Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats

Amperozide (FG5606), a 5-HT₂ receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT_1A and 5-HT_2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT_1A agonist/5-HT_2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.     

Volitional consumption of ethanol by fawn-hooded rats: Effects of alternative solutions and drug treatments

Behavioral and neurochemical measures of brain 5-hydroxytryptamine (5-HT) function in the Fawn-Hooded rat are abnormal relative to outbred strains of rats. Fawn-Hooded rats freely drink large amounts of 10% ethanol in the presence of water and have been proposed to be an animal model for studies related to alcoholism. In this study, Fawn-Hooded rats were given solutions of ethanol increasing in concentration from 3% to 30% (w/v in tap water) over 10 days with tap water in a second drinking tube and a third tube left empty. The solutions of ethanol that produced maximal drinking with a preference (ml ethanol/ml total fluid) near 50% ranged from 5% to 13%, which became: the fixed individual concentrations for each rat. After a 5-day baseline period the rats were offered a solution in the third drinking tube of either 0.5% aspartame or chocolate Ultra SlimFast (diluted with water 2: 1). The chocolate drink, but not aspartame, significantly reduced the consumption of alcohol by 73%. For the drug experiments, the rats were given successive 4-day periods of: baseline drinking; drug or saline injections b.i.d.; and a posttreatment period. Neither ipsapirone, a 5-HT_1a partial agonist, nor naltrexone injected inhibited the intakes of ethanol solutions. Treatment with 2.5 mg/kg of amperozide, a 5-HT₂ antagonist, decreased the consumption of ethanol by 38%, but also caused a decrease in consumption of food. These results show a pattern of drinking of increasing concentrations of ethanol different than other strains of rats. Because ethanol intakes of the Fawn-Hooded rat decline precipitously when offered palatable chocolate drink and fail to respond to drugs known to decrease human ethanol intake, this strain may not be a valid model for testing the effects of centrally acting drugs on the consumption of ethanol.     

Female Syrian golden hamster: drinking of high concentrations of ethanol aversive to other mammals

The present experiments were designed to determine: 1) the pattern of preference for different concentrations of ethanol in the female Syrian golden hamster (Mesocricetus auratus), and 2) the influence of drinking ethanol on their intakes of food and total calories. A standard three-bottle preference test was undertaken in six female hamsters over an 11-day period in which water was offered together with ethanol, which was increased in concentration over 11 clays from 3% to 50% as follows: 3%, 5%, 7%, 9%, 12%, 15%, 20%, 25%, 30%, 40%, 50%. Then, each hamster was offered its individually preferred concentration for a period of 8 days until the intake of ethanol had stabilized. During the preference testing for 3–25% solutions, the proportional intakes ranged between 0.6 and 0.8 whereas the mean absolute amount consumed per day increased from 2.3 to 16.1 g/kg at the 25% concentration. However, at the 50% concentration, ethanol drinking declined substantially to 8.7 g/kg per day. The overall mean percent concentration of ethanol preferred by the hamsters was 24.2 ± 1.5%. During the following 8-day period when the maximally preferred concentration of ethanol of each hamster was offered with water, the mean intake of ethanol was 17.9 ± 1.1 g/kg per day. Throughout the test sequence, the caloric intake of the animals was maintained in that calories obtained from food declined at the same rate as the calories obtained from ethanol in rising concentrations. These results reveal that the preference for ethanol of the female hamster is well above that reported in earlier studies in which preference was defined in terms of the proportion of ethanol to total fluid intake. Differences in procedure could account for these findings because the present experiments utilized single-animal housing, a triple bottle method, and measurement of g/kg per day obtained at 11 different concentrations of ethanol.     

Drinking Patterns in Genetic Low-Alcohol-Drinking (LAD) Rats After Systemic Cyanamide and Cerebral Injections of THP or 6-OHDA

A key question related to the role of acetaldehyde and aldehyde adducts in alcoholism concerns their relationship to the genetic mechanisms underlying drinking. Experimentally, the low-alcohol-drinking (LAD) rat represents a standard rodent model having a strong aversion to alcohol. In these experiments, preferences for water vs. alcohol, offered in concentrations from 3% to 30%, were determined over 10 days in adult LAD rats (N = 6 per group). Then a saline vehicle or either 10 or 20 mg/kg of the aldehyde dehydrogenase (AlDH) inhibitor, cyanamide, was injected SC twice daily for 3 days. Secondly, either 0.5 or 1.0 μg of tetrahydropapaveroline (THP) was infused ICV twice daily for 3 days in LAD rats (N = 8) and, as a genetic control, THP also was infused identically in Sprague–Dawley (SD) rats (N = 8). The results showed that the lower and higher doses of cyanamide augmented alcohol intakes in 33% and 50% of the LAD rats, respectively, with the patterns of drinking resembling that of genetic high-alcohol-drinking HAD or P rats. Although ICV infusions of THP had little effect on alcohol preference of LAD rats, alcohol drinking was enhanced significantly in the SD rats. In a supplementary study, 200 μg of 6-hydroxydopamine (6-OHDA) also was infused ICV in LAD rats (N = 7) on two consecutive days; no change occurred in the characteristic aversion to alcohol. These findings suggest that in certain individuals, a perturbation in the synthesis of AlDH can modify the genetically based aversion to alcohol, thus precipitating the liability for alcoholism. In that neither THP nor 6-OHDA lesioning exerted any effect on the genetic nondrinking LAD animal suggests that an unknown endogenous factor in the brain must underlie the cyanamide-induced shift to alcohol preference. We conclude that the genetic elements that normally prevent the progression to addictive drinking in most individuals appear to be invariant and irreversible.     

Ethanol drinking following 6-OHDA lesions of nucleus accumbens and tuberculum olfactorium of the rat

Previous studies have shown that lesions of the dopaminergic system in the brain produced by an intracerebroventricular injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), evoke significant changes in ethanol drinking. In the present experiments, dopaminergic systems of Sprague-Dawley rats were lesioned by 6-OHDA infused into either the tuberculum olfactorium or nucleus accumbens, two of the structures implicated in drug-related reinforcement. Prior to the lesion and immediately thereafter, tests for ethanol preference were undertaken in which water was offered in a self-selection situation together with ethanol which was increased in concentration from 3-30% over a 10-day interval. Following the circumscribed ablation of dopaminergic neurons within either the N. accumbens or tuberculum olfactorium, preference for ethanol increased significantly with absolute intakes exceeding 4.0 g/kg at the 7% concentration during the first postlesion drinking test. During the second postlesion preference test, the mean consumption of ethanol exceeded 6.0 g/kg at the 11% concentration and 4.0 to 5.0 g/kg at the 20 and 30 percent concentrations offered to the rats. When adjacent areas just dorsal or lateral to these structures were lesioned by 6-OHDA, no significant change in consumption of ethanol occurred. Thus, it is envisaged that one of the functional roles for the dopaminergic neurons of the N. accumbens and tuberculum olfactorium is to regulate the craving for a drug with addictive liability such as ethanol. As a result of an impairment of normal function of dopamine receptors or a perturbation in the release of this catecholaminergic neurotransmitter, ethanol becomes reinforcing upon repeated exposure. Thus, an addictive-like state consequently ensues. Finally, it is envisaged that the control mechanism underlying the function of the dopaminergic neurons in the medial-basal forebrain is functionally disinhibited in individuals that consume ethanol to the point of abuse.     

The mixed 5-HT1A2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT_1A and 5-HT_2A receptors in the brain. For example, amperoxide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide-like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate), exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15%, had stabilized for 4 days, saline of FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT_1A and 5-HT_2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.     

Irreversible suppression of alcohol drinking in cyanamide-treated rats after sustained delivery of the 5-HT2 antagonist amperozide

The purpose of this study was to evaluate the long-term effect of sustained treatment with amperozide, which has been shown to attenuate the volitional drinking of ethyl alcohol in the rat without side effects. Preference for alcohol first was induced pharmacologically in Sprague-Dawley rats by the inhibitor of aldehyde dehydrogenase, cyanamide, administered in a dose of 10 mg/kg twice daily for 3 days. Then following a standard preference test, each rat was offered water and its maximally preferred concentration of alcohol which ranged from 7% to 15%. Following a 4-day pre-drug test, saline control vehicle or amperozide was administered for 7 days by an osmotic minipump implanted in the intrascapular space. A single dose of 208 μg/kg/h (i.e., 5.0 mg/kg/day) was selected on the basis of a prior dose response study of amperozide. During the interval of sustained release of amperozide, the consumption of alcohol declined significantly in terms of both absolute g/kg intake and proportion of alcohol to water. When the preference of the rats was retested at 4, 30, 70, 110, and 140 day intervals after the pump had exhausted amperozide, the absolute g/kg consumption of alcohol continued to decline significantly. Unlike other drugs, amperozide did not produce any side effects, particularly on the intake of food or water or on body weight, which suggests a pharmacological specificity of its action. Because amperozide acts centrally on 5-HT₂ receptors as well as on dopaminergic synapses in the limbic system, it is envisaged that the drug exerts a unique effect on reward systems in the brain by affecting their receptor reuptake mechanisms, release of the respective transmitters, or other processes potentially involved in the abnormal imbibition of alcohol. Finally, because the effect of amperozide on alcohol drinking is progressive and irreversible, it thus may serve as a pharmacological adjunct to current therapy used in the clinical treatment of the disease of alcoholism.     

Drinking of high concentrations of ethanol versus palatable fluids in alcohol-preferring (P) rats: valid animal model of alcoholism

A genetically based animal model of alcoholism has been characterized in Wistar-derived rats in terms of their preference (P rats) or lack of preference (NP rats) for 10% ethanol over water. The present experiments were designed to determine: 1) whether a 10% solution of ethanol is the optimal concentration for differentiation of these lines; 2) what concentrations of ethanol are maximally preferred by P and NP rats; and 3) whether highly palatable fluids presented simultaneously with each rat's preferred solution of ethanol would alter the patterns of drinking by either the P or NP or both lines of rats. A three-bottle procedure was used to establish preference for ethanol in the presence of water as well as highly palatable solutions. The results showed that, when concentrations ranging from 3-30% were presented over a 12-day test interval, the mean absolute intake of ethanol of the P rats was 6.7 g/kg per day, with a maximum intake of 10.9 g/kg per day at the 25% concentration. These levels of intake were significantly higher than the 4.3 g/kg per day consumed during the presentation of the commonly used constant concentration of 10%. Similarly, the mean absolute intake of ethanol by the NP rats was also elevated significantly at concentrations of 15-30% (2.0 g/kg per day) above that consumed at the 10% concentration (0.4 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex differences in pattern of drinking.

Drinking patterns of male and female Long-Evans rats were compared during a 15-day drinking period. All animals were tested for preference for alcohol for 24 h during which food, water, and beer containing 5% ethanol were freely available. Animals drinking 50 ml or more of beer were chosen for the experiments. On days 1-5, animals were offered food, water, and beer containing 5% ethanol (v/v). On days 6-15, the concentration of ethanol in the beer was doubled to 10% (v/v). Preference ratios (beer/total fluid) were higher for females than males, and females consumed more grams of alcohol per unit of body weight. When alcohol concentration was doubled, females increased alcohol intake (g/kg), while males tended to titrate alcohol intake to levels consumed at 5% concentration. Female patterns of drinking differed from male patterns of drinking.     

Effects of a metabotropic, mglu5, glutamate receptor antagonist on ethanol consumption by genetic drinking rats

AIMS: To compare the effect of an antagonist of the mGlu5 glutamate receptor, 2-methyl-6-(phenylethynyl)pyridine (MPEP) on a test for anxiety and on the volitional consumption of ethanol. METHODS: The test for anxiety was placement of a Sprague-Dawley rat for a 5 min observation period in an elevated plus-maze. Volitional consumption of ethanol in a two-choice paradigm was determined for male and female myers high ethanol-preferring rats after a 10-day 'step-up' test of 3-30% v/v ethanol vs water used to determine each rat's preferred concentration of ethanol. Each rat received a 4-day baseline period, 3-days of drug injection b.i.d., and a 4-day post-treatment period and then rotated to a different dose of drug or vehicle. RESULTS: The effects of MPEP on elevated plus-maze activity were not significant at doses up to 3.0 mg/kg subcutaneously 60 min. before observation. There was a dose-dependent, 0.3, 1.0, 3.0 mg/kg, decrease in consumption of preferred concentrations of ethanol, along with a decrease in the proportion of ethanol consumed to total fluids consumed. The 3.0 mg/kg b.i.d. dose of MPEP reduced consumption by 57%, proportion by 45%, and food intake by 10%. CONCLUSIONS: MPEP did not appear to have an anti-anxiety effect, but volitional drinking in a genetic model was reduced. The mGlu5 receptor may provide a target for drug action to reduce the consumption of ethanol.     

Comparison of the action of the 5-HT2 antagonists amperozide and trazodone on preference for alcohol in rats

Previous studies in the rat demonstrated that the 5-hydroxytryptamine₂ (5-HT₂) antagonist amperozide attenuates the volitional intake of both alcohol and cocaine solutions in a free-choice situation. However, another 5-HT₂ antagonist, ritanserin, has not been found to reduce alcohol drinking consistently in the rat. In this study, trazodone was compared to amperozide for its effect on the volitional consumption of alcohol because, like amperozide, trazodone is a potent 5-HT₂ receptor antagonist but a weak inhibitor of 5-HT reuptake. Male Sprague-Dawley rats were induced to drink alcohol by 10 mg/kg cyanamide injected for 3 days b.i.d. One week later the rats were offered a choice of water and increasing concentrations of alcohol solutions ranging from 3% to 30% v/v in a three-bottle two-choice paradigm. After the concentration of alcohol that produced maximal daily intake was determined for each rat, trazodone or amperozide was injected b.i.d. SC in doses of 1.0 mg/kg or 2.5 mg/kg for three days. Whereas the higher dose of amperozide produced a significant, 55.6% decrease from pretreatment baseline of alcohol intake, trazodone did not alter alcohol preference at either the 1.0- or 2.5-mg/kg dose. These results are discussed in terms of whether the antagonism of 5-HT₂ receptors by amperozide is critical to its attenuating effect on preference for alcohol solutions.     

Caffeine promotes ethanol drinking in rats. Examination using a limited-access free choice paradigm.

There is growing evidence that caffeine may alter the pattern of intake of a variety of drugs. The present study was designed to assess the effect of caffeine pretreatment on voluntary ethanol consumption. The first experiment examined the effect of caffeine on the acquisition of ethanol intake in a limited-access-choice procedure in which water and ethanol were presented concurrently. Male Wistar rats, exposed to food and water ad lib, were presented with a daily 1-h choice session between water and progressively increasing concentrations of ethanol (2-10%). Each ethanol concentration was made available for 4-6 days for a total of 20 days of access to ethanol. Intraperitoneal injections of caffeine (5 or 10 mg/kg) or saline were administered to the rats 30 min prior to each choice session. Caffeine produced a dose-related facilitation in ethanol drinking whereby the lower caffeine dose produced enhancement in ethanol drinking. The second experiment examined the effect of caffeine on the maintenance of established ethanol consumption. Male Wistar rats, initially acclimatized to increasing concentrations of ethanol (2%-10), were presented with an additional 18 ethanol (10%) presentations, comprised of a 6-day baseline period followed by 6 days of treatment where animals were given one of three doses of caffeine (2.5, 5 or 10 mg/kg) or saline prior to ethanol presentation. A final 6-day post-treatment period followed treatment. These results revealed an inverted-U effect of caffeine dose on ethanol ingestion where the low and high caffeine doses produced no effect but the moderate dose of 5 mg/kg enhanced ethanol drinking that persisted throughout the post-treatment period. A third experiment revealed that caffeine did not alter levels of blood ethanol within the time period used for the ethanol drinking session.     

Anatomical localization in hippocampus of tetrahydro-beta-carboline-induced alcohol drinking in the rat

Guide cannulae for unilateral or bilateral micro-injection were implanted stereotaxically into the dorsal hippocampus of the male adult Sprague-Dawley rat. Following post-operative recovery, the animal's individual preference for ethyl alcohol in concentrations from 3-30% (v/v) was tested over a 9-day period by a three-bottle, two-choice technique. Following this pre-screen, 3.0 microliter of 1,2,3,4-tetrahydro-beta-carboline (TH beta C) hydrochloride, a benzodiazepine receptor antagonist, was infused in a concentration of 25-200 ng into the hippocampus of each unrestrained rat twice a day for three to six days. After the first two days of infusion, the 9-day preference test for alcohol drinking was begun and continued identically as in the earlier test. A third alcohol preference test during which no injections were given was conducted at an interval of two weeks following the second. The micro-injection of TH beta C into certain sites in the hippocampus enhanced alcohol consumption from 0.5-2.0 g/kg during the 9-day test interval. The magnitude of this elevated intake was dependent on the site of infusion and was more pronounced when intermediate concentrations of 7-12% alcohol were offered to the rat. At sites in coronal planes encompassing AP 3.0 and AP 3.5, the micro-injection of TH beta C enhanced alcohol drinking significantly in 75% of the animals; however, when delivered at sites in coronal planes AP 1.0 through AP 2.5, TH beta C augmented alcohol drinking significantly in 15% of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of concurrent access to a single concentration or multiple concentrations of ethanol on ethanol intake by periadolescent high-alcohol-drinking rats.

The objectives of the current study were to assess the effects of access to different concentrations of ethanol and sex of the animal on ethanol consumption of high-alcohol-drinking (HAD-1 and HAD-2) rats during adolescence [postnatal days (PNDs) 30 through 60]. At the beginning of adolescence (PND 30), the rats were given concurrent access to either a single concentration [15% volume/volume (vol./vol.)] or multiple concentrations [10%, 20%, and 30% (vol./vol.)] of ethanol and water. Analyses of ethanol consumption data revealed significant (P < .025) main effects of line, ethanol condition, and week, and a significant line by sex by ethanol condition by week interaction. For the first week, both male and female HAD-1 and HAD-2 rats consumed more ethanol under the multiple ethanol concentration condition than under the single ethanol concentration condition. However, across the second through fourth weeks, this pattern was seen primarily in male and female HAD-1 rats and to a lesser degree in female HAD-2 rats. In general, female rats consumed more fluids than consumed by male rats, and male rats displayed a higher preference for ethanol over water ratio than observed for their female counterparts. In addition, in comparison with HAD-2 rats, HAD-1 rats drank more ethanol and displayed a higher preference for ethanol ratio. Overall, the current study results indicate that, compared with access to a single concentration (which is used in most studies), concurrent access to multiple concentrations of ethanol produced significantly higher ethanol intakes in periadolescent HAD rats, supporting the suggestion that this ethanol drinking condition would have a greater impact on neuronal development. In addition, although the replicate lines were selectively bred by using the same criteria and foundation stock, the higher ethanol intakes of the HAD-1 line, compared with intakes for the HAD-2 line, seen in the current study support the suggestion that there are some differences in their genetic make-up, affecting ethanol intake, which are expressed during periadolescence.     

Genetics of Alcoholism: Rapid Development of a New High-Ethanol-Preferring (HEP) Strain of Female and Male Rats

A genetically based animal model of alcoholism has been developed in a relatively short period of 3 years. The new strain is characterized by an intense preference for ethanol over water as well as unique behavioral, neurochemical and other attributes. This new strain, termed high-ethanol-preferring (HEP) rats, was derived initially from selective cross-breeding of a variant strain of female Harlan Sprague–Dawley (SD) rats with the outbred Wistar line of male ethanol-preferring (P) rats. In this study, drinking patterns of both genders were obtained over 10 days by presenting water and ethanol in concentrations ranging from 3% to 30%. To expedite the development of the new strain, only three to five female and male rats served as breeders, which were chosen from all litters on the basis of their maximum g/kg intake integrated with proportion of ethanol to total fluid values. Profiles of intake of preferred concentrations of ethanol were obtained over 24 h of unlimited access as well as during 2-h intervals of limited access to ethanol. Levels of blood ethanol were measured in both female and male HEP animals during bouts of ethanol drinking in the limited access paradigm. By the sixth generation of HEP rats, ethanol consumption of the females often exceeded that of any other rat genetically bred to drink ethanol (e.g., at a concentration of 15.7%, 10.3 g/kg per day). Seven additional characteristics are notable: 1) the HEP rats prefer ethanol in the presence of a nutritious chocolate drink or nonnutrient sweetened solution (aspartame); 2) high levels of blood ethanol are associated with their drinking; 3) females drink significantly greater g/kg amounts of ethanol than HEP males and prefer a higher percent concentration of ethanol; 4) the drinking of ethanol by the female HEP animals does not fluctuate during the estrous cycle; 5) neurochemical assays show differential profiles of 5-HT, dopamine, and their metabolites in different regions of the brain; 6) measures of activity using the elevated plus maze, open field, and cork gnawing reveal differences between genders of HEP rats and SD rats; and 7) the HEP animals are without phenotypically expressed abnormalities. Finally, one cardinal principle derived from this study revealed that the breeding strategy to develop high-ethanol-drinking rats centers on the use of multiple solutions of ethanol whereby the intakes of ethanol in concentration of 9% through 20% dictate the ultimate selection of breeding pairs over successive F generations. Further, it is concluded that because of an intense rise in ethanol drinking of the F₁ generation of female HEP rats well above that of the parental SD female breeders, the complex genotypic characteristic of the male P rat is predominantly responsible for evoking ethanol drinking in female offspring.     

Interaction of tetrahydropapaveroline with inhibition of dopa-decarboxylase by Ro 4-4602 in brain: effects on alcohol drinking in the rat

The effects of the 1-aromatic amino acid decarboxylase inhibitor, Ro 4-4602 (benserazide), was determined on alcohol drinking induced in the rat by tetrahydropapaveroline (THP) injected by the intracerebroventricular (ICV) route. After ICV guide cannulae were implanted stereotaxically in 19 Sprague-Dawley rats, an artificial CSF solution containing 5.0 ng/micrograms THP was infused twice daily for 3 days in a volume of 5.0 microliters. Following a standard self-selection procedure, concentrations of alcohol which ranged from 3-30% were presented to the rats. A single maximally preferred solution, which in these rats ranged from 9-12% alcohol, was then offered in the presence of water. After a 4-day pretest in which alcohol intakes had stabilized, either 50 or 100 micrograms Ro 4-4602 plus THP were infused ICV to the animal during a 3-day period. Both doses of Ro 4-4602 significantly antagonized the g amount and proportional intakes of alcohol, but the higher dose was nearly twice as potent as the lower. During the 4-day postdrug test period, alcohol drinking continued to be suppressed. When THP was infused ICV over a 3-day period following the injections of Ro 4-4602, the predrug alcohol intake was partially reinstated, suggesting that this TIQ, when delivered directly into the brain, partly reversed the potent central action of Ro 4-4602. These results show that interference with the functional activity of central catecholamine pathways in the rat, by means of the inhibition of dopamine synthesis, serves to modify markedly the mechanisms underlying alcohol drinking in this species.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glycyl-l-Glutamine Injected Centrally Suppresses Alcohol Drinking in P Rats

Recent reports show that central β-endorphin (1–31) injection augments the volitional intake of alcohol. Correspondingly, alcohol drinking stimulates β-endorphin (1-31) release from the hypothalamus of the rat. Glycyl-l-glutamine (Gly-Gln) is produced in β-endorphin-containing neurons and is coreleased with β-endorphin(1–31) and other processing products. Because Gly-Gln is apparently an endogenous antagonist of β-endorphin(1–31) in several systems, the present study was designed to investigate the hypothesis that Gly-Gln injected ICV would alter voluntary alcohol drinking in the genetic, high-alcohol-preferring P rat. After a guide tube was implanted stereotaxically above the lateral cerebral ventricle, the rats were offered 3–30% alcohol over 10 days, and then given their maximally preferred concentration of alcohol in the presence of water for the remainder of the experiment. Gly-Gln or artificial cerebrospinal fluid (CSF) vehicle then was injected ICV in a dose of 10 or 100 nmol for 3 consecutive days, which was followed by a 7-day postinjection interval. Gly-Gln suppressed significantly the intakes of alcohol in terms of both g/kg and proportion to total fluid. During the postinjection days, alcohol drinking continued to be suppressed, whereas neither the daily intakes of food or water nor the body weights of the rats were changed. The present results are consistent with the concept of a functional antagonism by Gly-Gln of the role of β-endorphin(1–31) in mediating certain central functions. These results demonstrate that alcohol consumption is suppressed by the direct intracerebral application of this unique peptide.     

Development of alcohol deprivation effect in rats: lack of correlation with saccharin drinking and locomotor activity.

The present study addressed the relationship between the parameters of saccharin drinking behaviour and locomotor activity in an open field environment and long-term alcohol self-administration. In a 22-day initiation phase, male Wistar rats were presented with increasing concentrations of ethanol (2-8%, v/v) in a choice with water. The rats were then given the choice between water and two ethanol solutions (8 and 16%). Every 28 days, ethanol was withdrawn for 5 days. The ethanol intake and the transient increase in ethanol consumption after each of six deprivation episodes (alcohol deprivation effect) was monitored and correlated with parameters of the subsequent saccharin drinking and open field tests. The total ethanol intake (g/kg/24 h) as well as the consumption of 16% ethanol were stable over time. However, the magnitude of the alcohol deprivation effect increased with the repeated deprivation episodes. None of the parameters measured in the open field or the saccharin drinking tests correlated with either ethanol consumption or the alcohol deprivation effect. These results suggest that (1) repeated episodes of ethanol deprivation may increase the magnitude of the alcohol deprivation effect, (2) neither saccharin drinking nor locomotor activity correlates with long-term ethanol drinking behaviour in rats.     

Dose-dependent suppression of the high alcohol intake of chronically intoxicated rats by Ca-acetyl homotaurinate

The effect of taurine derivative, Ca-acetyl homotaurinate, on voluntary alcohol intake was investigated in ethanol-dependent and naive rats. A high 24 hr oral intake of a 10% ethyl alcohol solution (9-10 g/kg) was exhibited by rats following 15 days of intragastric infusions of ethanol (7-8 g/kg/day). In four groups, rats were IG injected by short pulses of isotonic saline or a daily dose of 200, 300 and 450 mg/kg respectively, distributed over six daily infusions during alternating 8 hr presentations of ethanol solution and water. Compared to their respective basal intakes during the first two days of injection, the rats demonstrated a dose-dependent 50 to 70% reduction in alcohol consumption with drug treatment. This suppression effect was specific to the ethanol solution and persisted during 4 days of post-treatment observation. In ethanol-naive rats similarly tested and drinking half the amount of alcohol drunk by their ethanol-dependent counterparts, only the highest dose of drug (450 mg/kg) significantly suppressed their alcohol intake. It is suggested that Ca-acetyl homotaurinate interacts with CNS mechanisms involved in the ethanol tolerance-dependence state, underlying an enhanced reinforcing property of ethanol oral intake. Opioid receptors could be the targets in this action.     

CONSTANT ABSOLUTE ETHANOL INTAKE BY SARDINIAN ALCOHOL-PREFERRING RATS INDEPENDENT OF ETHANOL CONCENTRATIONS

The present study was designed to evaluate ethanol drinkingbehaviour in Sardinian alcohol-preferring (sP) and Sardinianalcohol-non-preferring (sNP) rats in the presence of differentethanol concentrations. Ethanol intake was tested under thetwo-bottle, free-choice regimen and continuous access schedule.Ethanol-naive sP and sNP rats were initially given ethanol solutionat the standard, constant concentration of 10% (v/v) for 8 consecutivedays (Phase 1). As expected, daily ethanol intake in sP ratsrose from 4 to {small tilde}l6g/kg; in contrast sNP rats consumed<10g/kg/day ethanol. Subsequently, an ascending series ofethanol concentrations, ranging from 3 to 60% (v/v), was presentedto sP and sNP rats over a 28-day period (Phase 2). At concentrationsvarying from 7 to 30%, sP rats consumed constant amounts ofabsolute ethanol per kg of body weight ({small tilde}6.0 g/kg/day).Daily ethanol intake in sNP rats remained constantly lower than1.0 g/kg, irrespective of the ethanol concentration. Data fromPhase 2 demonstrate the ability of sP rats to precisely adjustdaily ethanol intake and support the hypothesis that voluntaryethanol drinking in sP rats is sustained by specific pharmacologicaleffects of ethanol.