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5-HT2C Receptors in the Pathophysiology of CNS Disease pp 275–291Cite as

The 5-HT2C Receptor as a Target for Schizophrenia

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Part of the book series: The Receptors ((REC,volume 22))

Abstract

Clinical and preclinical evidence that suggests the serotonin-2C (5-HT2C) receptor plays a significant role in key elements of the pathophysiology of schizophrenia, including psychosis, negative symptoms, and the mechanism of action and side effects of antipsychotic drugs is reviewed here. The clinical evidence consists of phenotype-genotype studies linking one or more of three common polymorphisms of the 5-HT2C receptor to positive or negative symptoms, weight gain, and extrapyramidal side effects secondary to some antipsychotic drugs. In addition, the expression of the 5-HT2C receptor in post-mortem specimens from patients with schizophrenia is reduced. Edited forms of the 5-HT2C receptor do not appear to be abnormal in schizophrenia. The cortisol or ACTH response to the 5-HT2A/2C receptor agonist meta-chlorophenylpiperazine (mCPP) in patients with schizophrenia has been reported to predict the subsequent response to treatment with clozapine.

Although 5-HT2C receptors have an important role to regulate cortical and limbic dopamine (DA) release, 5-HT2C knockout mice do not show any phenotype particularly associated with schizophrenia. Although 5-HT2A receptor stimulation is thought to be the basis for hallucinogenic action of LSD and related drugs, a role for 5-HT2C receptors with regard to hallucinations or delusions in man remains a viable possibility. There is conflicting evidence concerning the effect of 5-HT2C receptor blockade by selective 5-HT2C antagonists on animal models of psychosis, such as increased locomotor activity produced by NMDA receptor antagonists. WAY 163909, a 5-HT2C receptor agonist, has shown activity as a cognitive enhancing antipsychotic agent in a variety of animal models. Since the 5-HT2A receptor is so clearly involved in the action of atypical antipsychotic drugs, and aspects of the pathophysiology of schizophrenia, and since there is clear evidence for interactions between the 5-HT2A and 5-HT2C receptors, by default, the 5-HT2C receptor is important for schizophrenia. Thus, there is reason to intensively investigate the role of the 5-HT2C receptor in the pathophysiology of schizophrenia and the action of antipsychotic drugs, but no firm conclusions can be drawn at this time.

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Acknowledgments

Supported, in part, by a grant from the Weisman Family Foundation and a Distinguished Investigator Award from NARSAD. Ki determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth, M.D., Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda, MD.

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  1. Department of Psychiatry and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37212, USA

    Herbert Y. Meltzer

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  1. Herbert Y. Meltzer
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  2. Liwen Sun
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  3. Hitoshi Hashimoto
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Correspondence to Herbert Y. Meltzer .

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  1. , Department of Physiology and Biochemistr, University of Malta, Msida, Malta, MSD 2080, Italy

    Giuseppe Di Giovanni

  2. Centro di Ricerche Farmacologiche e, Biomediche, Consorzio Mario Negri Sud, Via Nazionale 8, Santa Maria Imbaro, 66030, Chieti, Italy

    Ennio Esposito

  3. Centro di Ricerche Farmacologiche e, Biomediche, Consorzio Mario Negri Sud, Via Nazionale 8, Santa Maria Imbaro, 66030, Chieti, Italy

    Vincenzo Di Matteo

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Meltzer, H.Y., Sun, L., Hashimoto, H. (2011). The 5-HT2C Receptor as a Target for Schizophrenia. In: Di Giovanni, G., Esposito, E., Di Matteo, V. (eds) 5-HT2C Receptors in the Pathophysiology of CNS Disease. The Receptors, vol 22. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-941-3_14

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