The effect of clozapine on extracellular dopamine levels in the shell subregion of the rat nucleus accumbens is reversed following chronic administration: comparison with a selective 5-HT(2C) receptor antagonist.
The clinical onset of both the therapeutic and side effects of antipsychotic drugs can take days/weeks to develop. Therefore, it is likely that adaptive changes in neurotransmission of key systems may only manifest upon chronic administration. Thus, using in vivo microdialysis we have evaluated the acute and chronic (21 days) effects of the atypical antipsychotic clozapine on nucleus accumbens (NAcc) dopamine (DA) output in the rat. Clozapine (10 mg/kg p.o.) produced an acute 60% increase in extracellular levels of DA in the shell but not the core subregion of the NAcc. This clozapine-induced effect was also apparent on day 8 (59% increase) of chronic administration. However, on day 22 (following 21 days chronic administration), clozapine-induced a significant decrease in extracellular DA levels (44% decrease). Since clozapine possesses significant affinity for the 5-HT(2C) receptor these clozapine-induced effects were compared to those of SB-243213, a selective 5-HT(2C) receptor antagonist. SB-243213 (10 mg/kg p.o.) had no effect on NAcc DA levels either acutely or following 21 days chronic administration. These data demonstrate that the atypical neuroleptic clozapine is more effective at eliciting changes in the shell vs the core subregion of the NAcc. In contrast, chronic treatment produces a time-dependent reduction in clozapine-induced DA efflux in the shell subregion. This selective temporal change in dopaminergic neurotransmission may be associated with the delayed therapeutic onset of antipsychotic activity. However, since SB-243213 had no effect on DA levels in the NAcc, it is likely that 5-HT(2C) receptor antagonism alone is not the mechanism by which clozapine exerts is actions.
Shilliam
Claire S
CS
Department of Neuropharmacology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK. Claire.S.Shilliam@gsk.com
Dawson
Lee A
LA
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D014150:Antipsychotic Agents; D007211:Indoles; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D003024:Clozapine; C406343:SB 243213; D004298:Dopamine