Effects of acute and chronic clozapine on dopaminergic function in medial prefrontal cortex of awake, freely moving rats

We previously showed that chronic administration of the clinically atypical and clinically superior antipsychotic drug clozapine selectively reduces dopamine (DA) release in the nucleus accumbens but not neostriatum, and that this effect appears mediated by anatomically selective mesolimbic DA depolarization blockade. The present study extends that research to another mesocorticolimbic DA locus, the medial prefrontal cortex. Acute clozapine challenge (5-40 mg/kg i.p) produced dose-dependent increased extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the medial prefrontal cortex of awake, free-moving rats as measured by in vivo brain microdialysis. Chronic clozapine treatment (20 mg/kg/day for 21 days) did not significantly change basal extracellular levels of DA, DOPAC or HVA. Acute clozapine challenge on day 22 in the chronic clozapine-treated animals produced no significant differences in medial prefrontal cortex, DA, DOPAC or HVA as compared to chronic vehicle-treated animals, indicating that tolerance to clozapine does not develop in the mesocortical DA system, in contrast to the mesolimbic system. The DA agonist apomorphine (100 μg/kg) produced decreased basal extracellular levels of DA, DOPAC and HVA in medial prefrontal cortex of both chronic clozapine-treated and chronic vehicle-treated rats. These results suggest that: (1) mesocortical DA neurons respond to acute clozapine in similar manner to both mesolimbic and mesostriatal DA neurons; (2) mesocortical DA neurons respond to chronic clozapine in similar manner to mesostriatal DA neurons but not to mesolimbic DA neurons; (3) mesocortical DA neurons do not develop tolerance to acute clozapine after chronic clozapine treatment; (4) a functional DA autoreceptor appears to exist within the mesocortical DA system; and (5) chronic clozapine does not induce depolarization blockade in the mesocortical DA system, in contrast to the profound depolarization blockade induced by chronic clozapine in the mesolimbic DA system.