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Preclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated.We performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11-12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 μg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout.Liraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle.The present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.

Studies on laboratory animals have provided conflicting results regarding the actions of stressors on the rewarding effects of alcohol. In the present study, we first examined the effects of footshock or social defeat, given during deprivation, on the alcohol deprivation effect (ADE). We then tested the effects of stressors on place conditioning to alcohol, another technique used to measure drug reward.Male Wistar rats were trained to drink 10% alcohol in a 24 h access, free-choice design and received intermittent footshock or defeat 5 times during a 2-week alcohol deprivation period, followed by 2 weeks of free access to alcohol. There were three such cycles. In the place conditioning studies, animals received footshock, defeat, or no stress immediately prior to conditioning sessions where they received alcohol (0.6 or 1.0 g/kg, i.p.) or vehicle injections.Alcohol intake of footshock-treated animals was significantly higher than that of controls following the first and second, but not the third period of alcohol deprivation and stress exposure. Defeat caused a smaller increase in alcohol intake that was significant only after the first deprivation and stress cycle. In the place conditioning studies, we found that either stressor blocked the place aversion induced by 1.0 g/kg alcohol.These results demonstrate that stressors can modify the rewarding and aversive properties of alcohol, measured using two different paradigms. Footshock and defeat produced transient, but significant increases in the magnitude of ADE, while exposure to either stressor reduced the aversive effects of a high dose of alcohol measured using the place conditioning paradigm.

Each of 40 fasting human subjects (20 men and 20 women) consumed 1 g ethanol (absolute) per kilogram body weight as a 20% solution by volume in orange juice. The time to peak BAC was found to be 24.0 min later than the time to peak alcohol effect as measured by magnitude estimation. This difference is both large and statistically reliable. These data are compared with those in the literature which usually show these events to be synchronous. Discussion includes reasons for this empirical discrepancy, implications of the theory of acute tolerance, and plans for future research. Examination of group data shows the same general trends obtained in the analysis of individual data: alcohol-effect scores reach peak earlier than BAC for the group as a whole (n = 40), or for men alone, or for women alone. Moreover, alcohol-effect scores decline more rapidly in later trials than BAC scores, as has been reported earlier.

Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

Early exposure to stress and teratogenic substances have an impact on brain structures involved in cognition and mental health. While moderate-to-high levels of prenatal alcohol exposure (PAE) have repeatedly been associated with long-term neurodevelopmental deficits, no consensus has yet been reached on the detrimental effects of low-to-moderate PAE on the children's functioning, including the limbic-hypothalamic-pituitary-adrenal axis.The study aims to examine the association between low PAE and cortisol response to unfamiliar situations in 19-month-old children and to determine whether this association was moderated by sex and testosterone levels.Information regarding PAE, cortisol response to unfamiliar situations, and testosterone activity was available in a total of 130 children participating to the Québec Newborn Twin Study (Montréal, QC, Canada). Mother alcohol consumption during pregnancy was assessed via a semistructured interview conducted when the children were 6 months of age. The contribution of prenatal and postnatal confounds were examined.Disrupted patterns of cortisol activity were observed only in PAE males. Testosterone tended to be negatively associated with the cortisol response, but not for PAE males, suggesting an altered sensitivity to the inhibitory effects of testosterone in these participants.Low levels of PAE were associated with disrupted cortisol activity, and males may be at higher risk. These findings challenge the existence of a "safe level" of alcohol consumption during pregnancy and have public health implications.

Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training.Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats ( n=11-12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5-10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC).Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure.The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.

Many theories of addictive behavior propose that cues signaling drug administration influence the likelihood of drug-taking and drug-seeking behavior.We investigated the behavioral impact of cues associated with unsweetened ethanol and their interaction with responding maintained by ethanol self-administration. Our goal was to establish the influence of such cues on ethanol seeking.The experiment used a matching contingency and saccharin-fading procedure to establish equal levels of responding to two spatially distinct levers using unsweetened 10% ethanol solution. After ethanol self-administration was established, a brief cue light located alternately over each lever location was either paired or unpaired (control) with the opportunity to consume the same ethanol solution. Finally, self-administration was re-established, and the effect of the cue was measured in a transfer design.The reaction to lights paired with the opportunity to ingest unsweetened ethanol had three main effects: (1) induction of operant behavior reinforced by ethanol, (2) stimulation of ethanol-seeking behavior (drinker entries), and (3) cue-directed approach and contact behavior (i.e. autoshaping or sign-tracking). Cue-directed behavior to the light interacted with choice behavior in a manner predicted by the location of the cue light, enhancing responding only when the approach response did not interfere with the operant response.These findings replicate and extend the effects of Pavlovian conditioning on ethanol-seeking and support-conditioned incentive theories of addictive behavior. Signals for ethanol influence spatial choice behavior and may be relevant to attentional bias shown to alcohol-associated stimuli in humans.

Alcohol and nicotine are the most commonly abused drugs, and they are often taken together. We have developed a procedure in which rats self-administer nicotine intravenously and alcohol orally during the same operant session.Male Wistar rats were trained to self-administer alcohol (12%, w/v; 0.19 ml/alcohol delivery) or implanted with jugular catheters and trained to self-administer nicotine (30 microg/kg i.v./infusion) by pressing a lever or were trained to self-administer both drugs, some with alcohol first, and others with nicotine first. The effects of extinction of responding for either or both drugs in animals trained to coadminister alcohol and nicotine and the effects of alcohol and nicotine primes on reinstatement were also determined.Animals readily coadministered alcohol and nicotine concurrently. Access to alcohol reduced nicotine self-administration significantly. When responding for alcohol was extinguished with nicotine still available, extinction of alcohol seeking was slowed significantly. In rats trained to coadminister nicotine and alcohol, priming with nicotine or alcohol reinstated extinguished responding for both drugs. Reinstatement of extinguished nicotine or alcohol seeking by, respectively, nicotine or alcohol priming was unaffected by continued access to the other drug.These results show that rats will self-administer relevant amounts of intravenous nicotine and oral alcohol concurrently. They also provide further support for the important relationship between nicotine and alcohol.