Consequence of long-term exposure to corticosterone or dexamethasone on ethanol consumption in the adrenalectomized rat,and the effect of type I and type II corticosteroid receptor antagonists

The daily fluid intake of male Wistar rats with simultaneous access to 6% ethanol and water was determined during a baseline period (1 week), following adrenalectomy (1 week) and for 3 weeks following SC implantation of hormone pellets containing corticosterone (CORT) or dexamethasone (DEX). Ethanol consumption dropped during the first week of adrenalectomy (ADX) but increased again in the absence of hormone replacement to reach preoperative levels during the ensuing weeks. The CORT treatment, which produced plasma hormone levels similar to the 24-h mean concentration of adrenally intact rats, not only reversed the effect of ADX on alcohol consumption but also enhanced it to levels above those observed in intact rats. Water intake was not affected by the CORT treatment. DEX implants stimulated water intake, but did not enhance the drinking of ethanol. SC injections of RU 28318 (type I corticosterone receptor antagonist; 10 mg/kg) or mifepristone (RU 38486; type II receptor antagonist; 25 mg/kg) at the beginning and halfway through three daily, 6-h tests failed to affect ethanol drinking in adrenally intact rats or in ADX rats bearing CORT implants. Similarly, there was no effect of giving the two antagonists in combination. These results suggest that exogenous CORT can induce excessive alcohol intake in genetically unselected rats and that this facilitatory effect may be mediated by non-genomic cellular mechanisms.     

Stress-induced cross-sensitization to cocaine: effect of adrenalectomy and corticosterone after short- and long-term withdrawal

 We have recently shown that adrenalectomy (ADX) in rats blocks the appearance of cocaine-induced sensitization when this behavioral response is tested at early withdrawal times (1–2 days), but not after later withdrawal from cocaine (12 days). To determine if a similar phenomenon occurred with stress-induced sensitization, male Sprague-Dawley rats were given a sham ADX, ADX surgery, or ADX plus SC implanted corticosterone (CORT) pellets (CORT 12.5% pellets or CORT 50% pellets). A fifth group was given ADX surgery, but CORT 50% pellets were implanted after repeated stress treatment. One week after surgery, each group was divided into two additional groups, naive and stress. Naive animals remained unhandled, while stress rats were given a variety of daily stressors administered twice per day for 6 consecutive days. One day after the last stress, rats were given a saline injection followed by a cocaine injection (15 mg/kg, IP) the next day, and locomotor activity was monitored (early withdrawal). Two weeks after the last stress, the locomotor responses to an additional saline and cocaine injection were monitored (late withdrawal). At early withdrawal, no significant sensitization occurred for horizontal activity, but cross-sensitization was demonstrated for vertical activity. At late withdrawal, sham controls showed a stress-induced elevation in horizontal activity, with only a trend toward increased vertical activity. Animals given ADX surgery or ADX and CORT 12.5% pellets did not demonstrate sensitization to repeated stress, while CORT 50% pellets in ADX rats restored the sensitized horizontal response to cocaine challenge at late withdrawal. In contrast, stress-pretreated rats which were given CORT 50% pellets during the 2-week withdrawal period after the stress showed a marked decrease in horizontal activity in response to cocaine challenge at late withdrawal. The results provide evidence for a necessary role for adrenal hormones in long term, but not short-term, stress-induced cross-sensitization. Together with our previous study on the role of CORT in cocaine-induced sensitization, the results indicate that CORT is not the common factor mediating the long-term sensitization to cocaine and stress. Received: 10 April 1997 / Final version: 19 August 1997     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

Naloxone alters alcohol drinking induced in the rat by tetrahydropapaveroline (THP) infused ICV

In male rats of the Sprague-Dawley or Long-Evans strain, intracerebroventricular (ICV) cannulae were implanted permanently using stereotaxic techniques. Tetrahydropapaveroline (THP) was infused ICV for up to 14 days either chronically around the clock or acutely once per day in doses previously found to induce an abnormally high intake of alcohol. During these periods, alcohol preference for individual rats was determined by a self-selection procedure in which the concentration of alcohol was increased from 3 to 30% on each day of a 12-day interval. Those rats which displayed a substantial increase in their intake of alcohol were selected for naloxone treatment and subsequently assigned a fixed concentration of alcohol at which maximum consumption occurred. Naloxone was administered subcutaneously two to six times per day for three consecutive days in total daily doses ranging from 1.5 to 3.0 mg/kg. Each rat served as its own control and was given 0.9% saline isovolumetrically according to the same temporal schedule. Naloxone generally suppressed alcohol intake in animals by 20% to 45%, but the reduction in drinking depended upon the injection regimen as well as the prior level of alcohol consumption. In "high drinking" rats, the mean alcohol intake of 6.2 g/kg/day was reduced to 3.7 g/kg/day by naloxone whereas in "low drinkers" the mean intake of 3.5 g/kg/day was suppressed to 2.8 g/kg/day by the opiate antagonist. These results further support the suggestion of a possible opiate receptor link in the pathogenesis and maintenance of aberrant drinking of alcohol, the mechanism of which may involve the endogenous action of an amine-aldehyde condensation product in the brain.     

Neuropeptide Y (NPY)-induced reductions in alcohol intake during continuous access and following alcohol deprivation are not altered by restraint stress in alcohol-preferring (P) rats

Administration of neuropeptide Y (NPY) reduces anxiety-like behavior and alcohol intake in alcohol-preferring rats. The present experiment examined whether the effects of NPY on alcohol drinking are modulated by stress exposure during continuous access or following ethanol deprivation. Female P rats underwent 6 weeks of continuous access to 15% v/v ethanol and water prior to intracerebroventricular (ICV) cannula implantation. Deprived rats underwent two cycles of 5 days of ethanol exposure followed by 2 days of ethanol deprivation, while non-deprived rats had uninterrupted access to ethanol. Stressed rats in both ethanol access groups were exposed to restraint stress for 1 h 4-6 h after ethanol was removed from the deprived group in both cycles. ICV infusions of 5.0 μg NPY or aCSF were administered 48 h following the deprivation/stress procedure, after which ethanol was returned. Rats showed increased ethanol intake following ethanol deprivation compared to non-deprived controls. Food and water intake were increased, while ethanol intake was decreased, in rats infused with NPY. Stress did not increase ethanol intake or alter the response to NPY. Although no stress effects were found, the present experiment replicates previous findings regarding the effectiveness of NPY in reducing ethanol consumption. Future studies aimed at determining the extent to which stress may affect relapse to ethanol drinking and response to NPY would benefit from implementing different stress paradigms and varying the pattern of ethanol access.     

Effects of adrenalectomy on macronutrient selection patterns in the rat

The present studies examined the effects of adrenalectomy (ADX) on nutrient selection of rats over the 24-h period, as well as during the first 2 h of the nocturnal feeding cycle. Results indicate that ADX, in rats showing generally similar preferences for carbohydrate and fat, equally suppresses intake of both of these nutrients over the 24-h period. The relative impact of ADX on carbohydrate and fat intake may shift depending upon baseline, with carbohydrate-preferring rats showing a stronger decrease in intake of this diet after ADX and fat-preferring rats exhibiting a greater decline in fat intake after ADX. Acute injections of corticosterone (CORT) and aldosterone (ALDO) are both found to restore carbohydrate as well as fat intake to ADX rats over the 24-h period. However, in the first 2 h of the dark feeding cycle, carbohydrate intake is found to be selectively suppressed after ADX, and CORT injection (0.5 and 2.0 mg/kg, SC) restores carbohydrate intake during this early dark period, while producing a small increase in fat intake only at the higher dose. This is in contrast to ALDO administration at dark onset, which has a stronger stimulatory effect on fat intake in the ADX rat but does not fully restore carbohydrate intake. These findings indicate that CORT and ALDO have differential effects on nutrient intake in ADX rats particularly at the onset of the dark cycle, and it is suggested that these are mediated, respectively, by the type I and type II steroid receptor systems in the brain.     

Benzodiazepines enhance the consumption and palatability of alcohol in the rat

This study examined the effect of the benzodiazepine, midazolam, on the consumption and palatability of 6% ethanol in male Wistar rats. In the first experiment, it was found that midazolam (5 mg/kg) increased home cage ethanol drinking 0–2 h after administration. Another intake experiment, in which ethanol was infused directly into the oral cavity through an indwelling catheter, also showed that midazolam (10 mg/kg) stimulated alcohol ingestion. The affective response to intraoral infusions of ethanol (1 ml during 1 min) was subsequently monitored in benzodiazepine-treated rats. Taste reactivity testing showed that midazolam (5–10 mg/kg) significantly increased the occurrence of hedonic orofacial responses and suppressed the number of passive drippings. A similar response pattern was observed following administration of diazepam (5 mg/kg) and chlordiazepoxide (10 mg/kg), but not after exposure to cis(Z)flupentixol (10 mg/kg). Midazolam also increased the incidence of hedonic responses in alcohol-naive rats with no previous access to ethanol in the home cages. Hedonic responsiveness did not appear to diminish with repeated benzodiazepine exposure: the behaviour of rats given five midazolam injections (10 mg/kg every second day) was similar to that shown by rats with no benzodiazepine pre-exposure. The increased hedonic response to ethanol induced by midazolam was blocked by pretreatment with the benzodiazepine receptor antagonist flumazenil (10 mg/kg), the latter drug exerting no effects on its own. The present results suggest that benzodiazepines, by acting on GABA_A receptors, may facilitate ethanol intake by increasing ethanol’s taste hedonic properties. Received: 22 April 1997/Final version: 14 October 1997     

Cyamemazine decreases ethanol intake in rats and convulsions during ethanol withdrawal syndrome in mice

The effect of cyamemazine a dopamine D₂ receptor antagonist on voluntary ethanol consumption in rats and on ethanol withdrawal in mice was examined. Male Sprague-Dawley rats were tested in a free choice (water and 10% ethanol) experiment and consumed 5 g/kg ethanol daily. Rats were treated daily IP with cyamemazine ( 0.5, 1, or 2 mg/kg) or acamprosate (100 mg/kg) during 2 weeks. Both acamprosate and 1 mg/kg cyamemazine significantly decreased ethanol intake by 45% without affecting either fluid or food intake. The lowest dose of cyamemazine had no effect on alcohol intake but increased food intake. The highest dose had no effect on any variables. During the post-treatment period, only 1 mg/kg cyamemazine decreased both ethanol and fluid intakes. Mice were made dependent on alcohol using a chocolate fluid diet containing increasing concentrations of alcohol and withdrawn after 9 days. Mice were treated with cyamemazine (1 or 0.5 mg/kg, respectively) or with the same doses of lorazepam acutely on the day of withdrawal or chronically (during alcohol treatment). Both chronic and acute cyamemazine and lorazepam treatments decreased convulsions during ethanol withdrawal. Both acute treatments decreased locomotor activity in control and alcohol dependent mice. Chronic treatment had no effect on locomotor activity. We suggest that cyamemazine could reduce alcohol consumption by antagonizing the activation of the dopaminergic pathways during the induction of alcohol dependence. The action of cyamemazine on 5-HT₃ receptors could also explain its effect on alcohol convulsions during withdrawal convulsions. Received: 19 October 1997/Final version: 6 April 1998     

Acetaldehyde metabolism by isolated hepatic mitochondria from rats consuming different amounts of ethanol

We have previously reported that in rats, ethanol intake as low as 4 g/kg per day induced mitochondrial alterations, detected by a decrease in mitochondrial O2 uptake supported by substrates entering at the three sites of coupled phosphorylation. Since it has been reported that acetaldehyde oxidation occurs mainly inside the mitochondria, linked to the respiration chain, the effect of daily previous administration of low doses of ethanol during a month, on the acetaldehyde oxidation rate by intact rat liver mitochondria was studied. Determination of acetaldehyde oxidation rate and O2 uptake accompanying acetaldehyde removal by liver mitochondria indicates that the mean value of these parameters studied in rats consuming low amount of ethanol (0.5-3.0 g/kg per day) was significantly higher than that of controls drinking only water (P less than 0.001, in state 3, and P less than 0.05, in state 4). This enhancing effect of ethanol cannot be ascribed to an uncoupling of oxidative phosphorylation and also not to a change in aldehyde dehydrogenase activity which was measured in disrupted mitochondria. On the other hand, high ethanol consumption (4-7 g/kg per day), which alters mitochondrial function, did not decrease mitochondrial acetaldehyde oxidation, as compared to rats drinking water only. This result differs from the decrease induced by higher levels of previous ethanol intake (12-14 g/kg per day) as reported by several authors, showing that possibly this effect is dose dependent.     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

Serotonin receptors in the caudal brainstem are necessary and sufficient for the anorectic effect of peripherally administered mCPP

 The role of caudal brainstem 5-HT receptors in mediating the anorectic effect of the direct 5-HT_2C/1B agonist, mCPP [1-(3-chlorophenyl)piperazine dihydrochloride], was evaluated. We demonstrated, first, that systemic injections of mCPP yielded a dose-related suppression of intra-oral intake of 12.5% glucose in intact rats and in chronically maintained supracollicular decerebrate rats. The results of the decerebrate experiment suggest that 5-HT receptors in the caudal brainstem are sufficient for mediating the drug’s intake effect. We also showed a dose-related intake suppression when mCPP was delivered to the fourth ventricle of intact rats, with potent suppression obtained at doses well below threshold for systemic administration. Whether and to what extent the 5-HT_2C/2A antagonist, mesulergine reverses the intake suppression that follows systemic or 4th ICV injection of mCPP was examined. Fourth ICV co-administration of mesulergine (60 μg) and mCPP (40 μg) eliminated the approximately 50% intake suppression observed when mCPP was delivered alone, a result that affirms the receptor selectivity of the 4th ICV agonist effect. We showed, further, that 4th ICV mesulergine (60 μg) completely reversed the intake suppression produced by systemic mCPP (2 mg/kg). The latter result indicates that stimulation of 5-HT receptors in the caudal brainstem is necessary for the intake suppression produced by systemic administration of this 5-HT agonist in the intact rat. Received: 24 June 1997 / Final version: 13 November 1997     

Effect of acute and chronic conditions of over-crowding on free choice ethanol intake in rats

Male albino rats of Wistar strain were exposed to overcrowding stress in two different groups for a period of seven days. One group of rats was kept under stress for six hours per day (acute stressed group) and the other group rats was kept under stress continuously (chronic stressed group). The effect of these acute and chronic stresses on voluntary alcohol (2% w/v) intake was monitored during the 7 days of stress exposure, and ethanol preference and total ethanol intake in terms of g/kg body weight were also studied. A significant increase in ethanol preference and ethanol intake was observed in one-day and 7 days chronic stressed group. No significant increase in ethanol intake was observed in acute stress. Thus a short lasting stressor may not increase ethanol-drinking behavior, whereas when animals were exposed to more intense stressor continuously for 7 days, an increase in voluntary drinking behavior may be seen.     

Activity stress effects on voluntary ethanol consumption, mortality and ulcer development in rats

The present study was designed to investigate the relationship between activity stress, alcohol consumption and ulcer proliferation. Ethanol consuming rats were initially divided into low, medium or high ethanol preferring groups on the basis of daily ethanol intake (g/kg/day). Following a habituation period in activity cages, animals were fed for 1 hr per day. Access to both water and ethanol remained ad lib. Yoked control home cage animals were fed the same amount of food consumed by their wheel-housed partners. This procedure continued until wheel-housed animals died, at which time they and their yoked home cage control partners were examined for ulcers. Results indicated that in contrast to the yoked controls, only the high ethanol-preferring rats reduced their ethanol consumption. Although no differences were apparent in ulcer frequency (mean number of ulcers per rat) or severity (mean cumulative ulcer length in millimeters), animals exposed to ethanol had a lower ulcer incidence (number of rats per group developing ulcers) and mortality rate than non-ethanol exposed animals.     

Dose and route dependency of metabolism and toxicity of chloroform in ethanol-treated rats

 The effects of a single dose of ethanol on the metabolism and toxicity of chloroform administered to rats per os (p.o.), intraperitoneally (i.p.), or by inhalation (inh) at different doses were investigated. Rats that had been given either ethanol (2 g/kg) or vehicle (water) alone at 4 p.m. on the previous day were challenged with chloroform at 10 a.m. p.o. (0, 0.1, 0.2, or 0.4 g/kg), i.p. (0, 0.1, 0.2, or 0.4 g/kg), or inh (for 6 h each at 0, 50, 100, or 500 ppm). The ethanol treatment, which had no influence on the intake of food and water, increased chloroform metabolism in vitro about 1.5-fold with no significant influence on liver glutathione content. The treatment had a dose-dependent effect on the metabolism and toxicity of chloroform, and the effect differed depending on the route of administration. Compared at the same dose level, the area under the curve (AUC) of blood chloroform concentration was invariably smaller following p.o. than i.p. administration. In accordance with this, chloroform administered p.o. caused more deleterious hepatic damage than the same amount of chloroform administered i.p. Although ethanol treatment had no significant influence on the AUC at any dose by any route of administration, the toxicity of p.o.-administered chloroform was significantly higher in ethanol-treated rats than in control rats at a dose as low as 0.1 g/kg, whereas no significant difference was observed in toxicity between both groups of rats at such a low dose administered i.p. When rats were exposed inh to air containing chloroform vapor, ethanol consumption had no effect on hepatotoxicity until the exposure concentration was raised to 500 ppm, a finding which suggests that a single dose of ethanol (2 g/kg) affects the toxicokinetics of inhaled chloroform in rats only at a concentration as high as 500 ppm. Received: 6 December 1993 / Accepted: 25 May 1994     

14-methoxymetopon,a highly potent μ opioid agonist,biphasically affects ethanol intake in Sardinian alcohol-preferring rats

Rationale Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective μ opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. Objective To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. Methods Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 μg/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 μg/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 μg/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 μg/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003–100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Results Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose. Conclusions The novel μ analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain μ opioid receptor stimulation on ethanol intake. Valentina Sabino and Pietro Cottone contributed equally to this work.     

Satietin: route of injection, dose response, effect on food and water intake and on running-wheel activity in the rat

Semipurified satietin significantly (p less than 0.05) reduced food intake when injected subcutaneously at 10, 15, 20 mg/kg into 48 hr fasted rats with no indication of a dose response. When infused intracerebroventricularly (ICV) at 12.5, 25 and 50 micrograms/rat (10 microliter vol) into ad lib fed rats at the end of the light period there was no effect on food intake for the first hour but 24 hr food intake was (p less than 0.001) reduced at all doses. The ICV dose response curve was shallow, with similar suppression at both 12.5 and 25 micrograms doses, but a (p less than 0.05) greater suppression with the 50 micrograms dose. An ICV threshold between 6.25 micrograms and 12.5 micrograms appears to exist since no suppression occurred after a dose of 6.25 micrograms. Four consecutive daily ICV infusions of satietin (25 micrograms/rat) in two rats progressively suppressed food intake to low levels, suggesting a cumulative effect. Following termination of satietin treatment daily food intake slowly returned towards normal without evidence of rebound feeding. In other ad lib fed rats, four ICV infusions of semipurified satietin, on days alternated with no infusion, reduced food intake (p less than 0.001), water intake (p less than 0.003) and running wheel activity (p less than 0.001) on the first day of injection but not on subsequent injection days. Suppression of activity approached significance on the second injection day. Highly purified satietin infused ICV produced similar responses. These findings may indicate a general disruption of behavior by satietin, thus, it may not play a physiological role in feeding behavior because of its apparent non-specificity.     

Comparative characteristics of voluntary and semivoluntary methods of the alcoholization of rats

Water and ethanol consumption, blood and urine ethanol concentrations were measured in male rats aged 1.5 to 8 months. The animals had ethanol solutions (5-25%) and water as alternate fluid (two-bottle choice) or a 10% ethanol solution as a sole water source. In both cases, the rats did not exceed 7 g/kg of ethanol consumption per day. From 10 a.m. to 16 p.m. the blood ethanol concentration was no more than 0.1 g/l. Ethanol excretion with urine did not go beyond 0.1% of the daily dose. Ethanol consumption was increased by 1-2 g/kg a day if saccharin (0.125%) and sodium chloride (1%) were added to ethanol solution. In this case the withdrawal signs developed after ethanol consumption cessation.     

Effects of bromocriptine on self-administration of sweetened ethanol solutions in rats

The effect of bromocriptine (BRO), a D₂ receptor agonist, on chronic oral ethanol (ETOH) self-administration was tested in a home-cage environment. Male Wistar rats (n = 77) were food deprived for 24 h. Then, a period of 15 days of limited-access (1h/day) to food and to a sweetened ETOH solution was started [3% w/v of glucose and several concentrations of ETOH depending upon the group: 0% (control group), 1.5%, 5% or 10% v/v]. Later, another period started in which rats were maintained in a free-choice, two-bottle situation with food, tap-water and the sweetened solution available for 24 h/day, for 14 days. Following this period, BRO (5 mg/kg, SC) was administered, once daily, for 5 days, in the same continuous free-access conditions. ETOH consumption was also studied for 4 days after the last BRO injection. BRO increased ETOH self-administration throughout the 5-day period, regardless of the ETOH concentration available, in the rats with previous higher ETOH intake, without effect in the control animals. In the control rats, water intake was increased, whereas in the group that had access to the lowest ETOH concentration a decrease in water consumption was found. The enhanced ETOH drinking was maintained after BRO treatment for the animals with previous higher ETOH intake. BRO effects on water consumption were also maintained. These data suggest that BRO can potentiate ETOH intake and provide further support for the role of dopamine (DA) systems in mediating volitional oral intake of ETOH. Received: 25 January 1996 / Final version: 12 June 1996     

Ontogeny of ethanol-induced motor impairment following acute ethanol: Assessment via the negative geotaxis reflex in adolescent and adult rats

Adolescent rats have been observed to be less sensitive than adults to a number of ethanol effects that may serve as feedback cues to reduce further ethanol intake. Among these findings are a few reports of attenuated sensitivities of adolescents to ethanol-induced motor impairment. The purpose of the present study was to further explore potential age-related differences in ethanol-induced motor impairment in both male and female adolescent (postnatal day [P]28-32), and adult (P68-72) Sprague-Dawley rats using an inclined plane assessment of the negative geotaxis reflex. Adult males displayed significant motor impairment at 1.5 g/kg, whereas adolescent males required higher doses, showing significant motor impairment only at doses of 2.25 g/kg ethanol or greater. Intoxicated practice did not significantly influence level of motor impairment at either age. When female rats of both ages were separately analyzed in terms of their response to ethanol, a dose of 1.5 g/kg ethanol was found to significantly impair adults, whereas adolescent females showed significant motor impairment when challenged with 2.25 g/kg but not 1.5 g/kg ethanol. Yet when the 1.5 g/kg data of females at the two ages were directly compared, no significant age difference was seen at this dose. These data document an attenuated sensitivity of adolescent relative to adult rats to the motor impairing effects of ethanol using a stationary inclined plane test, an effect particularly robust in male animals, and demonstrates the utility of this test for assessment of motor coordination in adolescent and adult rats.     

Effects of restraint stress on voluntary ethanol intake and ulcer proliferation in rats

The present study examined the effect of exposure to a schedule of predictable restraint stress on voluntary ethanol consumption and ulcer proliferation in rats. Following ethanol screening rats were divided into high, medium and low ethanol consuming groups on the basis of daily ethanol intake (g/kg/day) and exposed to daily 1 hr restraint stress for 10 consecutive days. Voluntary ethanol consumption was monitored both during the stress period and for an additional 25 days post-stress. Stomach pathology was assessed on days 1, 5 and 10 of the stress period as well as at the conclusion of the post-stress period. Results indicated a differential effect of stress on ethanol intake in that high ethanol preferring rats consumed less ethanol in the first 5 days of the post-stress period as compared to non-stressed controls. In contrast, the medium ethanol preferring group drank more ethanol than controls during days 1-5 of the post-stress period. Ethanol consumption for the low ethanol groups did not change during the entire experiment. Stomach pathology data revealed no ulcer formation in the stressed groups during the stress period. At the end of the post-stress period, however, stressed animals exhibited a significantly greater ulcer severity (mean cumulative ulcer length) and ulcer frequency (mean number of ulcers per rat) than non-stressed groups. Stomach pathology for ethanol consuming groups did not differ from controls, indicating that ethanol did not, by itself, affect ulcer development.