THE EFFECTS OF ACUTE AND CHRONIC HALOPERIDOL TREATMENT ON DOPAMINE RELEASE MEDIATED BY THE MEDIAL FOREBRAIN-BUNDLE IN THE STRIATUM AND NUCLEUS-ACCUMBENS

The delayed therapeutic effects of neuroleptics have been attributed t o D-2-mediated depolarization inactivation (DI) of mesolimbic dopamine rgic neurons and concomitant reduction in dopamine release. Several st udies have suggested, however, that DI may not reduce dopamine release and have hypothesized that this is due to increased impulse independe nt release. To examine the mechanisms that modulate dopamine release d uring DI, tetrodotoxin (TTX) was infused into the left medial forebrai n bundle (MFB) of Sprague Dawley rats. Three-methoxytyramine (3-MT) le vels 10 minutes after pargyline (75 mg/kg) were used as a measure of d opamine release. A dose response study showed that infusions of 10(-5) mol/L and 10(-4) mol/L TTX reduced 3-MT levels on the infused sine by 70% in the striatum and 50% to 60% in the nucleus accumbens. In a tim e course study, 10(-5) mol/L TTX reduced striatal 3-MT at 30, 90, and 120 minutes: After intraperitoneal injections of haloperidol (0.4 mg/k g)for 1 or 21 days, TTX infusions again reduced 3-MT levels by approxi mately 70% in the striatum and 53% to 59% in the nucleus accumbens on the infused side. Acute and chronic haloperidol treatment did not alte r the percent of TTX-induced reductions. These data suggest that dopam inergic neuronal impulse flow modulates similar amounts of total trans mitter release after both acute and chronic haloperidol treatment. The results do not support the notion that DI ?mediates the antipsychotic effects of neuroleptics by markedly reducing total basal dopamine rel ease or increasing impulse independent release. Alternatively, DI coul d reduce psychotic symptoms by changing the responsiveness of the dopa mine system to external stimuli or by reducing synaptic dopamine level s that have been hypothesized to be elevated in psychotic patients.