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The study of the biological mechanisms of ethanol reward has greatly suffered from problems to obtain ethanol-induced conditioned place preference (CPP) in rats. In the present study, CPP was obtained in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, derived from Sardinian alcohol-preferring rats, following intragastric (IG) ethanol administration by means of a permanent IG catheter, but not after intraperitoneal (IP) injection or IG gavage. Rats with permanent IG catheter, received IG administration of 0.35, 0.7, 1.5 or 2.8 g/kg ethanol, as a 10% v/v solution. In ethanol-experienced rats 0.7 or 1.5, but not 0.35 or 2.8 g/kg ethanol significantly increased in comparison to controls the time spent in the ethanol-associated previously non-preferred compartment, which became preferred in the post-conditioning test. In ethanol-naive rats, only 0.7 g/kg ethanol significantly increased the time spent in the ethanol-associated compartment. On the other hand, no effect was observed in alcohol-experienced rats following IG gavage, or IP injection of 0.35, 0.7 or 1.5 g/kg ethanol. The present results provide evidence that ethanol possesses postingestive rewarding properties in msP rats, and that it can reliably induce CPP in them, provided that an appropriate method of administration is adopted.

The opiate agonist morphine has been shown to increase ethanol intake and mesolimbic dopamine (DA) levels. Conversely, the 5-HT3/4 antagonist tropisetron has been shown to decrease ethanol intake and morphine-induced increases in mesolimbic DA levels. This study was designed to test the effects of acutely administered tropisetron on morphine-induced changes in ethanol (6% v/v) and water intake in a two-bottle test procedure. Ten water restricted male rats were injected with combinations of morphine (0.0, 0.56, 1.0, 1.5, 10.0, and 17.0 mg/kg, SC) and tropisetron (0.0, 1.0, 10.0, and 17.0 mg/kg, SC) prior to test sessions. Morphine (1.0 and 1.5 mg/kg) significantly increased absolute (g/kg) and relative ethanol intake (ethanol/total fluid). Tropisetron alone did not affect ethanol or water intake. When tropisetron (10.0 and 17.0 mg/kg) was administered in combination with morphine (1.5 mg/kg), the increase in ethanol intake induced by morphine was attenuated. Tropisetron (1.0 mg/kg) reversed a decrease in ethanol intake induced by morphine (17.0 mg/kg). The two highest doses of tropisetron partially attenuated a significant decrease in water intake produced by morphine (17.0 mg/kg). These data suggest that opiate and 5-HT3 mechanisms could interact in the regulation of ethanol intake. However, the doses of tropisetron tested were high and, therefore, the potential involvement of 5-HT4 receptors or other neurotransmitter systems in regulating ethanol intake is discussed.

The purpose of this study was to examine the long-term behavioral effects of prenatal ethanol exposure in C57BL mice. Pregnant mice received free access to a liquid diet containing 25% ethanol-derived calories (EDC) from gestation days 6 to 18. Control animals were pair-fed an isocaloric 0% EDC diet during the same period of time. An additional control group was included that was maintained on standard lab chow and water throughout pregnancy. At 30 days of age, female offspring were tested for spontaneous locomotor activity in an open field under two lighting conditions (dim or bright illumination). Male offspring were tested in a passive avoidance task at 25 days of age. The activity results demonstrated that the 25% EDC female progeny were more active than controls. This hyperactivity was observed under both lighting conditions, despite the fact that all groups evidenced suppressed activity when tested under bright lights. With regard to passive avoidance behavior, male EtOH-exposed offspring required a greater number of trials to reach criterion than controls. Additionally, they exhibited shorter latencies to enter the shock-associated chamber after receiving a single shock. Taken together, these results confirm our previous findings and demonstrate that C57BL mice are sensitive to both the deleterious behavioral and morphological consequences of prenatal ethanol exposure.

Abstract Rationale Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. Objective The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. Methods Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. Results The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. Conclusion Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

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.

Effects of psychological stress on acute alcohol intoxication following intake of 2 ml whisky/kg body weight were examined in 12 healthy subjects. Each subject performed a 45-min psychomotor task under four conditions, two of which increased achievement stress by promising the subject a monetary reward for rapid and accurate performance. The conditions were (a) task only, (b) task + reward, (c) task + alcohol, and (d) task + reward + alcohol. In condition (b) reward improved performance and heightened both physiological and subjective arousal, and in condition (c) alcohol impaired performance, lowered subjective arousal, and increased physiological arousal. In condition (d) the reward counteracted the depressant effects of alcohol on performance and mood, whereas an additive, arousing effect was obtained in all physiological variables, i.e., catecholamine and cortisol excretion and heart rate.

Two lines of rats bred for differences in motor impairment following alcohol treatment were also found to be differentially affected by sodium pentobarbital in three experiments. The most affected (MA) animals, bred for sensitivity to alcohol, showed a decrement in stabilimeter activity at doses of 8 mg and 16 mg pentobarbital per kg body weight. The least affected (LA) animals, bred for insensivity to alcohol, were affected only by the higher dose, at which the resulting impairment was still less than that of the MA group. This finding was partially replicated in a second study designed to test the possibility of an activating effect of pentobarbital on LA animals at 8 mg/kg. In a final study, MA animals were more likely to lose their righting reflex than LA animals at a dose of 18 mg/kg, and 'slept' longer following this dose. These results indicate that the differential sensitivity shown by these animals is not specific to alcohol, but can be generalized to another depressant.

Alcohol is a recreational substance that is generally socially acceptable and legal in most areas worldwide. An alcohol overdose will produce an inhibitory effect on the brain and impair cognition and memory. In this study, we examined the effect of alcohol on the acquisition, consolidation, and reconsolidation of drug reward memory induced by morphine and cocaine in rats.Rats were trained to acquire morphine sulfate (10 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) conditioned place preference (CPP) via an unbiased CPP paradigm. Vehicle or alcohol (0.25, 0.75, 1.5 g/kg, i.p.) was administered at various time-points, including 30 min before each CPP conditioning session (acquisition), immediately after each CPP conditioning session (consolidation), immediately after the reactivation of CPP (reconsolidation with re-exposure), or without reactivation to the drug-paired context (reconsolidation without re-exposure). Conditioning scores were recorded before or after each conditioning session or memory reactivation.Alcohol at a dose of 1.5 g/kg but not 0.25 g/kg or 0.75 g/kg significantly inhibited the acquisition and reconsolidation of morphine- and cocaine-associated memory. In contrast, alcohol had no effect on the consolidation of morphine- or cocaine-induced CPP.The results suggested that pre-exposure alcohol dose-dependently attenuated morphine- or cocaine-induced place preference and prevented drug reinstatement in rats by disrupting memory reconsolidation, which may be explained by the inhibitory effect of alcohol on dopaminergic and glutamatergic neurotransmission.