Effects of clozapine on the efflux of serotonin and dopamine in the rat brain: the role of 5-HT1A receptors.
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.
Hagino
Yoko
Y
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
Watanabe
Masayuki
M
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*
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D003024:Clozapine; D004298:Dopamine