Possible Involvement of Constitutive Activity of 5HT2C Receptors in the Control of Oral Function

It has been shown for several years that purposeless oral movement is also a common and extremely sensitive behavioral output consequent to the administration of nonselective 5-HT2C agonist including m-CPP and TFMPP (Stewart et al. 1989; Gong et al. 1992; Wolf et al. 2005). The effect is dependent on 5-HT2C receptors as numerous 5-HT2C antagonists abolish the abnormal oral response induced by the agonists. This abnormal behavior has been related to an alteration of basal ganglia function involving subthalamic nucleus and striatal 5-HT2C receptors (Plech et al. 1995; Eberle-Wang et al. 1996; De Deurwaerdère and Chesselet 2000).

Nonselective and selective 5-HT2C antagonists do not affect oral activity by themselves when administered at 1 or 2 mg/kg (Wolf et al. 2005). As in microdi-alysis studies, a higher dose might be required to unmask tonic or constitutive controls. We have recently obtained behavioral data showing that higher doses of SB 206553 (3-20 mg/kg), but not SB 243213 (1-10 mg/kg), induced a dose-dependent enhancement of purposeless oral movements (De Deurwaerdere et al. 2008). The effect elicited by SB 206553 is not associated with the other classical above-mentioned behaviors elicited by agonists. Most importantly, SB 243213 pretreatment abolishes purposeless oral movements induced by SB 206553 or the agonist m-CPP (Fig. 10.4) (De Deurwaerdere et al. 2008). These pharmacological data are in line with the possibility that SB 206553 behaves on oral movements as a 5-HT2C inverse agonist, suggesting that the constitutive activity of 5-HT2C receptors could play an endogenous role in maintaining optimal oral responses. It is difficult to determine if the same 5-HT2C receptors underline purposeless oral movements triggered by the opposite class of pharmacological agents. Indeed, several brain regions and circuits in basal ganglia may interfere with this behavior. These results suggest again that basal ganglia are housing a constitutive control, exerted by 5-HT2C receptors, that is operating in freely moving animals.

Fig. 10.4 The 5-HT2C antagonist SB 243213 blocks the effect of the 5-HT2C inverse agonist SB 206553 on purposeless oral movements in naïve rats. Histograms represent the number of oral bouts (±SEM) observed during 1 h for each experimental group (n = 6-7 rats per group). Measurements have been performed according to references Eberle-Wang et al. (1996) and De Deurwaerdère and Chesselet (2000). Rats were pretreated with SB 243213 (SB243: 1 mg/kg intraperitoneally [ip]) or its vehicle 1 h before the ip administration of SB 206553 (SB206: 10 mg/kg) or its vehicle. ***p < 0.001 versus the vehicles group; #p < 0.05, versus the SB 206553 group (Fisher PLSD test)

Fig. 10.4 The 5-HT2C antagonist SB 243213 blocks the effect of the 5-HT2C inverse agonist SB 206553 on purposeless oral movements in naïve rats. Histograms represent the number of oral bouts (±SEM) observed during 1 h for each experimental group (n = 6-7 rats per group). Measurements have been performed according to references Eberle-Wang et al. (1996) and De Deurwaerdère and Chesselet (2000). Rats were pretreated with SB 243213 (SB243: 1 mg/kg intraperitoneally [ip]) or its vehicle 1 h before the ip administration of SB 206553 (SB206: 10 mg/kg) or its vehicle. ***p < 0.001 versus the vehicles group; #p < 0.05, versus the SB 206553 group (Fisher PLSD test)

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