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Contrasting Contribution of 5-Hydroxytryptamine 1A Receptor Activation to Neurochemical Profile of Novel Antipsychotics: Frontocortical Dopamine and Hippocampal Serotonin Release in Rat Brain

2005; American Society for Pharmacology and Experimental Therapeutics; Volume: 315; Issue: 1 Linguagem: Inglês

10.1124/jpet.105.087163

1521-0103

Marie‐Bernadette Assié, Véronique Ravailhe, Valérie Faucillon, Adrian Newman‐Tancredi,

Ion channel regulation and function

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl- N -(((2 S )7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (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 high pressure liquid chromatography with electrochemical detection 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-hydroxy-2-(di- n -propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT 1A autoreceptors. These decreases were reversed by the selective 5-HT 1A antagonist, WAY100635 [ N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -(2-pyridinyl)cyclohexanecarboxamide]. 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 D 2 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 D 2 and 5-HT 1A receptors may present distinctive therapeutic properties.