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Adaptation to a repeated restraint stress schedule was monitored in ethanol-treated and control rats. A single episode of 2 h restraint decreased food intake in both control and ethanol-treated rats. The decreases in control rats were not observed following the 5th daily restraint of 2 h/day, suggesting that adaptation has occurred. Ethanol-treated rats, however, exhibited decreased food intake even after 5th daily restraint of 2 h/day. Ethanol administration decreased weekly but not daily cumulative food intake in unrestrained rats. Food intakes of ethanol-treated and control restrained rats were comparable following 1st-3rd daily restraints, but were smaller in ethanol-treated rats following the 4th and 5th daily restraints. Open-field ambulatory activities monitored 24 h after the 5th daily restraint on the 6th day were comparable in control restrained and unrestrained rats. Ethanol-treated and control unrestrained rats also exhibited comparable ambulation, but ethanol-treated rats exhibited smaller activity than control restrained or ethanol-treated unrestrained rats. Fluid intakes of ethanol and control rats were comparable during the 2 weeks of ethanol administration, but daily restraint schedule decreased ethanol intake. The findings show adaptation to repeated restraint in control rats and inability of ethanol-treated rats to adapt in the stress schedule. These findings imply that excessive alcohol consumption may impair adaptation to stress and thus conceivably precipitate depression.

Treatment of mice in vivo with 5% w/v ethanol given in a liquid diet causes marked changes in spleen, peripheral blood, and thymus lymphocytes. In both the thymus and spleen, there is an acute cellular depletion resulting in a significant decrease in gross tissue size and cell number. In spleen and peripheral blood, the percentage of T lymphocytes is increased relative to B lymphocytes, but the ratio of CD4+/CD8+ T cell sub‐populations remains unchanged. Splenic natural killer (NK) cell activity is increased in ethanol‐consuming mice, although the percentage of NK1.1+ cells is relatively unchanged.

Background:The ventral tegmental area (VTA) is involved in regulating ethanol drinking, and the posterior VTA seems to be a neuroanatomical substrate that mediates the reinforcing effects of ethanol in ethanol‐naïve Wistar and ethanol‐naïve alcohol‐preferring (P) rats. The objective of this study was to test the hypothesis that chronic ethanol drinking increases the sensitivity of the posterior VTA to the reinforcing effects of ethanol.Methods:Two groups of female P rats (one given water as its sole source of fluid and the other given 24‐hr free‐choice access to 15% ethanol and water for at least 8 weeks) were stereotaxically implanted with guide cannulae aimed at the posterior VTA. One week after surgery, rats were placed in standard two‐lever (active and inactive) operant chambers and connected to the microinfusion system. Depression of the active lever produced the infusion of 100 nl of artificial cerebrospinal fluid (CSF) or ethanol. The ethanol‐naïve and chronic ethanol‐drinking groups were assigned to subgroups to receive artificial CSF or 25, 50, 75, or 125 mg/dl of ethanol (n= 6–9/dose/group) to self‐infuse (FR1 schedule) during the 4‐hr sessions given every other day.Results:Compared with the infusions of artificial CSF, the control group reliably (p < 0.05) self‐infused 75 and 125 mg/dl of ethanol but not the lower concentrations. The ethanol‐drinking group had significantly (p < 0.05) higher self‐infusions of 50, 75, and 125 mg/dl of ethanol than artificial CSF during the four acquisition sessions; the number of infusions of all three doses was higher in the ethanol‐drinking group than in the ethanol‐naive group. Both groups decreased responding on the active lever when artificial CSF was substituted for ethanol, and both groups demonstrated robust reinstatement of responding on the active lever when ethanol was restored.Conclusions:Chronic ethanol drinking by P rats increased the sensitivity of the posterior VTA to the reinforcing effects of ethanol.

Acute ingestion of ethanol impairs memory, an effect which might be related to ethanol-induced inhibition of vasopressin release. This was studied using tests of memory and cognitive function in 26 normal subjects before and after ethanol ingestion. Equal numbers of subjects received randomly, by double-blind intranasal administration, placebo or 1-desamino-8-D-arginine vasopressin prior to ethanol ingestion. Administration of the vasopressin analog did not reverse the ethanol-induced deficits in memory and cognitive function.

Adolescents frequently engage in risky behaviours such as binge drinking. Binge drinking, in turn, perturbs neurodevelopment reinforcing reward seeking behaviour in adulthood. Current animal models are limited in their portrayal of this behaviour and the assessment of neuroimmune involvement (specifically the role of Toll-like receptor 4 (TLR4)). Therefore, the aims of this project were to develop a more relevant animal model of adolescent alcohol exposure and to characterise its effects on TLR4 signalling and alcohol-related behaviours later life. Balb/c mice received a short (P22-P25), low dose alcohol binge during in early adolescence, and underwent tests to investigate anxiety (elevated plus maze), alcohol seeking (conditioned place preference) and binge drinking behaviour (drinking in the dark) in adulthood. Four doses of alcohol during adolescence increased alcohol-induced conditioned place preference and alcohol intake in adulthood. However, this model did not affect basal elevated plus maze performance. Subsequent analysis of nucleus accumbal mRNA, revealed increased expression of TLR4-related mRNAs in mice who received alcohol during adolescence. To further elucidate the role of TLR4, (+)-Naltrexone, a biased TLR4 antagonist was administered 30 min before or after the adolescent binge paradigm. When tested in adulthood, (+)-Naltrexone treated mice exhibited reduced alcohol intake however, alcohol seeking and anxiety behaviour was unaltered. This study highlights that even a small amount of alcohol, when given during a critical neurodevelopmental period, can potentiate alcohol-related behaviours and TLR4 activation later in life. Interestingly, attenuation of TLR4 before or after adolescent alcohol exposure reduced only binge alcohol intake in adulthood.

At experimental “parties” where distilled spirits or beer was available, men demonstrated more interpersonal aggressive behavior than at parties where nonalcoholic beverages were served. Although t...

The development of alcohol use disorder (AUD) involves binge or heavy drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three heuristic stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.

The interaction between isolation and the response to ethanol was investigated with a social behavior test and a loss of righting reflex paradigm. The time a pair of mice spent in active social interaction, aggressive behavior, and avoidance‐irritability showed an isolation‐related increase, while locomotor activity was not affected by 0‐10 days of isolation. Ethanol (0.8 g/kg) reduced the social interaction time in mice isolated for 10 days and 2.0 g/kg ethanol reduced it in all groups. Ethanol induced a locomotor stimulatory effect both in group‐housed and isolated animals. An aggression‐inducing effect of 0.8 g/kg ethanol was observed only in mice isolated for 5 days, while mice isolated for 10 days reduced their aggressive behavior after this dose of ethanol. The loss of righting reflex after 3.5 g/kg ethanol did not appear to vary with isolation. The results suggest that isolation alters some effects of ethanol qualitatively (e.g., its effects on aggressive behavior) but leaves other effects (e.g., its locomotor stimulant and hypnotic effects) unchanged.