Antipsychotic Drugs Importance of 5HT2C Receptor Antagonism in the Action of 5HT2AD2 Antagonist Antipsychotic

After the discovery of the importance of 5-HT2A receptor blockade (inverse agonism), initiated by research to uncover the mechanism of action of clozapine, which has multiple receptor affinities, interest focused on other clozapine high affinity binding sites, including the 5-HT2C receptor. The 5-HT2C receptor was proposed to be an important site of action of atypical antipsychotic drugs by a number of investigators (Canton et al. 1990; Cussac et al. 2000; Duinkerke et al. 1993a; Herrick-Davis et al. 1998, 2000; Kuoppamaki et al. 1995), particularly for improvement in negative symptoms (Duinkerke et al. 1993b). However, this was based on research with ritanserin and ketanserin, which are not specific for the 5-HT2C receptor. Roth et al. (Roth et al. 1992), after examining the 5-HT2C receptor affinities of a large number of typical and atypical antipsychotic drugs (see Table 14.1), concluded that 5-HT2C receptor affinity alone or in relation to D2 receptor affinity did not differentiate typical and atypical antipsychotic drugs.

Herrick-Davis et al. (Herrick-Davis et al. 2000) next suggested that the atypical antipsychotic drugs, but not the typicals, were inverse agonists at a naturally occurring constitutively active isoforms of 5-HT2C receptor, However, this difference was not confirmed by Rauser et al. (Rauser et al. 2001), who found that many typical and atypical antipsychotic drugs were 5-HT2C inverse agonists, although the affinity of the typical drugs was much weaker than that of most of the atypical antipsychot-ics. Nevertheless, other investigators have also suggested specific differences among antipsychotic drugs with regards to activity as inverse agonists at variously edited 5-HT2C receptors or that the ability to downregulate 5-HT2C receptors may be important to individual differences in antipsychotic drug action. For example, sertindole, which has nanomolar affinity for the 5-HT2C receptor (Table 14.1), after 21-day treatment, did not induce significant changes in the density of 5-HT2C receptors, whereas clozapine treatment equally decreased 5-HT2C receptor binding for agonist and antagonist sites by about one third. However, only sertindole induced a highly significant decrease in agonist binding (Hietala et al. 2001). These authors suggested that the latter effect might be relevant to effects of sertindole on anxiety, cognition, and weight gain. However, no convincing clinical or preclinical correlates of such differences between clozapine and sertindole in favor of sertindole have been reported. It is conceivable, however, that the downregulation of 5-HT2C receptors by clozapine could contribute to its advantages for treatment resistant patients and for suicide risk reduction.

Rueter et al. (2000) studied the effect of clozapine in wild-type and 5-HT2C receptor null mice littermates in an effort to clarify the interaction of 5-HT2A and 5-HT2C receptors and their importance to the action of clozapine. The predominantly 5-HT2A agonist DOI, which is hallucinogenic, mCPP, a predominantly 5-HT2C agonist with weak 5-HT2A properties, and 5-HT were applied microionto-phoretically to the orbitofrontal cortex (OFC) and the head of the caudate nucleus. All three induced current-dependent inhibition of neuronal firing activity in both brain regions for both the wild-type and 5-HT2C null mice. Clozapine antagonized only mCPP in the wild-type mice. It was not effective to prevent the inhibitory effect of DOI. This suggests that clozapine may require the contribution of 5-HT2C receptor blockade to prevent the hallucinogenic properties of DOI. Dalton et al. (2004) used 5-HT2C null mice to show that in the absence of protective inhibitory effects of 5-HT2C receptor stimulation, enhanced response to 5-HT2A and 5-HT1B stimulation may occur. The implications of this for schizophrenia are unknown.

5-HT2C and 5-HT2A receptor signalings have been shown to depend upon the postsynaptic density protein (PSD-95), a scaffolding protein that has been shown to be necessary for the regulation of ionotropic glutamatergic signaling, to be a target for antipsychotic drugs, and to be necessary for some behavioral effects of clozap-ine (Abbas et al. 2009). Studies in PSD-95 knockout mice indicated that PSD-95 is crucial for normal 5-HT2A and 5-HT2C expression in vivo and downstream signaling by promoting apical dendritic targeting and stabilizing 5-HT2C and 5-HT2A receptor turnover in vivo. The apical dendrites are targets for clozapine action (Willins et al. 1999).

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