors. The purpose of this study was to assess the effects of voluntary alcohol consumption on the levels of these endocannabinoids in key brain areas mediating alcohol reinforcement. Methods: Female and male alcohol‐preferring AA (Alko, Alcohol) rats were trained to drink 10% (v/v) alcohol during 90‐min limited access sessions every second day. Following establishment of stable alcohol drinking, half of the subjects were killed immediately before the daily alcohol access (“pre‐session” group), while the other half was killed after the drinking session (“post‐session” group). A separate control group consisted of water‐drinking rats. AEA and 2‐AG levels were measured from prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), amygdala, and hippocampus using liquid chromatography–tandem mass spectrometry (LC/MS/MS). Results: Voluntary alcohol drinking caused widespread alterations in the levels of both AEA and 2‐AG. Compared to the water group, increased AEA levels were seen in the pre‐session group, but they were decreased immediately following limited access drinking in the female AA rats. Also 2‐AG levels were significantly elevated after long alcohol exposure, and an additional increase was found after limited access drinking in PFC. In males, however, the only alterations caused by alcohol drinking were significantly elevated AEA levels in NAc and CPu in the post‐session group. No changes were seen in the levels of 2‐AG. Conclusions: These results demonstrate that voluntary alcohol drinking modulates the levels of endocannabinoids in several brain areas implicated in alcohol reinforcement. AEA and 2‐AG were differentially affected, suggesting that they could have partially separate modulatory roles. Alterations were more widespread in females than males, possibly reflecting their higher alcohol intake. Taken together, alcohol‐induced release of endocannabinoids may have an important role in alcohol reinforcement and development of alcohol addiction.     

Naltrexone Increases the Latency to Drink Alcohol in Social Drinkers

We investigated the effects of naltrexone (NTX) on alcohol drinking, urge to drink alcohol, and alcohol-induced sensations and mood states in social drinkers consuming alcohol ad libitum in a cocktail bar. Sixteen college-age men and women participated in a double-blind, placebo-controlled, within-subjects, cross-over study. Subjects were tested during each of three drug conditions: NTX, 50 mg/day, po; inactive placebo; and no drug. Each treatment condition lasted 8 to 11 days. Small groups of subjects consumed alcohol ad libitum during three 2-hr evening drinking sessions, separated by ˜2 weeks. NTX treatment significantly increased the latency (time in seconds) to first sip the first ( p < 0.05) and second alcoholic beverages consumed ( p < 0.01). Moreover, the mean blood alcohol concentration at the end of the session was significantly lower when subjects were treated with NTX ( p < 0.05). No differences were found on self-report urge to drink alcohol. Subjects reported more fatigue and tension on the Profile of Mood States ( p < 0.05), before drinking, and increases in nausea on the Alcohol Sensation Scale ( p < 0.05) when treated with NTX. The increase in the latency to sip the first and second alcoholic beverages may reflect the capacity of NTX to block urge for alcohol elicited from external cues (before consuming alcohol), as well as urge for alcohol after priming from ingested alcohol. Thus, the effectiveness of NTX for reducing drinking behaviors of alcoholics may be partially caused by anticraving properties of NTX.     

Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: II. Adult exposure

Background In a preceding study, we reported that ethanol (EtOH) consumption during periadolescence in alcohol‐preferring (P) rats produced significant effects on the acquisition, extinction, Pavlovian spontaneous recovery (PSR), and reacquisition of operant self‐administration of EtOH. The objective of the present study was to determine if EtOH consumption during adulthood produced similar effects on subsequent operant behaviors. Methods Adult female P rats (>135 days of age) were given 24 hr free‐choice access to 15% EtOH for 30 days or were similarly housed and received water only. After a 15 day period of no EtOH access and without any prior training, adult alcohol drinking and adult alcohol‐naïve rats were placed in standard two‐lever (15% EtOH and water) chambers to examine acquisition of EtOH self‐administration. After stable responding was established on a concurrent fixed ratio (FR) 5 FR1 schedule for EtOH versus water, the P rats underwent extinction training for nine sessions. After extinction and a 2 week home cage period (with no operant sessions or access to EtOH), rats were returned to the operant chambers in the absence of reward for seven consecutive sessions to test for PSR. After PSR testing, animals were maintained in their home cage for a week, before being reintroduced to the operant chambers and allowed to respond for EtOH and water. Results Both the adult alcohol‐drinking and adult alcohol‐naïve groups rapidly acquired EtOH self‐administration, expressed a pronounced PSR, which was augmented by EtOH priming and the presence of a discriminative stimulus (odor cue), and increased responding when EtOH was reinstated. Adult pre‐exposure to EtOH did not alter any of the operant measures. Conclusions The results of this study suggest that, unlike the results with EtOH pre‐exposure during periadolescence, chronic alcohol drinking by P rats in adulthood did not produce sufficient long‐lasting changes in neuronal function to alter subsequent operant acquisition of alcohol self‐administration, alcohol relapse, or alcohol‐seeking behavior.     

Pharmacologic Dissociation Between Impulsivity and Alcohol Drinking in High Alcohol Preferring Mice

Background: Impulsivity is genetically correlated with, and precedes, addictive behaviors and alcoholism. If impulsivity or attention is causally related to addiction, certain pharmacological manipulations of impulsivity and/or attention may affect alcohol drinking, and vice versa. The current studies were designed to explore the relationship among impulsivity, drinking, and vigilance in selectively bred High Alcohol Preferring (HAP) mice, a line that has previously demonstrated both high impulsivity and high alcohol consumption. Amphetamine, naltrexone, and memantine were tested in a delay discounting (DD) task for their effects on impulsivity and vigilance. The same drugs and doses were also assessed for effects on alcohol drinking in a 2‐bottle choice test. Methods: HAP mice were subjected to a modified version of adjusting amount DD using 0.5‐second and 10‐second delays to detect decreases and increases, respectively, in impulsive responding. In 2 experiments, mice were given amphetamine (0.4, 0.8, or 1.2 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) before DD testing. Another pair of studies used scheduled access, 2‐bottle choice drinking to assess effects of amphetamine (0.4, 1.2, or 3.0 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) on alcohol consumption. Results: Amphetamine dose‐dependently reduced impulsivity and vigilance decrement in DD, but similar doses left alcohol drinking unaffected. Naltrexone and memantine decreased alcohol intake at doses that did not affect water drinking but had no effects on impulsivity or vigilance decrement in the DD task. Conclusions: Contrary to our hypothesis, none of the drugs tested here, while effective on either alcohol drinking or impulsivity, decreased both behaviors. These findings suggest that the genetic association between drinking and impulsivity observed in this population is mediated by mechanisms other than those targeted by the drugs tested in these studies.     

Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol

BACKGROUND: Central nicotinic cholinergic receptors modify alcohol-induced mesolimbic dopamine activation, which seems to be important in the reinforcing properties of alcohol. Consistent with this model, acute administration to rats of the tertiary nicotinic receptor antagonist mecamylamine blocks both alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens. This study was conducted to test the hypothesis that, during the ascending limb of the blood alcohol concentration curve, mecamylamine would reduce the stimulating and pleasurable effects of an intoxicating dose of alcohol in humans. METHODS: Ten female and 10 male volunteers with no history of alcohol or substance use disorders, including nicotine dependence, completed the study. During two laboratory sessions, subjects consumed three aliquots of an alcohol-containing drink, with a total ethanol content of 0.7 g/kg (in women) or 0.8 g/kg (in men), over a 30-min period. Two hours before the first drink, subjects were pretreated with mecamylamine or placebo, with the order of sessions counterbalanced. Primary outcome measures included the Drug Effect Questionnaire, the central stimulation subscale of the Alcohol Sensation Scale, and the stimulant subscale of the Biphasic Alcohol Effects Scale. Breath alcohol level (BAL) was examined to identify the ascending and descending limbs of the blood alcohol curve and to assess pharmacokinetic interactions between alcohol and mecamylamine. RESULTS: Significant effects of time, study drug, and their interaction were observed. Compared with placebo, mecamylamine reduced BAL. After controlling for BAL at each time point, mecamylamine also reduced the Drug Effect Questionnaire and Alcohol Sensation Scale stimulant subscale scores, with a trend for a similar effect on the Biphasic Alcohol Effects Scale score. CONCLUSIONS: Mecamylamine seems to modify both the pharmacokinetic profile of alcohol and the rewarding effects of alcohol in healthy volunteers.     

Regulation of operant oral ethanol self-administration: a dose-response curve study in rats

Background: Oral ethanol self‐administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose–response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose–response curve for oral ethanol self‐administration can be obtained in rats. Methods: Long‐Evans rats were trained to self‐administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self‐administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self‐administration of a 20, 40, and 60% ethanol solution. Results: Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U‐shaped dose–response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. Conclusion: This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders.     

Reasons for Drinking and Alcohol Use in Young Adults at High Risk and at Low Risk for Alcoholism

This study examined the relationship of attitudes towards the use of alcohol and alcohol consumption among young adult offspring of alcoholic (N=130) and non-alcoholic (N = 75) parents. No differences were found between the two samples in the subjects’reported reasons for drinking or reasons for limiting consumption. In general, the greater the total amount of alcohol consumed, the more important were social enhancement and relief of unpleasant affect as reasons for drinking. Further, reasons for limiting alcohol consumption did not distinguish the high risk and low risk groups. Across both samples, lower consumption was associated with not wanting to become intoxicated, not liking the alcohol effect and not liking the taste. The associations found between reasons for not drinking and decreased consumption were smaller than the associations found between reasons for drinking and increased consumption.