Enhanced 5-HT2C receptor signaling is associated with haloperidol-induced "early onset" vacuous chewing in rats: implications for antipsychotic drug therapy

Abstract

Rationale: Haloperidol is a representative of typical antipsychotics that are still in clinical use and which can lead to abnormal motor activity following repeated administration. The mechanisms underlying antipsychotic-induced dyskinesias are not well understood but are widely held to be related to excessive loss of dopamine function. In several models of dopamine hypofunction, serotonin 5-HT2C receptors have been shown to mediate vacuous chewing movements (VCM), a form of abnormal motor activity. It is well established that repeated haloperidol administration also elicits VCM, but there is no information on how repeated haloperidol administration affects 5-HT2C receptor signaling.

Objectives: In the present study, we tested the hypothesis that repeated daily administration of haloperidol leads to enhanced serotonin 5-HT2C receptor signaling that is associated with increased 5-HT2C-mediated VCM.

Methods: Rats were treated by subcutaneous injection once daily for 21 days with either vehicle, a low dose of haloperidol (0.1 mg kg(-1) day(-1)), or a high dose of haloperidol (1.0 mg kg(-1) day(-1)). Following 1-day withdrawal, rats were either used for behavioral scoring of VCM or sacrificed for biochemical assessment of 5-HT2 receptor-mediated phospholipase C activity and radioligand binding. VCM were scored following two successive "drug" challenges. The first challenge was an injection of vehicle (0.9% saline), and the second challenge was an injection of the 5-HT2C agonist meta-chlorophenylpiperazine (1.0 mg/kg). In this manner, a measure of "spontaneous" and "5-HT2C-elicited" orofacial activity could be made while minimizing animal use.

Results: Following 21-day haloperidol treatment at either dose, there was an increase in expression of meta-chlorophenylpiperazine-induced VCM. In a separate experiment, meta-chlorophenylpiperazine-induced VCM were shown to be mediated through 5-HT2C receptors. Striatal 5-HT2C receptor-mediated phospholipase C (PLC) activity and high-affinity agonist-labeled 5-HT2C receptors were also increased following either dose of haloperidol as compared to vehicle treatment. GTP-stimulated PLC activity and striatal Gq proteins were unchanged by haloperidol suggesting that enhanced signaling could be accounted for by alterations at the level of the receptor and not at downstream mechanisms.

Conclusions: Repeated daily administration of haloperidol leads to an adaptive increase in 5-HT2C signaling which may contribute to abnormal motor function associated with antipsychotic use.