The antipsychotic drug risperidone interacts with auto- and hetero-receptors regulating serotonin output in the rat frontal cortex

We have previously shown that the antipsychotic drug risperidone enhances s erotonin (5-MT) output in the rat frontal cortex (FC), but the precise unde rlying mechanism has not been revealed. Consequently, the present study usi ng in vivo microdialysis was undertaken to (i) characterize the effects of alpha(2D), 5-HT1B and 5-MT,, receptor stimulation or blockade on 5-HT efflu x in the FC given the purported regulatory role of these sites on 5-HT rele ase, and (ii) to investigate the ability of risperidone to interfere with t hese receptors in order to examine their putative role in the facilitatory action or risperidone on cortical 5-HT output. Cortical perfusion with risp eridone or the alpha(2A/D), 5-HT1B and 5-HT1B/1D receptor antagonists idazo xan, isamoltane or GR 127,935, respectively, dose-dependently increased 5-H T efflux in the FC. Conversely, agonists at these receptors, i.e. clonidine , CP 93,129 or CP 135,807, respectively, decreased extracellular 5-HT conce ntrations. The agonist-induced decreases in 5-HT efflux were antagonized by coadministration of respective receptor antagonists. Risperidone attenuate d the decrease in cortical 5-HT efflux elicited by clonidine or CP 135,807 but failed to affect the decrease elicited by CP 93,129. The present in viv o biochemical data indicate that the output of 5-HT in the FC is negatively regulated via alpha(2D), 5-HT1B and tentatively also via 5-HT1D receptors located in the nerve terminal area. Moreover, the results indicate that ris peridone acts as an antagonist at alpha(2D) and possibly 5-HT1D receptors i n vivo, two properties which most likely contribute to its stimulatory effe ct on cortical 5-HT efflux. The facilitatory effect of risperidone on corti cal serotonergic neurotransmission may be of significance for its therapeut ic effect in schizophrenia, particularly when associated with affective sym ptomatology and/or intense anxiety. The effect may also contribute to allev iate signs of cortical dysfunction such as impaired cognition. (C) 1999 Els evier Science Ltd. All rights reserved.