Received for publication April 1, 2005.
Revised June 22, 2005.
Accepted for publication June 23, 2005.

CONTRASTING CONTRIBUTION OF 5-HT_1A RECEPTOR ACTIVATION TO NEUROCHEMICAL PROFILE OF NOVEL ANTIPSYCHOTICS: FRONTOCORTICAL DOPAMINE AND HIPPOCAMPAL SEROTONIN RELEASE IN RAT BRAIN

Abstract

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 and SLV313, activate serotonin 5-HT_1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to HPLC-EC, to examine 5-HT_1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT_1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT_1A agonist, (+)8-OH-DPAT, consistent with activation of 5-HT_1A autoreceptors. These decreases were reversed by the selective 5-HT_1A antagonist, WAY100635. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT_1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride and the D₂ partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT_1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D₂ and 5-HT_1A receptors may present distinctive therapeutic properties.

Key words: antipsychotic, dopamine, frontal cortex, hippocampus, microdialysis, serotonin

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