Selective reduction by the 5-HT antagonist amperozide of alcohol preference induced in rats by systemic cyanamide.

This investigation was undertaken to determine the effect of a unique psychotropic agent on the volitional drinking of alcohol induced pharmacologically in the rat by an inhibitor of aldehyde dehydrogenase. Following administration of cyanamide in a dose of 10 mg/kg twice daily for 3 days, the pattern of drinking of ethyl alcohol was determined in each of 12 Sprague-Dawley rats by means of a standard preference test for 3-30% alcohol vs. water. Then, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7-15%. After a 4-day predrug test, either the saline control vehicle or the diphenylbutylpiperazinecarboxamide derivative, amperozide, was administered subcutaneously. The injections of amperozide were given b.i.d. at 1600 and 2200 h over 3 days in a dose of 0.5, 1.0, or 2.5 mg/kg. The intake of alcohol during the sequence of amperozide injections was significantly reduced in a dose-dependent manner in terms of both absolute g/kg and proportion of alcohol to water intake, whereas the saline control vehicle was without any effect on alcohol consumption. Although the highest dose of amperozide reduced the total intake of fluid due to the sharp decline in alcohol drinking, neither the consumption of food nor level of body weight was affected by any dose of the drug either during or after its administration. Because amperozide acts centrally on the synaptic activity of dopaminergic and serotonergic neurons in limbic system structures, it is envisaged that the drug ameliorates the aberrant drinking of alcohol by virtue of a direct effect on either one or both of these classes of neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of brain dopa-decarboxylase by RO 4-4602 infused ICV blocks alcohol drinking induced in rats by cyanamide.

Following the stereotaxic implantation of chronic cannulae for intracerebroventricular (ICV) infusion, rats were given an alcohol preference test to establish their preferred concentration in comparison with water. After alcohol was removed, 15 mg/kg cyanamide was then injected subcutaneously for 4 days in order to maximize volitional intake of single solutions of alcohol, which in these animals ranged from 7 to 15%. The L-dopa-decarboxylase inhibitor benserazide (Ro 4-4602) injected subcutaneously twice daily in doses of 50-100 mg/kg failed to alter the rats' alcohol consumption either in terms of g/kg or proportional values. However, when given ICV twice daily in concentrations of 10 ng-2.0 micrograms per 5.0 microliters volume, benserazide attenuated the rats' alcohol drinking significantly. This reduction occurred in a dose-dependent manner in terms of both absolute and proportional intakes of alcohol. Pre-treatment of the animals with 1.0 microgram benserazide given ICV, when alcohol was removed from the test situation, did not abolish the subsequent ingestion of alcohol but its peripheral administration (50 mg/kg) enhanced drinking. These results suggest that the interference with the metabolic pathway of dopamine or serotonin synthesis, possibly through the mechanism of reduced formation of aldehyde adducts in the brain, markedly alters the pattern of voluntary drinking in the rat. Alternatively, benserazide could act by its central inhibition of aldehyde dehydrogenase, which in turn would concomitantly elevate levels of acetaldehyde and thereby reduce alcohol drinking.

Alterations in brain aldehyde dehydrogenase activity modify ethanol-induced conditioned taste aversion.

The role of peripherally and centrally acting acetaldehyde in ethanol-induced conditioned taste aversion (CTA) was investigated using various enzyme manipulations. Cyanamide, an aldehyde dehydrogenase inhibitor (ALDH) elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by cyanamide. Under both treatment conditions brain and liver ALDH activity is inhibited. Water-deprived rats were pretreated 4 hr prior to fluid presentation with intraperitoneal injections of saline (S+S), 4-methylpyrazole (4MP+S), cyanamide (S+C), or 4-methylpyrazole + cyanamide (4MP+C). Subsequently, animals were presented with a novel saccharin solution followed immediately by intraperitoneal injection of one of three doses of ethanol (0.4, 0.8, or 1.2 g/kg) or saline vehicle on four occasions. Results suggested that animals pretreated with cyanamide (groups S+C and 4MP+C) drank significantly less saccharin after conditioning with a subthreshold dose of ethanol (0.4 g/kg) in comparison to groups S+S and 4MP+S. Moreover, at the conditioning dose of 1.2 g/kg, cyanamide-treated animals demonstrated an attenuation of CTA compared to the other two groups. These effects cannot be attributed to elevated blood acetaldehyde levels since pretreatment with 4MP+C prevented peripheral acetaldehyde accumulation. A characteristic common to both cyanamide-treated groups was the inhibition of brain ALDH. It is therefore suggested that brain ALDH may play a role in the mediation of ethanol-induced CTAs. It is conceivable that ALDH plays this role by regulating the levels of acetaldehyde in brain.