Repeated atypical neuroleptic administration: effects on central dopamine metabolism monitored by in vivo voltammetry

Abstract

Changes in extracellular DOPAC levels were monitored simultaneously in the nucleus accumbens and striatum of halothane/N 2O anaesthetised rats using in vivo differential pulse voltammetry with carbon fibre electrodes following repeated administration of the atypical neuroleptics thioridazine and clozapine. Thioridazine (20 mg/kg s.c.) increased the DOPAC peak in the nucleus accumbens and striatum of rats treated with saline for the previous 21 days by 66% ± 5 S.E.M. and 91% ± 16 respectively. No such increase was recorded in the nucleus accumbens of rats previously treated with thioridazine (20 mg/kg s.c.) for 21 days. Similarly the increase in the striatum produced by a challenge dose on day 22 was markedly attenuated compared to controls although analysis of absolute DOPAC peak heights revealed extracellular DOPAC to be elevated above basal levels in this region (but not the nucleus accumbens) indicating a possible selective action of this drug to induce absolute tolerance to its acute effects in the nucleus accumbens after repeated administration. Administration of increasing doses of apomorphine (0.05, 0.1, 0.25 mg/kg s.c.) 1 h after a challenge dose of thioridazine (20 mg/kg s.c.) on day 22 to rats treated with the neuroleptic for the previous 21 days produced a progressive decrease in extracellular DOPAC levels both in the nucleus accumbens and striatum. Repeated administration of clozapine (50 mg/kg s.c.) for 21 days failed to induce tolerance to the acute effects of this drug, extracellular DOPAC levels increasing by 60% ± 8 and 90% ± 18 in the nucleus accumbens and striatum respectively following challenge with the drug on day 22. These results suggest a dissociation of the mechanisms responsible for the reported actions of these atypical neuroleptics to induce selective depolarisation inactivation of DA cells and their effects on DA metabolism in terminal regions following repeated administration.