Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and the nucleus accumbens

The differential effects of haloperidol (HAL) and clozapine (CLOZ) on dopamine (DA) release and metabolism (dihydroxyphenylacetic acid levels) in striatum and nucleus accumbens (accumbens) of freely moving rats were investigated using microdialysis. Chronic HAL (2 mg/kg/day x 21 days in drinking water) decreased basal DA release and metabolism in both regions, and produced tolerance to HAL-induced increase in DA metabolism in striatum. No modification of HAL-induced increases in DA release and metabolism were observed in accumbens. Together with D₂ receptor blockade, this may produce decreased dopaminergic neurotransmission in both regions during chronic treatment. Chronic HAL (0.5 mg/kg/day x 21 days in drinking water) also decreased basal DA release and metabolism in both regions which were not reversed by 25 μg/kg of (-)-apomorphine, s.c. In marked contrast, chronic CLOZ (20 mg/kg/day x 21 days in drinking water) had no effect on basal DA release and metabolism in either region, whereas it produced tolerance to CLOZ-induced increase in DA release and metabolism in accumbens. Together with weak D₂ receptor blockade, this may lead to slightly decreased dopaminergic neurotransmission in accumbens and slightly increased dopaminergic neurotransmission in striatum during chronic CLOZ treatment. These differences may contribute to the clinical differences between the two agents.