Indirect Evidence Using the Nonselective 5HT2C Compounds Clozapine and Mesulergine

To date, only SB 206553 has been characterized as a 5-HT2C inverse agonist in vivo. Several other 5-HT2C compounds displaying 5-HT2C inverse agonist properties at PLC-dependent responses in vitro, such as mesulergine, clozapine, ritanserin, mianserin, or mirtazapine, could potentially join the class of 5-HT2C inverse agonist in vivo. Of note, all these compounds increase basal DA release in vivo (see Table 10.1), but their weak selectivity toward 5-HT2C receptors indicates the need for caution in interpreting these data. The pharmacological approach described above has been used to show that the increase in subcortical DA release induced by an optimal dose of clozapine involves the participation of its inverse agonist property at 5-HT2C receptors in vivo (Navailles et al. 2006b).

Indeed, clozapine significantly increases striatal and accumbal DA release at 1 mg/kg, a dose that induces only 5-10% of DA-D2 receptor occupancy (Schotte et al. 1993). Clozapine reverses the inhibitory effect of the 5-HT2C agonist Ro

60-0175, suggesting that clozapine already recruits its 5-HT2C component at this dose. Additionally, clozapine does not affect the facilitatory effect of the 5-HT2C inverse agonist SB 206553 on DA release (Navailles et al. 2006b), arguing against the idea that clozapine acts as a simple 5-HT2C antagonist in vivo (Prinssen et al. 2000; Di Matteo et al. 2002). Finally, the antagonists SB 243213 and SB 242084 block the effect of clozapine on DA release (Navailles et al. 2006b). These findings demonstrate that clozapine, in line with its inverse agonist profile in vitro at PLC-dependent responses (Fig. 10.1) (Rauser et al. 2001; Lefkowitz 1993; Herrick-Davis et al. 2000), enhances subcortical DA release by acting as an inverse agonist at 5-HT2C receptors to silence their constitutive activity in vivo.

Similarly, mesulergine displays inverse agonist property at 5-HT2C receptors in vitro (Barker et al. 1994). However, mesulergine has been classically defined and used as a 5-HT2C antagonist in vivo (Pazos et al. 1984; Kennett and Curzon 1988; Prisco et al. 1994). In line with this, mesulergine, at the optimal dose of 0.1 mg/kg (Fig. 10.3), blocks the decrease in subcortical DA release induced by Ro 60-0175. Interestingly, the selective 5-HT2C antagonist SB 242084 prevents a further increase in subcortical DA release induced by mesulergine (Navailles et al. unpublished data), confirming that mesulergine may affect DA neuron function independently of its DA-D2 antagonist properties (Di Matteo et al. 1998; Prisco et al. 1994; Van Wijngaarden et al. 1990). Although requiring further investigation, these data suggest that mesulergine may also behave as a 5-HT2C inverse agonist in vivo.

140 120 100

140 120 100

Fig. 10.3 Dose-response effect of mesulergine (0.1, 0.2, and 0.5 mg/kg) on extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) and the striatum (STR) of halothane-anesthe-tized rats. Mesulergine or its corresponding vehicle was subcutaneously administered at time zero. Baseline is calculated from the three fractions preceding the pharmacological treatment. Data represent mean ± SEM percentages of baseline in each sample (time courses) or averaged over 90 min monitoring (insets). Doses are shown in milligrams per kilogram (n = 5-7 animals per group). **p < 0.01, ***p < 0.001 versus the vehicle (0) group (Fisher PLSD test). Mesulergine at 0.1 mg/ kg, a dose that does not involve the blockade of D2 receptors (Di Matteo et al. 1998), increases DA release in the STR (+16%) and the NAc (+13%)

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