| Abstract: | Acute administration of five neuroleptics to rats produced a dose-dependent increase in brain homovanillic acid (HVA) which was of greater magnitude and of longer duration in the corpus striatum than in the tuberculum olfactorium. 4-p-Fluorophenyl-5-N(N'-o-methoxy-phenyl) piperazinoethyl-4-oxazolin-2-one (LR 511) appeared to be 5--10 times more potent than fluanisone and clozapine, as active as chlorpromazine (CPZ) but at least twentyfold less active than haloperidol. Time-course studies on dopamine turnover have indicated that LR 511 at a moderate pharmacological dose has some similarities with clozapine, e.g., a lower difference between striatal and limbic tissues. All the neuroleptics caused inhibition of the conditioned avoidance response and at their ED50S on this parameter (with the exception of clozapine) caused also an equal increment of the cerebral HVA level. At their ED50S on catalepsy, the neuroleptics evoked HVA changes which varied according to the drug tested. Thus, potent cataleptogenic agents caused either strong stimulation of the DA turnover in both brain structures (haloperidol and CPZ) or weak stimulation only in corpus striatum (fluanisone). On the other hand a poor cataleptogenic agent, such as LR 511, was accompanied by the highest HVA levels and also the non-cataleptogenic clozapine at the dose of 40 mg/kg increased the cerebral HVA levels. It is suggested that the acceleration of DA turnover in animals is not an essential prerequisite for predicting the antipsychotic activity in man and that the preferential reactivity of dopaminergic limbic receptors is not necessarily linked to a better ratio of antipsychotic versus extrapyramidal effects in man. |
