Role of Terminal Regions of Dopaminergic Neurons in the Effects Evoked by Inverse Agonists and Agonists

One emerging idea in the will to fully understand how 5-HT2C receptors control DA function is that this control may engage regionally distinct 5-HT2C populations (Filip and Cunningham 2002, 2003; Fletcher et al. 2004). Compelling data assessing the effect of locally administered 5-HT2C compounds (Table 10.3) begin to provide an interesting picture in this matter and suggest that the constitutive activity of 5-HT2C receptors participates in a region-dependent manner in the control of DA function.

The terminal regions of DA neurons in the NAc and the STR - but not the mPFC -may be a major site for the endogenous constitutive activity of 5-HT2C receptors on DA release. Indeed, the 5-HT2C inverse agonist SB 206553 increases accumbal DA release only when it is locally applied into the NAc and the STR but not into the VTA or the cortex (Navailles et al. 2006a; Alex et al. 2005). Moreover, SB 242084 applied into the NAc but not into the VTA is able to prevent the increase in accumbal DA release induced by the systemic administration of SB 206553. The intra-NAc infusion of clozapine also increases accumbal DA release (Ferré and Artigas 1995), but at the high concentration used (10 mmol/L), mechanisms other than the blockade of 5-HT2C receptors also have to be considered. Although a deeper pharmacological investigation would be required, these data suggest that the control exerted by the constitutive activity of 5-HT2C receptors may be restricted to subcortical DA terminal regions.

If the constitutive activity corresponds to that described theoretically from in vitro data, then we should expect that the intra-NAc infusion of a 5-HT2C agonist inhibits DA release. However, data have reported either no effect (Navailles et al. 2008) or even an increase in DA release (Parsons and Justice 1993). The lack of effect could not be related to a strong occupation of 5-HT2C receptors by endogenous 5-HT because the local application of the protean ligands SB 243213 and SB 242084 does not affect NAc DA release. An inhibitory action arising from 5-HT2C receptors located into the NAc can be observed only when agonists are systemically administered (Table 10.2). Indeed, the intra-VTA and/or intra-NAc application of 5-HT2C antagonists is effective in preventing Ro 60-0175-induced inhibition of accumbal DA release (Navailles et al. 2006a). This indicates that distinct populations of 5-HT2C receptors participate in the control of DA release. Some of them, outside the NAc, are likely to trigger the phasic inhibitory control exerted by 5-HT2C receptors that are not able to inhibit accumbal DA release per se. Consequently, it is possible that NAc 5-HT2C receptors respond globally in an opposite manner to the inverse agonist and the agonist, but in different situations. These findings suggest that the 5-HT2C receptor per se is not directly responsible for promoting its own constitutive activity. The constitutive activity exerted by 5-HT2C receptors in vivo would not correspond to the concept raised in vitro.

Compared with a preferential constitutive influence of 5-HT2C receptors on striatal and accumbal DA release (Tables 10.1 and 10.3), the tonic 5-HT2C receptor control may be predominant on the mesocortical DA pathway (Gobert et al. 2000; Millan et al. 1998; Pozzi et al. 2002; Dekeyne et al. 2008). Although no study has assessed the local effect of selective 5-HT2C antagonists on cortical DA release (Table 10.3), data obtained from their systemic administration in freely moving animals show that the overall blockade of endogenous 5-HT increases cortical, but not subcortical, DA release (Table 10.1). Despite the lack of data on the influence of the systemic administration of 5-HT2C antagonists on cortical DA release in anesthetized rats, the decrease in endogenous 5-HT levels induced by halothane (Kalen et al. 1988) suggests that the tonic influence of 5-HT2C receptors on cortical DA release might be blunted in the presence of anesthesia (see Section 10.5).

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