ON THE RELEVANCE OF PREFERENTIAL INCREASES OF MESOLIMBIC VERSUS STRIATAL DOPAMINE TURNOVER FOR THE PREDICTION OF ANTIPSYCHOTIC ACTIVITY OF PSYCHOTROPIC DRUGS

Abstract— Drugs possessing (chlorpromazine, haloperidol, clozapine, thioridazine and sulpiride) or lacking (benzoctamine and perlapine) antipsychotic activity were compared with respect to their ability to enhance x-methyl-p-tyrosine-induced dopamine disappearance from the mesolimbic area and corpus striutum of rat brain. In addition, their effects on the endogenous concentrations of homovanillic (HVA) and 3.4-dihydroxyphenylacetic (DOPAC) acids in these two brain areas were determined. Some of the drugs enhanced dopamine disappearance in the mesolimbic area more than in the striatum. The most active in this respect were sulpiride. perlapine and chlorpromazine. By contrast, haloperidol was slightly more active in the striatum than in the mesolimbic area. None of the drugs was more efficient in elevating HVA levels in the mesolimbic area than in the striatum. However, there were large differences in the relative extent of the HVA increases in the two regions. Benzoctamine, perlapine and chlorpromazine increased HVA concentrations in the mesolimbic area nearly as much as in the striatum. Thioridazine and haloperidol, however, elevated striatal HVA much more effectively. Haloperidol and clozapine increased the DOPAC concentration in both areas to about the same extent. The other drugs were more active in the striatum. The largest difference between both regions was shown by chlorpromazine. Perlapine and benzoctamine, both lacking antipsychotic activity, produced much larger increases of HVA than of DOPAC. This is in contrast to the results obtained with true neuroleptics and may reflect an involvement of release phenomena in the action of these two drugs on dopamine metabolism. These results suggest that a preferential increase of dopamine turnover in the mesolimbic area is not necessarily linked to a better ratio of antipsychotic activity vs. extrapyramidal side effects. Moreover, an antiacetylcholine component of dopamine receptor blocking drugs does not seem to be a prerequisite for preferential activity on dopamine turnover in the mesolimbic system.