RISPERIDONE - REGIONAL EFFECTS IN-VIVO ON RELEASE AND METABOLISM OF DOPAMINE AND SEROTONIN IN THE RAT-BRAIN

The antipsychotic drug risperidone shows high affinity for both centra l serotonin (5-HT)(2A) and dopamine (DA)-D-2 receptors in vivo. By emp loying microdialysis in freely moving rats, the effects of acute rispe ridone administration on regional brain DA and 5-HT release and metabo lism were compared with the corresponding effects of the atypical anti psychotic drug clozapine as well as amperozide, the selective DA-D-2 r eceptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg,/kg, SC) was found to increase DA release and metabolism to about the same extent in thre e major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, wh ereas raclopride instead preferentially increased DA release in the NA C and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not e xert ally major effects on DA metabolism in the three areas studied. I n contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-H T metabolism preferentially in the MPC, as indicated by the elevated e xtracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in t his region. A similar elevation of the 5-HIAA level in the MPC was obs erved after amperozide and, to some extent, after clozapine and ritans erin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be parall eled by an increased 5-HT release in this blain area. Consequently, ou r findings demonstrate a pharmacological profile of risperidone, as re flected in blain DA metabolism, in between that of clozapine and the D A-D-2 antagonists. The preferential activation of 5-HT release and met abolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizo phrenia, especially when associated with depression.