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

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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.

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Abbreviations

5-HT:

serotonin

DA:

dopamine

PLC:

phosphoinositide-specific phospholipase C

EPS:

extrapyramidal side effects

mCPP:

meta-chlorophenylpiperazine

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Acknowledgements

This work was supported by a Merit Award (to W.A.W.) from the Department of Veteran's Affairs and by PHS grant NS 36410 (W.A.W.).

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Authors and Affiliations

  1. Research Service-151, Edward Hines Jr. VA Hospital, Hines, IL, 60141, USA

    William A. Wolf, Gerald J. Bieganski & Veronica Guillen

  2. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    William A. Wolf

  3. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Laurence Mignon

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  1. William A. Wolf
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Correspondence to William A. Wolf.

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Wolf, W.A., Bieganski, G.J., Guillen, V. et al. Enhanced 5-HT2C receptor signaling is associated with haloperidol-induced “early onset” vacuous chewing in rats: implications for antipsychotic drug therapy. Psychopharmacology 182, 84–94 (2005). https://doi.org/10.1007/s00213-005-0033-4

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