RISPERIDONE DOSE-DEPENDENTLY INCREASES EXTRACELLULAR CONCENTRATIONS OF SEROTONIN IN THE RAT FRONTAL-CORTEX - ROLE OF ALPHA(2)-ADRENOCEPTOR ANTAGONISM

We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)(2A) and dopamine (DA), re ceptors, as well as for alpha(1)- and alpha(2)-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To furthe r study the influence of risperidone on central 5-HT systems, toe comp ared its effects on dialysate 5-HT in the FC, Its assessed by microdia lysis, with those obtained with other antipsychotic drugs, i.e., cloza pine, haloperidol, and amperozide, as well as with the selective alpha (2)- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectiv ely. The underlying mechanism for risperidone's effect on 5-HT output in the FC was also investigated using single-cell recording in the dor sal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was min-licked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administ ration of risperidone or idazoxan (1.0-1000 mu mol/L) in the FC dose d ependently increased dialysate levels of 5-HT in this region. On the o ther hand, risperidone 25-800 mu g/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely a ntagonized by pretreatment with the selective 5-HT,, receptor antagoni st WAY 100,635 (5.0 mu g/kg, IV). These results indicate that the risp eridone-increased 5-HT output in the FC may be related to its alpha(2) -adrenoceptor antagonistic action, a property shared with both amperoz ide and idazoxan, and that this action probably is executed at the ner ve terminal level. The inhibition of 5-HT cell firing by risperidone i s probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a 5-HT1A receptor antagonist. The en hanced 5-HT output in the FC by risperidone may be of particular relev ance for the treatment of schizophrenia when associated with depressio n and in schizoaffective disorder. (C) 1997 American College of Neurop sychopharmacology.