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-HT2C Receptor Antagonist

Abstract

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 clozapineinduced 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.

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

“…Atypical antipsychotic drugs, including clozapine and olanzapine, can increase DA efflux in the NAc, although the magnitude of the effect is significantly smaller than that produced in the mPFC (Ichikawa et al, 2002c;Kuroki et al, 1999;Shilliam and Dawson, 2005). Shilliam and Dawson (2005) demonstrated that this increase was confined to the shell of the NAc and did not occur in the NAc core.…”

“…Atypical antipsychotic drugs, including clozapine and olanzapine, can increase DA efflux in the NAc, although the magnitude of the effect is significantly smaller than that produced in the mPFC (Ichikawa et al, 2002c;Kuroki et al, 1999;Shilliam and Dawson, 2005). Shilliam and Dawson (2005) demonstrated that this increase was confined to the shell of the NAc and did not occur in the NAc core. We have previously shown that 5-HT 2C -receptor antagonism, in combination with D 2 -receptor antagonism, may contribute to the ability of these agents to enhance DA release in the NAc (Bonaccorso et al, 2002;Li et al, 2005).…”

Central Serotonin2C Receptor: From Physiology to Pathology

“…Antagonism at 5-HT 2C receptors by several antipsychotics was also observed in vivo. Indeed, clozapine produces an increase in extracellular levels of DA in the nucleus accumbens [192,193], reverses the inhibition of accumbal DA release induced by the 5-HT 2C agonist RO 60-0175 [192] and blocks the hypolocomotion induced by the 5-HT 2C agonist mCPP [194].…”

Effectiveness of clozapine, haloperidol and chlorpromazine in schizophrenia during a five-year period

“…However, the bias did not diminish the clozapine efficacy at the end of study, likely due to its more polyvalent, unique receptor pharmacology than other antipsychotic drugs 26 . The selective changes in neurotransmission produced by clozapine antipsychotic action were rather time-dependent than dose-dependent, which may be a reason of delayed therapeutic activity 27 and also the effectiveness of moderate to low doses in our study.…”