Aversive Effects Of Alcohol Research Articles

Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice

RationaleAlcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce.ObjectivesTo assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice.MethodsMale and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group.ResultsExendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects.ConclusionsIn male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.

Acute subjective response to alcohol as a function of reward and punishment sensitivity

Individual differences in subjective response to alcohol play a crucial role in the development of heavy drinking and related problems. In light of this, a growing focus of research has been identifying factors that contribute to differences in response. The aim of the present study was to determine whether individual differences in the subjective experience of rewarding and aversive effects of alcohol are a specific manifestation of general differences in reward and punishment sensitivity. Eighty-nine participants (M age=22.4, SD=1.9; 47.2% women) consumed a moderate dose of alcohol, i.e., peak breath alcohol concentration (BrAC)≈0.080g%, and rated their level of stimulation and sedation at seven timepoints over the BrAC curve. Sensitivity to reward and punishment were assessed by a self-report questionnaire prior to consumption. Multilevel growth models showed that post-consumption changes in stimulation ratings varied as a function of participants' level of reward and punishment sensitivity. Drinkers more sensitive to reward reported feeling more stimulated shortly after drinking and exhibited an attenuated rate of decline in stimulation over the blood alcohol curve, relative to drinkers with less strong reward sensitivity. Reward sensitivity was not related to subjective ratings of sedation, and punishment sensitivity was not related to either stimulation or sedation ratings. Findings suggest that reward sensitivity may increase risk for alcohol misuse among young adult social drinkers by increasing their subjective feelings of stimulation while drinking.

Una revisión de la literatura experimental sobre los efectos motivacionales del alcohol y su modulación por factores biológicos y ambientales.

Title: A review of experimental literature on alcohols motivational effects and its modulation by biological and environmental factors. Abstract: Alcohol is probably the most consumed psychoactive drug in the world. Controlled consumption of alcohol is common, but for many individuals this consumption becomes an addiction. The progression from an habitual consumption of alcohol to abuse of the substance could be due to the existence of a differential sensitivity, which would be genetically determined, to the reinforcing and aversive effects of alcohol. Likewise, it has been suggested that environmental factors such as stress might be involved in the onset of alcoholism, influencing on such a differential sensitivity and, ultimately, on the consumption of alcohol. In this paper it is reviewed the experimental published data on each of the elements of the relationship between stress and ethanol. Thus, on the one hand they are reviewed the main animals models of stress and, on the other hand, we approached the study of the reinforcing and aversive properties of ethanol, including data on the influence of variables such as age, sex, and previous experience with the drug. And, finally, we present a resume of data collected from animal research on the influence of stress on the perception of the motivational opposing properties of ethanol. Our purpose is help to clarify the existing knowledge about the relations between biological factors (such as sex or age) and environmental factors (previous experience and stress), and the behavior of alcohol intake, thus highlighting the importance of some factors of risk for developing alcoholism.

What Aspects of Human Alcohol Use Disorders Can Be Modeled Using Selectively Bred Rat Lines?

The use of selective breeding to produce animal models for the study of alcohol abuse and alcoholism represents one of the major advances in the field of alcohol research. Rats selectively bred for alcohol preference and alcohol nonpreference have been useful to both preclinical and clinical investigators in the alcohol research community for studying the behavioral, neurobiological, and molecular basis of alcohol drinking, for identifying the genes that may contribute to the development of alcohol abuse and alcoholism, and for evaluating the utility of drugs aimed at reducing alcohol intake and preventing alcohol relapse. Rats selectively bred for alcohol preference (alcohol preferring or “P” line) have enhanced responsiveness to the low dose reinforcing effects of alcohol, less aversion to moderate/high doses of alcohol, and are able to develop tolerance to the aversive effects of alcohol more rapidly and to maintain tolerance longer than rats selectively bred for alcohol nonpreference (alcohol nonpreferring or “NP” line). The increased potency of low-dose alcohol as a reinforcer for P rats might be expected to foster and maintain alcohol drinking. Weaker aversion to the pharmacological effects of moderate/high doses of alcohol in the P line would allow P rats to drink more alcohol than NP rats before the postingestional effects become aversive. Rapid induction of tolerance to the aversive effects of alcohol with repeated bouts of voluntary alcohol drinking, as well as persistence of alcohol tolerance in rats of the P line might serve to maintain alcohol drinking. These are powerful mechanisms that may serve to promote and maintain a high alcohol drinking behavior. Although these rat lines have been used to address several characteristics of excessive alcohol consumption in humans, they have not yet been used to model several aspects of human alcohol use disorders. New applications of these selectively bred rat lines are discussed which may further our understanding of the factors contributing to alcohol abuse and alcoholism.

Dissociation between the aversive and pharmacokinetic effects of ethanol in female Fischer and Lewis rats

In humans and laboratory animal models, vulnerability to alcohol abuse is influenced by endogenous factors such as genotype. Using the inbred Fischer and Lewis rat strains, we previously reported stronger conditioned taste aversions (CTA) in male Fischer rats that could not be predicted by genotypic differences in alcohol absorption [Roma PG, Flint WW, Higley JD, Riley AL. Assessment of the aversive and rewarding effects of alcohol in Fischer and Lewis rats. Psychopharmacology (Berl) 2006;189:187–99]. The present study made similar assessments in Fischer and Lewis females via four-trial CTA induced by 1 or 1.5 g/kg intraperitoneal (IP) ethanol ( n = 10–12/strain/dose) as well as measures of blood alcohol concentrations (BAC) at 15, 60 and 180 min post-injection with 1.5 g/kg IP ethanol or saline ( n = 7–8/strain/dose). Dose-dependent CTAs were produced, but the strains did not differ from each other in these measures; however, BACs in the Lewis females were significantly higher than Fischer at all three time points. As with males of the Fischer and Lewis genotypes, a dissociation between BACs and the aversive effects of alcohol was observed. These data are the first assessments of these particular phenotypes in Fischer and Lewis females, and when considered with the historical data, suggest a Genotype × Sex interaction in the centrally mediated sensitivity to alcohol's aversive effects.

Place Conditioning: Age‐Related Changes in the Rewarding and Aversive Effects of Alcohol

Background: Alcohol abuse levels are very high in adolescents, creating a significant societal issue. It has been shown that people who begin alcohol use as adolescents are more likely to become addicts than people who initiate alcohol use as adults. It is important to note that the development of addiction in humans is more rapid with initiation in adolescence than in adulthood.Methods: To determine changes in the reinforcing efficacy of alcohol as a function of adolescent development, we used a place‐conditioning paradigm. In this study, we assessed the ability of ethanol to support a conditioned place preference (CPP) or aversion. Animals [postnatal days (PND) 25, 35, 45, and 60] were tested for alcohol‐induced conditioning in response to a range of ethanol doses (0.2, 0.5, 1.0, and 2.0 g/kg intraperitoneally) or saline.Results: In general, there was a trend for alcohol to produce an aversion to the ethanol‐paired compartment at higher doses. These patterns differed significantly as a function of age. Younger animals (PND 25) exhibited a CPP to a low dose and an aversion at high doses. Late‐adolescent (PND 45) animals exhibited a CPP at two moderate doses but a conditioned place aversion at the highest dose. PND 35 and 60 animals did not exhibit a CPP at any examined dose, and PND 60 animals exhibited a progressive aversion with increasing dose.Conclusions: The data show that the developmental processes of adolescence influence general responsiveness to alcohol. Specifically, late‐adolescent animals (PND 45) seem to prefer doses of alcohol that are either not reinforcing (0.5 g/kg) or are aversive (1.0 g/kg) at other ages. These processes need to be examined thoroughly to understand the development of addiction in adolescence. This is especially important given that alcohol abuse in adolescence may interfere with the usual pattern of brain development as it relates to alcohol reinforcement.

Ondansetron alters human alcohol intoxication

There is considerable evidence that serotonin-3 (5-HT3) receptor antagonists modulate some of the behavioral effects of alcohol, and may decrease alcohol consumption. To better clarify the mechanism of action of 5-HT3 antagonists on these behaviors, we investigated the effects of the 5-HT3 antagonist, ondansetron, on several subjective and objective measures of alcohol intoxication in social drinkers. Twelve nonalcoholic, social drinkers received either 8 mg ondansetron, p.o., or placebo during one of two test sessions in a crossover, double-blind protocol. Both conditions were followed by a standard, intoxicating dose of alcohol. Subjective and objective measures of intoxication including mood, physical sensations, performance changes, and alcohol pharmacokinetics were determined. To control for ondansetron effects, 10 additional subjects received either ondansetron or placebo, followed by a nonintoxicating, "placebo" dose of alcohol during a second crossover double-blind protocol. Ondansetron was found to augment certain stimulant, sedative, and discriminant effects of alcohol, without affecting psychomotor performance or alcohol pharmacokinetics. Ondansetron had minimal effects on subjects receiving placebo alcohol. These data suggest that the reductions in alcohol consumption observed in animals and humans treated with ondansetron may be mediated by increases in subjective intoxication, and/or increases in the aversive effects of alcohol.

Defective habituation to nociceptive stimulation in alcohol-avoiding ANA rats.

Brain opioidergic mechanisms participate in the regulation of motivational and ingestive behaviours. Since alcohol is believed to activate endogenous opioid systems and to produce opioid-mediated antinociception, the present experiments were performed to find out if alcohol-induced antinociception differs between the alcohol-preferring AA and alcohol-avoiding ANA rat lines. Alcohol doses relevant to the voluntary alcohol intake by the AA rats (0.5-1.0 g/kg, intraperitoneally) failed to alter tail-flick (TF) latency in a 55 degrees C water bath by either rat line. However, repeated measurement of TF latency, even without any alcohol treatment, prolonged tail-flick latencies in AA but not in ANA rats. Prolongation of TF latency was also seen in non-selected Wistar rats, indicating that the ANA rats respond abnormally in this test. The antinociceptive effects of swimming-induced stress (3 min at 15 degrees C) and those of cumulative morphine administration (0.5-16.0 mg/kg, subcutaneously) were similar in both rat lines. Using higher, motor-impairing alcohol doses with repeated baseline TF determinations, it was observed that a dose of 1.5 g/kg induced slight antinociception only in the AA rats, while 2.0 g/kg produced similar effects in both rat lines. It is thus concluded that the alcohol-preferring AA rats do not show any enhanced alcohol-induced antinociception at relevant alcohol doses. However, the alcohol-avoiding ANA rats appear to have a defective ability to habituate to repeated sensory stimuli, which could contribute to their alcohol avoidance by preventing the development of tolerance to aversive effects of alcohol.