Effects of Taste Aversion Training on the Acquisition of Alcohol Drinking in Adolescent P and HAD Rat Lines

Early alcohol drinking has been hypothesized to cause alcohol-related problems in adulthood. In addition, a potential role for genetic factors exist in the etiology of some types of alcoholism. The objective of the present study was to determine if taste aversion training to ethanol during adolescence in previously ethanol-naive, alcohol-preferring P and high-alcohol drinking HAD-1 lines of rats would retard or prevent the onset of high alcohol drinking. Taste aversion training began at 30 days of age. Male and female rat pups were fluid-deprived for 24 hr before 30 min access to a 10% (v/v) ethanol solution, followed by an intraperitoneal injection of either saline or 0.15 M LiCl (10 ml/kg). A total of five training sessions were administered every other day with unrestricted access to water on intervening training days. Twenty-four hours after the last training trial, rats were given continuous free-choice between water and 10% ethanol for 4 weeks with food available ad libitum. There were no obvious gender or line differences to the effects of taste aversion training. All LiCl-treated subjects avoided the usually preferred ethanol solution for the entire 4-week test period, whereas saline-treated rats steadily increased their alcohol intake to over 6.0 g/kg/day by week 4. Rats in the saline and LiCl-treated groups gained weight at comparable rates, and the groups did not differ in total fluid intake. The findings demonstrate that early environmental intervention can prevent the onset of high alcohol drinking in the selectively bred alcohol-preferring P and high-alcohol drinking HAD-1 lines of rats.     

Effect of Calcitonin on the Alcohol Drinking of Rats

Previous work has shown that calcitonin inhibits eating by rats and that it affects several neurotransmitter systems suspected to play a role in alcohol consumption. The present study was an initial test of whether calcitonin does affect voluntary alcohol consumption by male Wistar rats with prolonged alcohol experience. Calcitonin (20 IU/kg) or saline was injected subcutaneously on 10 consecutive days when the rats (n = 20) had continual access to 10% (v/v) ethanol solution, and to food and water. Using a cross-over design, the effects of 40 IU/kg calcitonin vs. saline were then examined in a second 10-day treatment period. Similar patterns of effects were obtained with both calcitonin doses, but the patterns differed with alcohol, food, and water intake. Alcohol drinking showed biphasic changes with both doses, producing highly significant Treatment x Day interactions (p < 1E-10 and p = 6E-7): it was significantly reduced on the first day of calcitonin treatment and significantly increased on the last few days. Food intake was reduced on all calcitonin days although most markedly on the first. Water drinking was not altered on the first calcitonin day, but was greatly increased on the second, then gradually returned toward the baseline. In a second experiment, the animals were switched to 1 hr of alcohol access per day, and calcitonin (20 IU/kg) was administered periodically to one group 4 hr before the alcohol access. Alcohol drinking was significantly reduced in all cases when the calcitonin injection was preceded by at least 1 day without calcitonin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The α1-Adrenergic Receptor Antagonist, Prazosin, Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats

Background:  Preliminary evidence suggest that noradrenergic signaling may play a role in mediating alcohol drinking behavior in both humans and rats. Accordingly, we tested the hypothesis that blockade of α₁-adrenergic receptors will suppress alcohol drinking in rats selectively bred for alcohol preference (P line).
Methods:  Adult male P rats were given 24-hour access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were injected IP with the α₁-adrenergic receptor antagonist, prazosin (0, 0.5, 1.0, 1.5, or 2.0 mg/kg body weight), once a day at 15 minutes prior to onset of the daily 2-hour 2-bottle choice, alcohol versus water, access period for 2 consecutive days and then 3 weeks later for 5 consecutive days.
Results:  Prazosin significantly reduced ( p  < 0.01) alcohol intake during the initial 2 daily administrations, and this reduction of alcohol intake was maintained for 5 consecutive days by daily prazosin treatment in the subsequent more prolonged trial ( p  < 0.05). The prazosin-induced reduction of alcohol intake was not dependent upon drug-induced motor impairment since increases in water drinking ( p  < 0.05) were exhibited during the 2-hour access periods during both 2- and 5-day prazosin treatment.
Conclusions:  The results indicate that the noradrenergic system plays a role in mediating alcohol drinking in rats of the P line and suggest that prazosin—a safe, well-characterized, and well-tolerated drug—may be an effective pharmacotherapeutic agent for the treatment of alcohol use disorders.     

Sex Differences in Alcohol Preference and Drinking Patterns Emerge during the Early Postpubertal Period in Sprague-Dawley Rats

Young male and female Sprague-Dawley rats (30 days old) were assigned randomly to three treatment groups: (1) alcohol treatment—received beer with 5% ethanol added, food, and water ad libitum; (2) pair-fed treatment—received nonalcoholic beer plus sucrose and food to match intake by the alcohol-treated animals; and (3) control treatment—received food and water ad libitum. Animals were tested for alcohol preference for 24 hr and then received their assigned treatments for a period of 30 days, followed by a period of abstinence before alcohol preference testing again at 74 days of age. Males given free access to beer and water did not drink large quantities of beer. Females given free access to beer and water drank a lot of beer on the first day, but decreased intake until ˜52 days of age. A developmental change in young female rats at ˜52 days of age resulted in increased voluntary ethanol intake, possibly caused by hormonal changes associated with the establishment of estrous cycles. When the animals were tested for alcohol preference at 74 days of age after a period of abstinence, males and females in the pair-fed group had greater alcohol preference than animals in the other groups. Females in the pair-fed group had greater alcohol intake based on body weight than males in the pair-fed group and males and females in all other groups. These results provide insight into sex differences in the development of voluntary drinking behavior and responses of drinking behavior to the early stress of pair-feeding.     

Sex Differences in Voluntary Drinking by Long Evans Rats following Early Stress

Models for early stress and voluntary drinking were used to determine the contribution of early stress to increased intake of alcoholic beverages during puberty and adulthood. Newborn litters of Long Evans rats were: (1) stressed by daily separation from the mother for 15 midday on days 1 to 7 of life ["handled" (H)]; or (2) left untouched with the mother on days 1 to 7 of life ["nonhandled" (NH)]. All animals were weaned on day 22, separated by sex (M and F), and caged individually with an assignment of 10 animals per sex per treatment group (H and NH). From 25 to 85 days of age, all animals were given free access to beer containing 5% ethanol (v/v), water, and regular laboratory food. Beer, food, and water intake was measured daily at the same time each day, and animals were weighed weekly. HM had greater ethanol intake and preference for ethanol during the peripu-bertal period (days 32 to 45), compared with all other groups. There were no differences in ethanol intake between NHF and NHM. HM had greater ethanol preference than HF on 22 of the 60 drinking days. HF consumed the same amount of water as the males and significantly greater amounts of water than NHF on 28 of the 60 drinking days. HM had greater ethanol preference than NHM on 8 of the 60 drinking days. From day 75 to day 85, HF had greater ethanol intake than HM, and NHF had greater ethanol intake than NHM. There were no differences in body weights of HF and NHF throughout the study. Growth of HM lagged behind NHM into adulthood. Early stress of males was linked to increased ethanol intake during the peripubertal and adult periods and stunted body growth into adulthood. Early stress of females was linked to polydipsia (water) throughout development and continuing into adulthood, and to increased alcohol intake in adulthood.     

The Effect of Desglycinamide-(ARG8)-Vasopressin (DGAVP) on the Acquisition of Free-Choice Alcohol Drinking in Rhesus Monkeys

The vasopressin analog desglycinamide-(Arg8)-vasopressin (DGAVP) has been reported to reduce the acquisition of heroin and cocaine self-injection behavior in rats. This led to the hypothesis that DGAVP can reduce the self-administration of psycho-active drugs (including ethanol) by attenuating central reinforcement processes. Under forced ingestion conditions, DGAVP has been reported, however, to enhance alcohol drinking in rats. We studied the effect of DGAVP on the acquisition of voluntary, free-choice alcohol drinking in naive rhesus monkeys, that had concurrent access to either 1% and 2% (n = 12) or to 4% and 8% (n = 8) ethanol/water solutions in addition to drinking water. Half of the monkeys were injected twice per day with 50 micrograms.kg-1 of DGAVP for 14 successive days, the other half received placebo. Subsequently, all subjects had access to the same solutions for another 14 days without treatment. DGAVP did not significantly affect concentration preference behavior. With regard to net ethanol ingestion in animals drinking 1% and 2% solutions, DGAVP decreased net ethanol intakes, having a time-dependent and long lasting effect; placebo-treated animals gradually increased net ethanol intakes over time. The placebo-treated animals in the 4% and 8% group, showed a different acquisition pattern; DGAVP reduced net ethanol intake in two animals in a similar way as above. Two animals behaved differently. It is concluded that in a free-choice condition DGAVP did not enhance the acquisition of alcohol drinking in monkeys, but rather inhibited ethanol self-administration in the majority of the subjects.     

Increase in Alcohol Intake,Reduced Flexibility of Alcohol Drinking,and Evidence of Signs of Alcohol Intoxication in Sardinian Alcohol‐Preferring Rats Exposed to Intermittent Access to 20% Alcohol

Background: This study assessed in Sardinian alcohol‐preferring (sP) rats a procedure known to promote alcohol drinking and based on the intermittent (once every other day) access to 2 bottles containing alcohol (20%, v/v) and water, respectively (Wise, 1973). Methods: To this end, sP rats were exposed – under the 2‐bottle choice regimen – to: (i) 10% (v/v) alcohol with continuous access (CA10%; i.e., the procedure under which sP rats had been selectively bred); (ii) 10% (v/v) alcohol with intermittent access (IA10%); (iii) 20% (v/v) alcohol with continuous access (CA20%); (iv) 20% (v/v) alcohol with intermittent access (IA20%; the “Wise” condition) (Experiment 1). Additional experiments assessed the influence of (i) adulteration with quinine of the alcohol solution (Experiment 2) and (ii) concurrent presentation of a saccharin solution (Experiment 3) on alcohol drinking under the CA10% and IA20% conditions. Finally, it was assessed whether alcohol drinking under the CA10% and IA20% conditions resulted in motor incoordination at the Rota‐Rod task, as a possible sign of alcohol intoxication (Experiment 4). Results: Daily alcohol intake markedly escalated in rats exposed to the IA20% condition, averaging 9.0 g/kg (in comparison with the average intake of 6.5 g/kg in the CA10% rat group). CA20% and IA10% rats displayed intermediate values of daily alcohol intake between those of CA10% and IA20% rats. Alcohol intake was virtually abolished by addition of quinine or by concurrent presentation of the saccharin solution in CA10% rats; conversely, alcohol intake in IA20% rats was only partially affected by gustatory aversion or concurrent presentation of an alternative reinforcer. Finally, alcohol intake in IA20%, but not in CA10%, rats resulted in clear motor‐incoordinating effects. Conclusions: These data suggest that the “Wise” procedure is effective in inducing marked increases in alcohol intake in sP rats. These increases are associated with a reduced flexibility of alcohol drinking (suggesting the development of “behavioral” dependence) and produce signs of alcohol intoxication that are not detected when sP rats are exposed to the more conventional CA10% condition.     

Gender and age at drinking onset affect voluntary alcohol consumption but neither the alcohol deprivation effect nor the response to stress in mice

Background: Epidemiological studies suggest that initiation of alcohol drinking at an early age is associated with an increased risk of developing an alcohol use disorder later in life. Nevertheless, relatively few studies using animal models have investigated the relationship between age of onset of drinking and ethanol drinking patterns in adulthood. Besides age at drinking onset, other factors such as gender could also affect the pattern of development of alcohol consumption. In rodents, many studies have shown that females drink more than males. However, even if it is assumed that hormonal changes occurring at puberty could explain these differences, only one study performed in rats has investigated the emergence of sex‐specific alcohol drinking patterns in adolescence and the transition from adolescence to adulthood. The aim of the present study was to compare the acquisition of voluntary alcohol consumption, relapse‐like drinking (the Alcohol Deprivation Effect—ADE) and stress‐induced alcohol drinking in male and female outbred mice that acquired alcohol consumption during adolescence or adulthood. Methods: Separate groups of naïve female and male WSC‐1 mice aged ± 28 days (adolescents) or ±70 days (adults) were given ad libitum access to water and 6% ethanol solution for 8 weeks (1st to 8th week) before undergoing a 2‐week deprivation phase (9th and 10th week). After the deprivation period, 2‐bottle preference testing (ethanol vs. water) resumed for 3 weeks (11th to 13th). During the 13th week, all animals were subjected to restraint stress for 2 consecutive days. Results: Over the entire time course of the experiment, ethanol intake and preference increased in females (both adults and adolescents). Adolescent animals (both females and males) showed a transient increase in alcohol consumption and preference compared to adults. However, by the end of continuous alcohol exposure (when all mice were adults), ethanol intake was not affected by age at drinking onset. A deprivation phase was followed by a rise in ethanol intake (ADE) that was not affected by sex or age. Finally, stress did not alter alcohol self‐administration either during or after its occurrence. Conclusions: Emergence of greater alcohol consumption in adult females does not seem to be limited to a specific developmental period (i.e., puberty). Age of voluntary drinking onset (adolescence vs. adulthood) does not affect eventual alcohol intake in adult WSC‐1 mice and does not modify the transient increase in ethanol consumption after alcohol deprivation.     

Alcohol Self-Administration in a Nonrestricted Access Situation with Alcohol-Preferring (P) Rats

Genetic variables have been implicated as contributing factors in the development of alcoholic behavior. Rats bred selectively for alcohol preference have been used in laboratory studies to investigate the role of such variables. In the present study, rats from the alcohol preferring (P) line were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. Food pellets (45 mg) were presented on an FR 1 schedule of reinforcement, while ethanol was presented in a 0.1 ml dipper on an FR 4 schedule of reinforcement. Water was available in a drinking tube with licks monitored by a drinkometer. Data were analyzed in terms of both total daily intakes and computer defined bouts. The P rats showed greater daily ethanol intakes compared with Long-Evans (LE) animals previously studied under similar access conditions. The major difference in intake was a result of the P rats having a greater number of daily ethanol drinking bouts, while having only a slight increase in individual bout size. These data indicate that genetic selection for ethanol preference may result in the regulation of ethanol intake by means of changes in the frequency of ethanol drinking bouts but not by changes in bout size.     

Development of Alcohol Drinking Behavior in Rat Lines Selectively Bred for Divergent Alcohol Preference

A characteristic of heritable alcoholism is an early onset of alcohol abuse, which may begin at or before the age of adolescence. The objective of the present study was to determine the ontogeny of alcohol drinking behavior before and during puberty in the selectively bred alcohol-preferring (P), alcohol-nonpreferring (NP), high alcohol drinking (HAD), and low alcohol drinking (LAD) lines of rats. In addition, the effects of postweaning housing conditions (single- or pair-housed) and initiation procedure (4 days forced ethanol or free-choice) were evaluated in male and female P rats. Results indicate that high alcohol drinking in P and HAD (replicate line 2) rats, as well as low alcohol drinking behavior in NP and LAD (replicate line 2) rats, is present as early as 3 to 4 weeks of age. Ethanol intakes in juvenile P and HAD rats reached levels of ∼4 to 5 g/kg/day by 38 to 41 days of age and were comparable with levels observed in adults. Neither housing conditions nor ethanol initiation procedure significantly altered the acquisition or magnitude of alcohol intake levels in juvenile male and female P rats. These results suggest that the neural substrates underlying divergent ethanol drinking behavior in P/NP and HAD/LAD lines of rats are present early in life.     

Behavioral traits predicting alcohol drinking in outbred rats: an investigation of anxiety, novelty seeking, and cognitive flexibility

Background: Most adults in Western society consume alcohol regularly without negative consequences. For a small subpopulation, however, drinking can quickly progress to excessive and chronic intake. Given the dangers associated with alcohol abuse, it is critical to identify traits that may place an individual at risk for developing these behaviors. To that end, we used a rat model to determine whether anxiety‐related behaviors, novelty seeking, or cognitive flexibility predict excessive alcohol drinking under both limited and continuous access conditions. Methods: Adult male rats were assessed in a series of behavioral tasks (elevated plus maze [EPM], locomotor activity, and discrimination/reversal learning in a Y‐maze) followed by 6 weeks of daily, 1‐hour access to alcohol in a free‐choice, 2‐bottle paradigm (10% alcohol vs. tap water). Next, subjects were given the opportunity to consume alcohol for 72 hours in drinking chambers that permit separate measures of each drinking bout. Half of the animals experienced a 2‐week deprivation period between the limited and continuous access sessions. Results: Time spent on the open arms of the EPM, but not novelty seeking or discrimination/reversal learning, predicted alcohol consumption during limited, 1‐h/d access sessions to alcohol. Anxiety‐related behavior also predicted the escalation of intake when animals were given 72 hours of continuous access to alcohol. Bout size, but not frequency, was responsible for the increased consumption by high‐anxiety subjects during this period. Finally, intake during limited access sessions predicted intake during continuous access, but only in subjects with low intake during limited access. Conclusions: These findings confirm that preexisting anxiety‐related behavior predicts alcohol intake under several schedules of alcohol access. Moreover, when access is unlimited, the high‐anxiety‐related group exhibited an increase in bout size, but not frequency, of drinking. In addition, we show that modest intake when alcohol is restricted may or may not progress to excessive intake when the drug is freely available.     

Trajectories of drinking from 18 to 26 years: identification and prediction

Objective   To identify developmental trajectories of drinking between the ages of 18 and 26 years and to identify variables, amenable to policy influence, which predict these trajectories.
Design   Longitudinal data were analysed using latent class mixture modelling.
Setting   Participants were interviewed in a central location.
Participants   Provincial city birth cohort, cross-national studies suggest findings are generalizable to other similar market economies.
Measurements   The frequency of drinking over the past year and the typical quantity consumed per drinking occasion were computed from five location-specific questions. Measures used to predict membership of trajectory groups were ease of access to alcohol, drinking on licensed premises, response to alcohol advertising, educational achievement, parental consumption, age of onset of regular drinking and living arrangements.
Results   Three trajectories of quantities consumed showed reduced consumption after age 21 but one trajectory showed marked increases. Three trajectories of frequency of drinking increased or remained stable over time. Access to licensed premises at age 18 had the most significant impact on membership of the trajectory groups and educational achievement had a significant impact on membership of the heavier quantity trajectory groups. Parental alcohol consumption, access to alcohol at 15 years, liking for alcohol advertising, living arrangement and age of onset of regular drinking also influenced trajectory membership.
Conclusions   Quantity and frequency of drinking in adolescence and early adulthood had different trajectories. Membership of heavier drinking groups was affected by environmental influences which are subject to policy change, particularly that of earlier access to licensed premises. In a small group high-quantity consumption did not decrease at age 26.     

A Small Dose of Morphine Leads Rats to Drink More Alcohol and Achieve Higher Blood Alcohol Concentrations

Male Sprague-Dawley rats were maintained on a daily regimen of 22 hr of fluid deprivation followed by a 2-hr opportunity to take a sweetened alcoholic beverage and water for over 6 months. Durinc the week before the formal procedures of the experiment describee herein, access to the alcoholic beverage was limited to 1.5 hr, but access to water was still for 2 hr. Intakes of ethanol, in terms of g/kg, were tabulated at 30 min for half of the rats and at 90 min for the rest. On the day of formal procedures, half of the rats of the 30- and 90-min measures were given 1 mg/kg of morphine sulfate just before the drinking session, whereas the rest received physiological saline Morphine increased mean g/kg intakes of ethanol, as compared with controls, at 30 and 90 min. Blood alcohol levels were also increased These data suggest that the well-documented ability of small doses of morphine to increase rats' intake of ethanol is probably not related to its ability to produce gastrointestinal effects, but rather due to its ability to modulate central motivational mechanisms associated with ingestion.     

Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration

Background: We have developed an animal model of alcohol self‐administration that initially employs schedule‐induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Methods: Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed‐Time 300 seconds (FT‐300 seconds) schedule of banana‐flavored pellet delivery. The FT‐300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Results: Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5‐minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent “spree” drinking (intakes >4.0 g/kg/d). Conclusion: This model of ethanol self‐administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking.     

Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases

BACKGROUND: Onset of alcohol use during adolescence has potentially long-lasting consequences, e.g., prospective alcohol dependence. To obtain new insight into the effects of early chronic ethanol consumption, we compared the drinking behavior of two adult male Wistar rat groups: one that initiated alcohol consumption during adolescence (adolescent group) and the other that initiated their drinking during adulthood (adult group) in a model of long-term alcohol self-administration. We investigated the magnitude of the effects of deprivation and stress on alcohol intake and the influence of these events on the alcohol drinking behavior across time. METHODS: Heterogeneous Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as 5% and 20% ethanol solutions during an observation period of 30 wk. A deprivation phase of 14 days was instituted after eight wk of access to alcohol. After 16 and 26 wk of alcohol access, all animals were subjected for three consecutive days to forced swimming and electric foot shocks, respectively. RESULTS: At the onset of drinking, adolescent animals consumed less alcohol and showed lower preference than adults. The deprivation phase was followed by increased intake of highly concentrated ethanol solution without appreciable differences between age groups. Repeated swim stress produced a slight increase in ethanol consumption in both animal groups; however, alcohol intake was not significantly different between groups, whereas the foot shock stress-induced increase in alcohol intake was significantly higher in the animal group that initiated alcohol consumption during adolescence. After swim stress, the drinking behavior of the adolescent group resembled that of the adult group. In particular, the adolescent group increased their preference for 20% ethanol solution for the remainder of the experiment. CONCLUSIONS: Age of voluntary alcohol drinking onset does not appear to be a strong predictor for prospective alcohol intake and relapse-like drinking behavior under the present experimental conditions. However, male Wistar rats that initiated alcohol consumption during adolescence seem to be more susceptible to acute stressor-specific effects in terms of alcohol consumption.     

A comparative study on alcohol-preferring rat lines: effects of deprivation and stress phases on voluntary alcohol intake

BACKGROUND: Voluntary alcohol intake in rats can be influenced by alcohol deprivation phases and stress. We investigated the magnitude of the effects of both deprivation and stress (forced swimming in cold water and foot-shock had been chosen as stressors distinct in their physical and psychological features) on alcohol intake and the influence of these experiences on the time course of alcohol drinking behavior. For the alcohol drinking procedure, a long-term model of alcohol self-administration originally developed for heterogeneous Wistar rats was used and was compared with different alcohol-preferring rat lines. METHODS: Adult male Alko alcohol (AA), alcohol-preferring (P), high-alcohol-drinking (HAD), and unselected Wistar rats were given ad libitum access to water, 5%, and 20% alcohol solutions for 6 months. A deprivation phase of 14 days was performed after 8 weeks of access to alcohol. After 16 weeks and 22 weeks of alcohol access, all animals were subjected to forced swimming and foot-shock, respectively, for 3 consecutive days, while alcohol intake was still being measured. RESULTS: Alcohol deprivation led to a significant increase in alcohol intake in Wistar rats and P rats. No alcohol deprivation effect was observed in HAD and AA rats; after deprivation, however, their preference for the 20% alcohol solution increased, immediately in the HAD rats and gradually over time in the AA rats. Repeated swim stress caused an increase in alcohol intake in Wistar rats but no changes in the alcohol-preferring rat lines. Foot-shock stress increased alcohol consumption in all lines of rats, but the most pronounced effects were observed in HAD and P rats. CONCLUSIONS: Wistar, HAD, P, and AA rats differentially respond to alcohol deprivation and stress, showing that the genetic background of these different rat lines profoundly affects relapse-like drinking and stress-induced drinking.     

Dopamine Release During Ethanol Drinking in AA Rats

The dopamine overflow in the nucleus accumbens of rats from the high alcohol drinking AA line was measured by microdialysis before, during, and after one-half hour sessions of cued drinking of ethanol flavored with saccharin and peppermint or, as a control, saccharinpeppermint drinking. The animals had had extensive previous experience with ethanol drinking. Self-administration of the ethanol solution did not raise the dopamine level substantially: there was a small (17%) but significant increase only during the first 10 min after the onset of drinking. Giving the rats a cue for ethanol, which was part of their daily routine drinking regime, did not raise the dopamine level before ethanol was presented to the rats (i.e., during "anticipation"). The results are consistent with our previous studies showing a lack of a large ethanol-induced dopamine response in rats with previous experience of drinking ethanol and with the idea that although dopamine may play some role in alcohol drinking, it is not the central substrate producing the reinforcement from ethanol in AA rats.     

Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats

Background:  Selective breeding of rats over generations and induction of alcohol dependence via chronic vapor inhalation both enhance alcohol consumption in animal models. The purpose of this study was to determine whether dependence-induced increases in alcohol consumption by P rats is sensitive to naltrexone, a general opioid receptor antagonist (but with highest affinity at the μ-opioid receptor at low doses), and the recently characterized small molecule CRF₁-receptor antagonist MPZP ( N,N -bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5- a ]pyrimidin-7-amine).
Methods:  P rats ( n  =   20) were trained to respond for alcohol and water in a 2-lever operant situation during daily 30-minute sessions. P rats were then matched for alcohol intake and exposed to chronic intermittent alcohol vapor ( n  =   10) or ambient air ( n  =   10) for approximately 10 weeks. All rats were then administered MPZP and naltrexone in 2 separate and consecutive Latin-square designs.
Results:  MPZP attenuated dependence-induced increases in alcohol intake by P rats while having no effect on alcohol consumption by nondependent controls. Conversely, operant alcohol responding was reduced similarly in dependent and nondependent P rats by naltrexone.
Conclusions:  These results confirm a role for brain CRF₁-receptor systems in dependence-induced changes in the reinforcing properties of alcohol, and CRF₁-receptor blockade appears to suppress dependence-induced drinking at lower doses in P rats relative to other rat lines. Therefore, brain CRF₁-receptor systems are important in the regulation of dependence-induced alcohol consumption, whereas brain opioid systems are important in the regulation of basal alcohol consumption by rats.     

Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease

Aims   To examine the hypothesis that increases in UK liver deaths are a result of episodic or binge drinking as opposed to regular harmful drinking.
Design   A prospective survey of consecutive in-patients and out-patients.
Setting   The liver unit of a teaching hospital in the South of England.
Participants   A total of 234 consecutive in-patients and out-patients between October 2007 and March 2008.
Measurements   Face-to-face interviews, Alcohol Use Disorders Identification Test, 7-day drinking diary, Severity of Alcohol Dependence Questionnaire, Lifetime Drinking History and liver assessment.
Findings   Of the 234 subjects, 106 had alcohol as a major contributing factor (alcoholic liver disease: ALD), 80 of whom had evidence of cirrhosis or progressive fibrosis. Of these subjects, 57 (71%) drank on a daily basis; only 10 subjects (13%) drank on fewer than 4 days of the week—of these, five had stopped drinking recently and four had cut down. In ALD patients two life-time drinking patterns accounted for 82% of subjects, increasing from youth (51%), and a variable drinking pattern (31%). ALD patients had significantly more drinking days and units/drinking day than non-ALD patients from the age of 20 years onwards.
Conclusions   Increases in UK liver deaths are a result of daily or near-daily heavy drinking, not episodic or binge drinking, and this regular drinking pattern is often discernable at an early age.     

Reverse microdialysis of a dopamine uptake inhibitor in the nucleus accumbens of alcohol-preferring rats: effects on dialysate dopamine levels and ethanol intake

Background: The mesolimbic dopamine (DA) system has been implicated in mediating the reinforcing actions of ethanol (EtOH). This study examines the effects of local perfusion of the DA uptake inhibitor GBR12909 (GBR) on (1) DA levels in the nucleus accumbens (NAc) and (2) EtOH drinking in alcohol‐preferring rats. Methods: Stable drinking of a 15% (v/v) EtOH solution (minimum of 0.75 g/kg body weight) was established in daily 1 hr limited access sessions. Rats were then implanted with bilateral guide cannulae aimed 4 mm above the NAc. After recovery from surgery, concentric microdialysis probes (2 mm dialysis membrane surface) were inserted into the NAc. Most placements were in the shell or overlapping both shell and core. Two days later, the probes were perfused at 1.0 μl/min with artificial cerebral spinal fluid (aCSF) for at least a 90 min washout period followed by collection of five basal samples over 150 min. Rats were then perfused with either aCSF alone or 10, 25, 100, or 200 μM of GBR for 240 min on the first day of microdialysis. During the last 60 min of the drug treatment phase, rats were given their scheduled access to 15% EtOH. All rats were then perfused with aCSF for the last 90 min of the experiment. The following day, the procedure was repeated, but animals that received aCSF on the first day were given a dose of GBR and rats given GBR on the first day received only aCSF. Results: GBR perfusion increased extracellular NAc DA levels dose dependently to more than 800% of basal levels at 100 to 200 μM but failed to alter EtOH intake (p > 0.05, paired t test) at any concentration tested. Moreover, after 100 μM of GBR perfusion had terminated, the extracellular levels of DA in the NAc remained elevated for approximately 24 hr (790% of day 1 basal;p < 0.05). The increase in dialysate DA levels observed during GBR perfusion with 100 μM was significantly greater for EtOH‐experienced rats than for EtOH‐naïve rats [F (7,59) = 14.85, p < 0.0001, analysis of variance, Student‐Newman‐Keuls post hoc test]. Conclusions: The results suggest (1) that EtOH drinking experience induces neuroadaptations that increase DA release in the NAc, and (2) that additional elevation in synaptic levels of DA in the NAc does not influence the maintenance of ongoing alcohol drinking under scheduled access conditions in alcohol‐preferring animals.