Taste Reactivity in High Alcohol Drinking and Low Alcohol Drinking Rats

High alcohol drinking (HAD) and low alcohol drinking (LAD) rats were tested, in three exposures, for taste reactivity to five concentrations of alcohol (5%, 10%, 20%, 30%, and 40%, v/v), water, and one concentration each of sucrose and quinine. Of the three reactivity exposures, one was done before a 3-week period of continuous access to water and 10% alcohol, the second test was done immediately after the consumption period, and the final reactivity test was done after 1 month of alcohol abstinence. The results showed that the groups did not differ in reactivity on the initial test. After the consumption tests (when the HAD rats consumed significantly more alcohol than the LAD rats), differences in reactivity were found: HAD rats produced significantly more ingestive responses (which promote consumption) and significantly fewer aversive responses (which facilitate fluid rejection) than LAD rats. These differences were maintained even after 1 month of alcohol abstinence. The present data replicate an earlier experiment with alcohol-preferring (P) rats and alcohol-non-preferring (NP) rats, and indicate that the selective breeding process does not produce differences in the innate perception of the taste of alcohol. However, after experience with drinking alcohol, rats selectively bred for high alcohol consumption exhibit a palatability shift reflected by high ingestive responding and little or no aversive responding. Such a shift would clearly contribute to the maintenance of high levels of alcohol consumption.     

The Long-Term Behavioral Effects of Prenatal Alcohol Exposure in Rats

Prenatal exposure to alcohol can cause a variety of behavioral disturbances later in life. Many of the reports in animals of the behavioral teratogenic effects of alcohol have focused on assessing younger animals. The purpose of this paper is to review some of the longer lasting behavioral consequences of gestational alcohol exposure in animals. It is not meant as a comprehensive review, but rather focuses on selected studies. It is concluded that prenatal alcohol exposure does have long lasting effects, although some of these might only occur under challenging or stressful circumstances. It is hypothesized that as the animal matures compensatory mechanisms or strategies develop to compensate for these dysfunctions. Thus, behavioral problems may only be detected when these compensatory systems break down, either as a result of stress, because of complex testing procedures, or old age.     

Biological Markers of Alcohol Consumption and Effect of Calcitonin in Nonalcoholic Men: A Prospective, Double-Blind Study

The objective of this study was to study the ability of biological markers of alcohol consumption in differentiating subjects below weekly consumption of 400 or 600 g of absolute ethanol from those above, and to study the effect of intranasal calcitonin on alcohol drinking. A prospective 12-week double-blind study that used anonymous data collection with drinking diaries was done. The drug that was studied (calcitonin or placebo) was used during study weeks5–8. This study was performed at the research unit of a university hospital. The subjects consisted of 59-nine men aged 26 to 57 years who considered themselves as regular but modest drinkers and were recruited by advertisements. The measurements were obtained from monthly questionnaires and daily anonymous diaries for alcohol drinking data, and biological markers of alcohol consumption (aspartate ami-notransferase, alanine aminotransferase, y-glutamyt transpepti-dase, beta hexosaminidase, and carbohydrate deficient transferrin). The results indicated intranasal calcitonin with a dose of 2001U three times a week had no effect on alcohol use. All biological markers studied had only a modest ability to differentiate those with weekly alcohol consumption of 400 or 600 g or over from those below these limits. The areas under receiver operating characteristic (ROC) curve with the limit 400 g/week were 0.71 for aspartate aminotransferase, 0.61 for alanine aminotransferase, 0.74 for γ-glutamyl transpepti-dase, 0.68 for β-hexosaminidase, and 0.78 for carbohydrate deficient transferrin. Respective numbers for the 600-g limit were more uniform. As evaluated by ROC analysis, carbohydrate deficient transferrin was the best biological marker to find men with weekly alcohol consumption over 400 g. lntranasal salmon calcitonin had no affect on alcohol drinking.     

Effect of Bestatin, an Aminopeptidase Inhibitor, on Alcohol Intake in Alcohol-Preferring P Rats

Bestatin is an aminopeptidase and enkephalinase inhibitor that elevates the levels of angiotensin II and angiotensin III. Although it has been used for years in the treatment of various forms of cancer, its application as an antialcohol drug has not been explored, despite its ability to stimulate angiotensin activity. The present study assesses the ability of bestatin to reduce chronic alcohol consumption in the genetically selected high alcohol-consuming P rats. Two groups of P rats were given 24-hr access to food, water, and 10% (v/v) alcohol. After a baseline period, half the rats received the saline vehicle and the other half ascending doses of bestatin (2.5,10,20, and 30 mg/kg, bid). Each dose was administered for a minimum of 7 days. Bestatin had little effect on water intake or weight gain, but did produce a dose-dependent reduction in alcohol intake that averaged 33% and was sustained over the course of the 1-month period of administration. Years of experience with bestatin have shown it to be safe and free of major side effects. The present findings suggest that bestatin (Ubenimex®) might also be useful in the treatment of alcohol abuse in humans.     

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.     

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.     

Gamma-Aminobutyric Acid-Activated Chloride Channels in Rats Selectively Bred for Differential Acute Sensitivity to Alcohol

Effects of various sedative hypnotic agents on GABA-mediated chloride flux were evaluated in whole brain membrane vesicles (microsacs) prepared from rats selectively bred for high (HAS) and low sensitivity (LAS) to an acute hypnotic dose of alcohol. The HAS rats were more sensitive to the effects of pentobarbital, phenobarbital, flunitrazepam, and ethanol on GABA-mediated chloride flux compared with the LAS rats. No differences between the lines in GABA-stimulated chloride flux were observed. Modulation of 1-[3H]-phenyl-4-butyl-2,6,7-trioxabicyclo(2.2.2)octane ([3H]-TBOB) and [3H]-diazepam binding also was measured. The lines did not differ in inhibition of [3H]-TBOB binding by pentobarbital, phenobarbital, muscimol or picrotoxin. Although the lines displayed almost identical KD and Bmax for [3H]-diazepam binding, the GABA agonist, muscimol, was a more potent stimulator of [3H]-diazepam binding in membranes prepared from HAS rats than from LAS rats. These findings are discussed in light of previous work using other selected lines.     

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.     

Alterations in Activity Following Alcohol Administration During the Third Trimester Equivalent in P and NP Rats

There is considerable variation in the consequences of alcohol abuse during pregnancy on infant outcome. Although it is clear that a number of factors contribute to this variability, one hypothesis that has received recent attention is the role of genetic differences in response to alcohol. This study examined activity levels in the alcohol-preferring (P) and alcohol-nonpreferring (NP) rats following neonatal alcohol exposure. Although these lines were selectively bred for differences in voluntary alcohol consumption, they also differ in their sensitivity and tolerance to alcohol. The P and NP offspring were artificially reared and administered ethanol (either 6 or 4 g/kg/day) from postnatal day 4 (PN 4) until PN 10 via intragastric cannula. An artificially reared isocaloric maltose group and a normally reared control group were also included. From PN 18 to PN 21, subjects were tested daily for 30 min in an automated activity monitor. Exposure to either the 4 or 6 g/kg dose of ethanol resulted in overactivity in P rats. However, only the 6 g/kg dose group displayed overactivity among the NP offspring. Furthermore, the level of overactivity displayed by the alcohol-exposed P rats was significantly greater than that displayed by the alcohol-exposed NP rats. These data suggest that genetic differences in response to alcohol may be a predictor for the behavioral teratogenic effects of alcohol.     

Effect of Alcohol on Bacterial Translocation in Rats

Bacterial translocation has been proposed to be important in the pathophysiology of sepsis, as well as to be a consequence of sepsis. To study the effect of alcohol on bacterial translocation from the gut, normal Sprague-Dawley rats were administered alcohol by gavage by two regimens: Acute (3.7 g/kg, one dose) or Subacute (1 of 2 doses, 2.4 or 3.7 g/kg/day once daily for 14 days). Mesenteric lymph node cultures were performed, and portal venous blood was assayed for endotoxin. Ileal and cecal permeability studies were performed in the Acute and Subacute groups using fluorescein isothiocyanate-labeled dextrans of either 4,000 or 70,000 kDa size. As an index of the effect of systemic endotoxin, tissues from mesenteric lymph nodes, liver, and intestinal Peyer's patches were assayed for the presence of mRNA for tumor necrosis factor. Additionally, because extrapulmonary sepsis has been shown to suppress pulmonary antibacterial defenses, animals in the Subacute group were challenged by aerosol inoculation with Pseudomonas aenrginosa to determine bacterial clearance and alveolar cellular responses. The results show that neither of the alcohol regimens resulted in bacterial growth from mesenteric lymph nodes or portal blood. Animals in the Subacute group had more endotoxin present in portal blood than did the Control group (92.9 pg/ml vs. 40.2 pg/ml; p < 0.02). None of the animals had demonstrable mRNA for tumor necrosis factor in any of the tissues assayed. There were no demonstrable increases in ileal or cecal permeability for either the small or large molecular weight dextran in either alcohol group. Furthermore, there was no delay in the clearance of P. aeruginosa from the lung in the Subacute group, but these animals recruited fewer neutrophils into the airspaces in response to this challenge than did the Control animals. Thus, alcohol intoxication does not result in bacterial translocation from the gut in this model. Despite higher levels of portal venous endotoxin in the animals in the Subacute alcohol group, no adverse systemic consequences of this phenomenon could be demonstrated.     

Difficulties with Questions on Usual Drinking and the Measurement of Alcohol Consumption

Questions about usual drinking play an important role in the construction of alcohol consumption measures. However, little is known about difficulties in answering these questions for respondents with variability in their drinking patterns. We investigated this in a community sample of 945 drinkers and in a clinical sample of 400 patients treated for alcohol and/or drug problems. Demographic variables were not consistently related to self-reported difficulty in answering, but a diagnosis of current DSM-IV alcohol dependence was significantly related in both samples. In modeling the relationship between alcohol consumption and DSM-IV alcohol dependence, the fit of the model to the data was significantly improved by the addition of a variable indicating respondents'difficulty answering the usual drinking questions. Using this information in the development of alcohol consumption questions may provide more precise estimates of the risk from alcohol consumption to outcomes such as alcohol dependence.