Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release

Abstract

Using in vivo microdialysis, changes in extracellular dorsolateral striatum and nucleus accumbens dopamine, GABA and acetylcholine following acute and chronic haloperidol (0.25 mg/kg, s.c.) were evaluated in rats concurrent with the measurement of catalepsy. When administered to drug-naive and chronically treated rats, haloperidol was associated with a consistent and prolonged (> 150 min) increase in dorsolateral striatum and nucleus accumbens DA release and a transient (60 min) increase in dorsolateral striatum GABA release. Haloperidol was also associated with a transient (30 min) increase in dorsolateral striatum acetylcholine release in the chronically treated rats. Basal dopamine and acetylcholine levels were similar in both brain regions; however, basal dorsolateral striatum GABA levels were two-fold higher in the chronically treated rats. Administration of haloperidol was associated with a prolonged (> 150 min) catalepsy in the drug-naive rats which was greatly diminished or absent in chronically treated rats. Additionally, serum haloperidol levels were shown to be similar 120 min following administration of haloperidol in both groups. These results indicate a marked behavioral difference in the effects of haloperidol in drug-naive and chronically treated rats which is not related to an altered bioavailability of the drug and which is dissociated from both basal and haloperidol induced effects on dopamine and acetylcholine release in both brain regions. However, the selective elevation of basal dorsolateral striatum GABA release following chronic administration of haloperidol may contribute to the development of tolerance to catalepsy as well as providing an in vivo neurochemical marker of the long-term effects of haloperidol.