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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.

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.

Human ethanol withdrawal manifests as multiple behavioral deficits with distinct time courses. Most studies with mice index ethanol withdrawal severity with the handling-induced convulsion (HIC). Using the accelerating rotarod (ARR), we recently showed that ethanol withdrawal produced motor impairment.This study aimed (a) to characterize further the ARR withdrawal trait, (b) to assess generalizability across additional behavioral assays, and (c) to test the genetic correlation between ethanol withdrawal ARR impairment and HICs.The severity of the ARR performance deficit depends on ethanol vapor dose and exposure duration, and lasts 1-4 days. Fatigue could not explain the deficits, which were also evident after intermittent exposure to ethanol vapor. Withdrawing mice were also impaired on a balance beam, but not on a static dowel or in foot slip errors per distance traveled in the parallel rod floor test, where they showed reduced locomotor activity. To assess genetic influences, we compared Withdrawal Seizure-Prone and -Resistant mice, genetically selected to express severe vs. mild withdrawal HICs, respectively. The ARR scores were approximately equivalent in all groups treated with ethanol vapor, though Withdrawal Seizure-Prone (WSP) mice may have displayed a slightly more severe deficit as control-treated WSP mice performed better than control-treated Withdrawal Seizure-Resistant mice.These studies show that ethanol withdrawal motor impairment is sensitive to a range of ethanol doses and lasts for several days. Multiple assays of behavioral impairment are affected, but the effects depend on the assay employed. Genetic contributions to withdrawal-induced ARR impairment appear largely distinct from those leading to severe or mild HICs.

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults.

Background: Alcohol priming can modulate the value of rewards, as observed through the effects of acute alcohol administration on cue reactivity. However, little is known about the psychophysiological mechanisms driving these effects. Here we examine how alcohol-induced changes in bodily states shape the development of implicit attentional biases and explicit cue reactivity. Aims: To characterize the interoceptive correlates of alcohol priming effects on alcohol attentional biases and cue reactivityMethods: In a two-session double blind alcohol administration procedure, participants (n=31) were given a 0.4g/kg dose of alcohol or a placebo drink. Cardiovascular responses were measured before and after alcohol administration to observe the effects of alcohol on viscero-afferent reactivity, as indexed through changes in heart-rate variability (HRV) at or near 0.1Hz (0.1Hz HRV). Next, participants completed a modified Flanker task to examine implicit alcohol attentional biases and provided subjective valence and arousal ratings of alcohol cues to examine explicit cue reactivity. Results: We found that changes in 0.1Hz HRV after alcohol administration positively correlated with attentional biases, and negatively correlated with alcohol valence ratings; breath alcohol content was a null predictor. Conclusion: This is novel evidence that suggests alcohol-induced changes in bodily states may mediate the occurrence of alcohol priming effects, and highlights the potentially generative role of interoceptive mechanisms in alcohol-related behaviors. The differential patterns revealed by implicit biases and explicit response tendencies is considered within the context of the dissociation between wanting and liking.