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.