SYSTEMIC ADMINISTRATION OF AMPEROZIDE, A NEW ATYPICAL ANTIPSYCHOTIC DRUG, PREFERENTIALLY INCREASES DOPAMINE RELEASE IN THE RAT MEDIAL PREFRONTAL CORTEX

The putative atypical antipsychotic drug amperozide (APZ) shows high a ffinity for serotonin 5-HT2 receptors but only low affinity for dopami ne (DA) D-2 receptors. By employing microdialysis, we examined the eff ects of APZ on extracellular concentrations of DA in the nucleus accum bens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to aff ect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, S C) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a g reater release of DA in the MPC (+ 127 and + 279%) than in the NAC(+ 5 2 and + 98%). The selective 5-HT2 receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA outp ut in the MPC (+ 25 and + 47%) compared with the NAC ( + 19 and + 21%) . In contrast, the selective D-2 receptor antagonist raclopride (0.5 a nd 2.0 mg/kg, SC) increased DA release in the NBC (+ 65 and + 119%) to a greater extent than in the MPC ( + 45 and + 67%). These data sugges t that the 5-HT2 receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in th e MPC. Infusion of low doses (1, 10 mu M, 40 min) of APZ through the p robe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 mu M, 40 min) resulted in a m ore pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in t he MPC is most likely mediated at a level other than the terminal regi on. Taken together, the present results provide support for the notion that 5-HT2 receptor antagonism may be of considerable significance fo r the action of atypical antipsychotic drugs on mesolimbocortical dopa minergic neurotransmission.