title: Effects of clozapine on the efflux of serotonin and dopamine in the rat brain: the role of 5-HT1A receptors.
abstract: In vivo microdialysis in conscious rats was used to examine the effect of clozapine on serotonin (5-hydroxytryptamine, 5-HT) efflux in the prefrontal cortex and dorsal raphe nucleus and dopamine efflux in the prefrontal cortex. Both systemic and local administration of clozapine (systemic, 10 or 20 mg/kg, i.p.; local, 100 microM) increased 5-HT efflux in the dorsal raphe. However, in the prefrontal cortex, dialysate 5-HT increased when clozapine (100 microM) was administered through the probe, while no effect was observed when it was administered systemically. By pretreatment with the selective 5-HT1A receptor antagonist p-MPPI (3 mg/kg, i.p.), systemic treatment of clozapine (10 mg/kg, i.p.) significantly increased 5-HT efflux in the prefrontal cortex. This result suggests that the ability of clozapine to enhance the extracellular concentrations of 5-HT in the dorsal raphe attenuates this drug's effect in the frontal cortex, probably through the stimulation of 5-HT1A somatodendritic autoreceptors in the dorsal raphe. We also found that pretreatment with p-MPPI (3 mg/kg, i.p.) attenuated by 45% the rise in cortical dopamine levels induced by clozapine (10 mg/kg, i.p.). These findings imply that the reduction in serotonergic input from the dorsal raphe nucleus induced by clozapine could lead to an increase in dopamine release in the prefrontal cortex.
authors.affiliation: Department of Molecular Psychiatry, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. hagino@prit.go.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagino
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*
chemical_list: D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D003024:Clozapine; D004298:Dopamine