Clozapine decreases serotonin extracellular levels in the nucleus accumbens by a dopamine receptor-independent mechanism.
By using brain microdialysis, clear differences in the effects of the systemic administration of clozapine and haloperidol on the extracellular concentration of dopamine (DA) and serotonin (5-HT) were found in the nucleus accumbens of freely moving rats. Haloperidol (0.5 mg/kg s.c.) significantly increased DA (ca. 40%) but did not modify 5-HT extracellular concentration, while clozapine (5 mg/kg s.c.) significantly decreased 5-HT (ca. 40%) but did not change DA concentration. Locally infused, clozapine (10(-5) M) significantly increased DA (75%) and reduced 5-HT extracellular concentration (50%). The reduction of 5-HT cannot be explained by a clozapine-induced blockade of DA receptors, because the local infusion (10(-5) M) of the DA D2-like antagonist raclopride and the DA D1-like antagonist SCH 23390 significantly increased DA (ca. 300% and 200%, respectively) but did not modify 5-HT extracellular concentration. Conversely, the DA D2-like agonist quinpirole and the DA D1-like agonist SKF-38393 significantly decreased (ca. 60% in both cases) DA extracellular concentration without affecting that of 5-HT. The present results indicate that clozapine displays a powerful anti-serotoninergic effect by inhibiting 5-HT release in the nucleus accumbens, an effect probably derived from the reduction of firing activity at the dorsal raphe and by local mechanisms that may involve some 5-HT receptor subtype(s).
Ferré
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Department of Neurochemistry, C.S.I.C., Barcelona, Spain.
Artigas
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D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects*; D019257:Quinpirole; D020891:Raclopride; D051381:Rats; D011954:Receptors, Dopamine / Q000502:physiology; D012457:Salicylamides / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D018491:Dopamine Agonists; D004873:Ergolines; D011954:Receptors, Dopamine; D012457:Salicylamides; D019257:Quinpirole; D012701:Serotonin; D020891:Raclopride; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine