Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex

The aim of the present study was to compare the effects of the typical anti psychotic haloperidol and the atypical antipsychotics clozapine and olanzap ine on both extracellular dopamine (DA) levels in the medial prefrontal cor tex (mPFC) as well as electrical activity of mesoprefrontal DA (mPFC-DA) ne urons. Extracellular single unit recordings and microdialysis experiments w ere carried out in different groups of chloral hydrate anesthetised rats un der identical experimental conditions. Intravenous administration of halope ridol, clozapine, and olanzapine increased the firing rate and burst activi ty of antidromically-identified mPFC-DA neurons; maximal increase in firing rate of approximately 140, 155, and 70%, was produced by haloperidol, cloz apine, and olanzapine at doses of 0.2, 2.5, and 1 mg/kg, i.v., respectively . Intravenous administration of the same doses increased extracellular DA l evels in mPFC by 20%, 190%, and 70%, respectively. Moreover, while haloperi dol and olanzapine increased extracellular levels of the deaminated DA meta bolite DOPAC, by 60% and 40%, respectively, clozapine was totally ineffecti ve. The D1 receptor antagonist SCH 23390 modified neither DA output nor neu ronal firing. To determine whether the effect of the three antipsychotics o n DA release might depend on a direct action on the mPFC, rats were perfuse d locally via inverse dialysis in the mPFC at concentrations ranging from 1 0(-6) to 10(-4) M. While clozapine and olanzapine increased extracellular D A concentrations by up to 400% of basal level, haloperidol was totally inef fective. The results obtained from this study indicate that the rank potenc y of the three antipsychotics in stimulating the firing rate of DA neurons projecting to mPFC, correlates with their affinity for D2 receptors and dos es used clinically. On the other hand, their stimulating effect on DA relea se does not correlate with their effect on neuronal firing but depends on a direct action on the mPFC. (C) 2000 American College of Neuropsychopharmac ology. Published by Elsevier Science Inc.