Dietary regulation of voluntary alcohol consumption in rats. Influence of a high protein diet and a methylene blue diet.

The importance of glucose homeostasis for high voluntary alcohol consumption was studied in alcohol-preferring (AA) and alcohol-avoiding (ANA) rats fed either a control diet, a protein-rich diet or a control diet supplemented with methylene blue. AA rats on the control diet were found to receive 13.6% of their daily energy intake from alcohol. On the high-protein or methylene blue diet, the alcohol consumption of the AA rats was respectively 40% and 48% higher than on the control diet. The voluntary alcohol consumption of ANA rats corresponded to 0.8-2.3% of their daily energy intake irrespective of diet. The protein diet increased the blood glucose concentration of AA rats by 20% but no increase was observed after the methylene blue diet. The diets had no effect on the blood glucose levels of ANA rats. In AA rats, the protein diet reduced the hepatic concentration of the three major glucogenic amino acids (serine, glycine, alanine) on average by 24%, suggesting an increased utilization for gluconeogenesis. No such reduction was observed in AA rats on the methylene blue diet or in ANA rats on any diet. The utilization of amino acids for maintenance of glucose balance in AA rats is further supported by the observed negative correlation between plasma concentration of urea, the end product of amino acid catabolism, and the sum of the concentrations of the three glucogenic amino acids in the liver, and by the positive correlation between plasma urea and blood glucose concentration. Furthermore, in AA rats, but not in ANA rats, the concentration of alanine, the main amino acid used in gluconeogenesis, correlated negatively with the amount of alcohol consumed. These findings indicate that the maintenance of glucose homeostatis is important for high voluntary alcohol consumption.

Effects of serotonin uptake blockers and of 5-hydroxytryptophan on the voluntary consumption of ethanol, water and solid food by UChA and UChB rats.

The effects of zimelidine, fluvoxamine, and citalopram (serotonin uptake blockers), as well as those of 5-hydroxytryptophan (serotonin precursor), on the voluntary consumption of 10% ethanol solution, distilled water and solid food were tested in UChA (genetically low ethanol consumer) and UChB (genetically high ethanol consumer) rats. Since it is well known that drugs which stimulate central serotonergic synapses decrease food and water intake, the data concerning the difference of the respective consumption during the treatment period and the pretreatment one were analysed with a method previously proposed (Alcohol 5:15-19; 1988) to recognize specific effects on ethanol intake. The results showed that while the decrease of ethanol consumption induced by the three serotonin uptake blockers appeared not to be specific of ethanol, the effects of 5-hydroxytryptophan in UChB rats satisfy the criteria for being considered as an expression of a decrease of the specific appetite--or increase satiety--for ethanol. Experimental results cannot help in the explanation of this difference.

Prostaglandin E2 reduces voluntary ethanol consumption in the rat.

A number of prior studies have suggested that the prostaglandins may mediate some of the physiological effects of ethanol, and while it has been suggested that PGE2 may be involved in regulating ethanol consumption, evidence for this has been inconclusive. In the present study, rats injected with PGE2 at doses of 50, 100 and 200 micrograms/kg consumed significantly less alcohol than vehicle-treated controls. Doses of PGE2 which were highly effective in reducing ethanol intake produced only marginal changes in the consumption of water and glucose solution. These data, together with previous studies demonstrating a link between ethanol and the prostaglandins, suggest that PGE2 may be involved in the control of ethanol consumption.

Intracerebroventricular morphine enhances alcohol consumption by rats.

Previous experiments have shown that systemically administered low doses of opioid agonists increase subsequent alcohol consumption by rats. In this experiment, 10 micrograms of morphine were infused intracerebroventricularly (ICV) in free-feeding rats, daily for 6 days, 30 min prior to one-hour access to a 12% alcohol solution. Alcohol consumption was significantly increased in the morphine-treated group compared to that of a saline-treated control group, confirming that the locus of the effect is within the central nervous system.

Noradrenergic system: effect of DSP4 and FLA-57 on ethanol intake in ethanol preferring rats.

Ethanol preferring rats (male Long-Evans; n = 6) were selected as drinking rats (DR) and treated with DSP4 (50 mg.kg-1 IP) at the end of the preference selection. Two more groups received DSP4 (50 mg.kg-1 IP) + the inhibitor of dopamine beta-hydroxylase FLA-57 (1 mg.kg-1.d-1 during two weeks), IP (n = 5) or FLA-57 alone (1 mg.kg-1.d-1 during two weeks IP) (n = 5). The control DR group (n = 6) received NaCl 0.9%. 3H-Noradrenaline uptake was studied at the 17th day of treatment in DR, treated or not with DSP4, and in ethanol naive rats treated (n = 6) or not (n = 6) with DSP4 (50 mg.kg-1, IP) DSP4 does not modify ethanol intake in DR, and both treated groups (DR or ethanol naive rats). 3H-Noradrenaline uptake was decreased (about 60%), both in cortex and hippocampus. But the association of FLA-57 and DSP4 decreases both ethanol and fluid intakes. It was suggested 1) that the 40% of intact neurons was able to compensate the DSP4-induced noradrenergic neurons destruction, 2) that the destruction of noradrenergic pathways (FLA-57 + DSP4) is associated with a decrease in ethanol intake but also in fluid intakes, suggesting finally 3) that the modulation of ethanol intake by the noradrenergic system was partial or indirect.

The role of the gastric and hepatic vagus in voluntary alcohol intake.

The present study investigated a possible role for neural signals sent from the liver and stomach to the brain in the regulation of alcohol intake. Experiment 1 showed that gastric vagotomy (GVX) reduced the intake of 3% alcohol and 6% alcohol, while water intake was increased. This effect was not due to an alteration in pharmacokinetics, although an alteration in taste function could not be ruled out. Angiotensin II reduced the intake of 6% alcohol and stimulated the intake of water similarly in both GVX and sham groups. In Experiment 2 rats were subjected to hepatic vagotomy or sham laparotomy and then offered a choice between an alcohol solution and tap water for 40 min each day. Although hepatic vagotomy (HVX) did not alter the intake of 3% alcohol or water, 6% alcohol intake was significantly reduced. Angiotensin II decreased 6% alcohol intake and increased water intake similarly in both groups. These experiments indicated that interrupting information from the liver and stomach to the brain by selective gastric and hepatic vagotomy can decrease voluntary alcohol intake. Since vagal afferent nerves are thought to participate in the control of food intake, the present findings support the hypothesis that the "food-like" qualities of alcohol, i.e., calories and taste, can contribute to the regulation of alcohol intake.

Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers.

The effects of fluoxetine, a relatively selective long-acting serotonin uptake inhibitor, on the consumption of alcoholic and nonalcoholic drinks, cigarette smoking, and body weight were assessed in 29 men who were early stage problem drinkers. After a 2-week baseline, subjects were randomly assigned to receive 40 mg/day fluoxetine (n = 8), 60 mg/day fluoxetine (n = 11), or placebo (n = 10) for 4 weeks. Fluoxetine 60 mg/day decreased mean daily alcoholic drinks from (X +/- SEM) 8.3 +/- 0.7 during baseline to 6.9 +/- 0.7 and decreased total drinks per 14 days from 115.8 +/- 9.3 to 96.5 +/- 9.5 (p less than 0.01; 17.3% decrease from baseline), with no significant increase in days of abstinence. Neither 40 mg/day fluoxetine nor placebo had effects on intake of alcohol. Fluoxetine 60 mg/day decreased total and mean daily alcoholic drinks compared with 40 mg/day fluoxetine (ANCOVA, both p less than 0.02), but neither dose of fluoxetine was different from placebo. Compared with placebo, both 40 mg/day fluoxetine and 60 mg/day fluoxetine no differences were detected between treatment groups, 60 mg/day fluoxetine increased mean daily nonalcoholic beverages from baseline (5.0 +/- 0.4 to 5.6 +/- 0.3, p less than 0.01) and increased daily cigarettes smoked (from 25.1 +/- 4.6 to 26.9 +/- 4.5, p less than 0.05), whereas no significant changes from baseline were observed with 40 mg/day fluoxetine or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Papaverine, tetrahydropapaverine and ethanol metabolizing enzymes.

The effects of tetrahydropapaverine (THP) and papaverine (PAP), an O-methylated analogue, on rat liver alcohol dehydrogenase (L-ADH) and aldehyde-dehydrogenase (L-ALDH) were studied in vitro. The action of THP on these enzymes was also evaluated in vivo in conjunction with its effect on voluntary intake of ethanol by the rat. Both L-ADH and mitochondrial L-ALDH were inhibited in vitro in the presence of 10(-4) M THP. Conversely, stimulation of L-ADH and L-ALDH occurred by PAP in the concentration range between 10(-4) to 10(-6) M in vitro. Acute or daily administration of THP for five consecutive days did not alter voluntary intake of ET by the rat or changed specific activity of these hepatic enzymes in vivo. The structure activity of these compounds in relationship to the enzymes studied suggest the importance of O-methylation on the enzymatic effect studied which may possibly underlie some of the hypothesized action of THP on libation of alcohol.

[Evaluation of accelerated development of stable alcoholic motivation in rats for studying potential alcohol deterrents]. / Otsenka uskorennogo razvitiia ustoichivoi alkogol'noi motivatsii u krys s tsel'iu izucheniia potentsial'nykh protivoalkogol'nykh sredstv.

The express technique reflecting an acquisition of a clear alcohol addiction during short-term voluntary alcoholization for further antialcoholic drugs testing was performed in male albino rats. By VARIMAX factor analysis of indexes related with preference of alcohol solutions with different tastes the conditions of short-term (2 months) voluntary alcoholization leading to persistent ethanol intake were studied. Isolation stress inducing a specific alcohol drive was excluded from rearing conditions. 0.1% saccharin solution in 15% ethanol was used for alcoholization. Statistical analysis revealed factor of "developed alcohol abuse" which may be detected in conditions of one-trail sweet ethanol intake after 3 days alcohol deprivation (similar to heavy drinking syndrome in humans). Using pharmacological drugs (pyrazidol, piracetam) validity of the method for specific drug design was confirmed.

Effects of alpha 2-adrenergic drugs on the alcohol consumption of alcohol-preferring rats.

The effects of seven-day subcutaneous infusion of an alpha 2-adrenoceptor agonist, medetomidine, and an alpha 2-adrenoceptor antagonist, atipamezole, on the voluntary alcohol consumption of alcohol-preferring rats were studied. The drugs were administered by means of implanted osmotic minipumps. Sham-operated control rats had no pumps implanted. The rats had a free choice between 10% alcohol and plain water for 30 days before pump implantation and again for six days starting 24 hr after the operation. Atipamezole increased the alcohol consumption during the first day of free choice. Medetomidine had no significant effect. During the remaining period of infusion, the alcohol consumption did not differ from that preceding the pump implantation in each treatment group. Animals in the atipamezole group gained more weight during the seven-day trial than did those in the medetomidine and control groups. The amine changes in different regions of the brain were consistent with medetomidine decreasing and atipamezole increasing the noradrenaline turnover. The present results indicate that specific drugs acting on the alpha 2-adrenoceptors produce only minor changes in the voluntary alcohol drinking of alcohol-preferring rats.

Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference.

The effect of naloxone on voluntary ethanol intake was examined in rats which were selectively bred for oral ethanol preference (High Alcohol Drinking or HAD line). Rats of the HAD line were treated with naloxone in doses of 0.05-18.0 mg/kg b.wt. before access to water alone or to a free-choice between a 10% (v/v) ethanol solution and water. Naloxone suppressed water intake when water was presented as the sole source of fluid. In contrast, naloxone produced a dose-dependent decrease in ethanol consumption, without altering water intake, when rats were given a free-choice between the ethanol solution and water. Selective suppression of ethanol consumption by naloxone was not attributable to changes in blood ethanol concentrations or ethanol elimination rates following naloxone treatment. It appears that although naloxone may attenuate the positively reinforcing properties of both ethanol and water, ethanol drinking is a subset of consummatory behaviors that is particularly sensitive to opioid receptor blockade. The results suggest that activation of the endogenous opioid system may be an important mechanism which serves to maintain continued ethanol drinking.

Central action of an inhibitor of brain dopa-decarboxylase, NSD-1015, on cyanamide-induced alcohol drinking in rats.

A cannula for repeated intracerebroventricular (ICV) infusion was implanted stereotaxically in 16 male Sprague-Dawley rats. Subsequently, an alcohol preference test was given to each animal to establish its preferred concentration in the presence of water. After the alcohol solution was removed, 15 mg/kg cyanamide was injected subcutaneously for 4 days to maximize volitional intake of the single preferred solution of alcohol, which ranged from 7-15% in these animals. The L-aromatic amino acid decarboxylase inhibitor, NSD-1015 (3-hydroxybenzylhydrazine dihydrochloride) was then given ICV twice daily in a volume of 5.0 microliters in the following doses: 0.005, 0.01, 0.1 and 1.0 micrograms. NSD-1015 in all doses attenuated the g/kg alcohol intake of the rats; however, this decline was significant only at the lowest dose, which was pharmacologically specific, since neither food nor water intakes were altered by the treatment. Following the ICV infusions of NSD-1015, alcohol drinking returned essentially to postcyanamide levels. Further, during the interval of administration of NSD-1015, the cyanamide-induced decline in food consumption was reversed. These observations are in agreement with previous findings obtained under similar experimental conditions with the L-aromatic amino acid decarboxylase inhibitor, benserazide (Ro4-4602). They suggest that central decarboxylation or other effects of this drug on limbic system structures involved in the intake of alcohol could comprise a part of the mechanism underlying the induction of drinking. Further support is also provided for the involvement of brain dopamine and/or serotonin in the specific pattern of alcohol consumption in the rat.

Cholecystokinin octapeptide reduces ethanol intake in food- and water-sated rats.

The putative satiety peptide cholecystokinin octapeptide (CCK-8) has been shown to reduce ethanol intake induced by prior fluid deprivation. Since fluid-deprived animals tend to reduce their food intake and consequently become hungry, the ability of CCK-8 to reduce ethanol intake might be limited to conditions where the motivation for food and fluid are accentuated. The present study assessed this possibility by examining the effect of peripheral injections of CCK-8 on voluntary ethanol intake fostered by the limited access procedure which uses food- and water-sated rats. Under these conditions CCK-8 still produced a dose-dependent decrease in ethanol intake. These results demonstrate that CCK-8 reduces ethanol intake even in the absence of hunger and thirst drives.

Angiotensin converting enzyme inhibitors reduce alcohol consumption: some possible mechanisms and important conditions for its therapeutic use.

Alcoholism is a prevalent problem of contemporary society, yet there are virtually no clinically effective drugs for the management of this disorder. A previous study demonstrating the ability of angiotensin-converting enzyme (ACE) inhibitors to attenuate voluntary alcohol intake in rats prompted the suggestion that these drugs, currently marketed for the treatment of hypertension, may also be useful in dealing with human alcohol abuse. The present experiments explored in more detail the effect and possible mechanisms of action of this class of drug on alcohol consumption in rats. Experiment one demonstrated that Abutapril, a new ACE inhibitor, significantly reduced alcohol intake and that this effect could not be blocked by either an ANG II or an opiate receptor antagonist suggesting that neither the peripheral renin-angiotensin system (RAS) nor the endogenous enkephalins are involved in the ability of ACE inhibition to attenuate alcohol intake. Experiments two and three showed that ACE inhibition effectively reduced alcohol drinking faster in animals with elevated RAS activity and not at all in animals with suppressed RAS activity indicating that initial levels of RAS activity may determine the speed and ability of ACE inhibition to attenuate alcohol intake. ACE inhibitors may reduce alcohol intake by elevating a nonapeptide fragment or by elevating central ANG II levels. The assessment of this class of drugs to reduce alcohol intake in humans should include a monitoring of the initial level of activity in the renin-angiotensin system since this may be a predictor of the effectiveness of treatment with the ACE inhibitors.

The effect of clonidine and related substances on voluntary ethanol consumption in rats.

Clonidine, guanfacine and tiamenidine, in equihypotensive doses, significantly reduced alcohol intake in ethanol-preferring rats having free choice between 10% ethanol and drinking water. Water intake was only slightly reduced, especially during the first hours following the administration of clonidine. Simultaneous treatment with yohimbine attenuated the clonidine-induced reduction in ethanol intake. Putative central mechanisms underlying the observed inhibitory actions of clonidine and other alpha-2 adrenoceptor agonists on oral self-administration of alcohol are discussed.

[The clinico-immunological efficacy of dioxidine in the combined treatment of acute abscessing pneumonias in persons who abuse alcohol]. / Kliniko-immunologicheskaia éffektivnost' dioksidina v kompleksnom lechenii ostrykh abstsediruiushchikh pnevmonii u lits, zloupotrebliaiushchikh alkogolem.

The results of clinico-immunologic studies of the efficacy of dioxidin in persons abusing alcohol have demonstrated that unlike antibiotics, dioxidin does not provoke any immunosuppressive disorders. It is recommended that dioxidin should be included into multimodality treatment of patients with acute lung abscesses, abusing alcohol.

Reduction in ethanol preference following injection of centrally and peripherally acting antimuscarinic agents.

Selectively bred alcohol-preferring (P) and alcohol non-preferring (NP) lines of rats were administered saline subcutaneously, and doses of 0.5 and 2.0 mg/kg of two antimuscarinic agents scopolamine (centrally acting) and methscopolamine (peripherally acting), twice daily respectively for a period of one day. Compared to saline, both doses of scopolamine and methscopolamine induced a significant reduction in ethanol consumption in the P line of rats, and both antimuscarinic agents significantly increased water intake. Thus, ethanol preference was dramatically reduced in these rats. In contrast, scopolamine had relatively little effect on either ethanol or water intake in the NP line of rats, while methscopolamine tended to suppress both ethanol and water intake. These findings suggest that peripheral muscarinic mechanisms may be involved in ethanol preference in P rats.

Alcoholics' attitudes toward and experiences with disulfiram.

We studied 345 alcoholic inpatients utilizing a 43-item questionnaire designed to assess these patients' attitudes toward and experiences with disulfiram. A surprisingly high number of patients who had received disulfiram drank ethanol while taking or within 1 week of stopping disulfiram and experienced a disulfiram ethanol reaction. This finding and others derived from the questionnaire are reported, and the potential implications of the findings are discussed.

Effects of the kappa opioid receptor antagonist MR-2266-BS on the acquisition of ethanol preference.

Using a paradigm by which rats forced to drink a weak ethanol solution (2.5% w/v) (conditioning session) develop ethanol preference in consecutive retention testing days, the effects of the administration of the kappa opioid antagonist MR-2266-BS, prior to or after the forced ethanol session, were studied. Pre-conditioning subcutaneous (s.c.) administration of 1 mg/kg of MR-2266-BS induced a decrease in subsequent ethanol consumption without significantly modifying the acquisition of ethanol preference. Post-conditioning administration of MR-2266-BS (0.1, 1, 5 or 10 mg/kg) induced both a dose-dependent reduction in ethanol consumption and in preference throughout the three following days. The results of the present study provide further support of the involvement of kappa-type opioids on drinking behavior, and suggest that kappa receptors may be involved in the consumption and development of preference to ethanol.

Effects of dopaminergic agents on alcohol consumption by rats in a limited access paradigm.

The effects of several dopaminergic drugs on alcohol consumption were studied in free-feeding rats using a limited access paradigm. Ascending doses of amphetamine (0.1, 0.3 and 1.0 mg/kg), haloperidol (0.1, 0.3 and 1.0 mg/kg), SKF 38393 (a D1 receptor agonist - 0.3, 1.0 and 3.0 mg/kg), quinpirole (LY 171555, a D2 receptor agonist - 0.03, 0.1 and 0.3 mg/kg), SCH 23,390 (a D1 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) and spiperone (a D2 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) were administered IP to rats approximately 30 min prior to their 1-h per day access to alcohol. Each dose was administered for 5 successive days, and the effects of the drugs were compared to those of respective saline or 0.4% lactic acid solution controls. Although there was an overall significant dose effect of amphetamine on alcohol consumption, no single dose altered alcohol consumption significantly from baseline. SKF 38,393 specifically decreased alcohol consumption at the highest dose of 3 mg/kg. Quinpirole significantly increased water consumption at the highest dose but had no effect on alcohol consumption. The antagonist haloperidol decreased alcohol consumption but only at doses that also reduced water consumption. The specific antagonists SCH 23,390 and spiperone decreased water consumption at the highest doses tested without modifying alcohol consumption. Taken together, these data suggest that dopamine does not play as critical a role in mediating the reinforcing effects of alcohol (insofar as they are reflected by alcohol consumption) as it does in relation to other psychoactive drugs, particularly the psychomotor stimulants.