HT2C Receptors and the Motor Control of Orofacial Responses

The available, nonselective, 5-HT2C agonists elicit various alterations of motor responses including grooming, penile erection, hypolocomotor activity, forms of stereotypies, and purposeless oral movements. This latter response is interesting because it is observed at low doses of agonists and, at variance with some of the other behaviors evoked above, is only dependent on 5-HT2C receptors. Stewart and colleagues (1989) observed an increase in purposeless oral movements elicited by the nonselective 5-HT agonists mCPP and TFMPP (Stewart et al. 1989). The oral bouts consisted of vacuous chewing, jaw tremor, and tongue darting occurring without any physical object. The intensity of oral bouts induced by the 5-HT agonist was dose dependent and decreased when very high doses of mCPP were used

(Stewart et al. 1989; Gong and Kostrzewa 1992; Gong et al. 1992). The oral bouts induced by mCPP correspond to 5-HT2C receptor-dependent mechanisms because a variety of drugs able to block 5-HT2C receptors including mianserin, mesulergine, SDZ SER-082, or SB 206553 suppresses the oral responses to mCPP (Stewart et al. 1989; Gong and Kostrzewa 1992; Gong et al. 1992; Eberle-Wang et al. 1996; Wolf et al. 2005). Conversely, 5-HT1B, 5-HT2A, or 5-HT3 antagonists do not affect mCPP-induced abnormal oral movements, while 5-HT1A, 5-HT1B, 5-HT3 agonists do not elicit oral dyskinesia (Stewart et al. 1989; Gong et al. 1992; Kostrzewa et al. 1993). Although these latter data do not exclude a role of these receptors in the control of orofacial activity, these results emphasize a strong link between oral motor control and 5-HT2C receptors.

Intracerebral microinjections of drugs provided evidence that the abnormal oral response to mCPP is due to effects of the drug on receptors located within the basal ganglia, specifically in the STN and the striatum. Indeed, either unilateral or bilateral administration of low doses mCPP into the STN elicits oral bouts, and the effect is blocked by mesulergine (De Deurwaerdere and Chesselet 2000a; Eberle-Wang et al. 1996). Furthermore, the oral bouts elicited by the systemic administration of mCPP are abolished by the intra-STN administration of mesul-ergine (Eberle-Wang et al. 1996). Oral movements observed after systemic injection of mCPP are enhanced by a 5,7-dihydroxytryptamine lesion of 5-HT neurons, which indicates that these receptors are normally stimulated by endogenous 5HT (Mehta et al. 2001).

While the above studies favor the idea of an almost exclusive influence of STN 5-HT2C receptor in mCPP's effects, Plech et al. (1995) have also reported that intrastriatal administration of mCPP induced purposeless oral movements that are abolished by the intrastriatal administration of mianserin (Plech et al. 1995). Interestingly, despite the role of EPN in mediating abnormal movements (Adachi et al. 2002), we have found that the stimulation of EPN 5-HT2C receptors via the local administration of mCPP does not produce oral bouts. On the other hand, high doses of mCPP or TFMPP directly administered into the SNr have been shown to elicit abnormal oral movements (Liminga et al. 1993). For these authors, the fact that the nonselective 5-HT2 agonist DOB did not induce vacuous chewing suggests a role for 5-HT1B receptors in these effects. Altogether these data suggest that striatal and STN 5-HT2C receptors are involved in the abnormal oral responses induced by 5-HT2C agonists in naive rats.

Nonselective 5-HT2C receptor antagonists also reduce oral bouts elicited by DA and muscarinic agonists (Gong et al. 1992; Carlson et al. 2003). Rosengarten and colleagues (1999) have shown that the effect of DA agonists and mCPP on vacuous chewing movements are additive. Nonetheless, mianserin is able to slightly reduce DA agonists-induced abnormal orofacial movements (Gong et al. 1992). In another study, mianserin blocked tacrine-induced vacuous chewing when injected into the dorsolateral part of the SNr (Carlson et al. 2003), a zone involved in facial motor control (Deniau et al. 1996). This study suggests that modification of basal ganglia activity may trigger phasic/tonic responses involving 5-HT2C receptors in the output regions.

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