Experimental Arguments Using the Prototypical Inverse Agonist SB 206553

Along with the fact that the PLC pathway is a prominent target of 5-HT2C receptors in basal ganglia (Wolf and Schultz 1997), the pharmacological characterization of 5-HT2C compounds at PLC-dependent responses has been taken into account to determine their in vivo profile on DA release. First, their effects on DA release have been assessed through dose-response studies and reveal large differences in their magnitude of effects (De Deurwaerdere et al. 2004; Berg et al. 2005; De Deurwaerdere and Spampinato 2001). While SB 206553 dose dependently enhances DA release, SB 242084 and/or SB 243213 induce an increase in DA release that reaches their maximal effect at low doses (Fig. 10.2). Second, the 5-HT2C antagonists SB 242084 and SB 243213 block the excitatory effect of SB 2065523 (De Deurwaerdere et al. 2004; Berg et al. 2006). Altogether, these results suggest that SB 206553 behaves as a 5-HT2C inverse agonist and increases DA release by silencing the constitutive activity of 5-HT2C receptors. In contrast to heterologous recombinant systems in vitro, the continuous presence of endogenous 5-HT in vivo (Sharp et al. 1989) may confound this interpretation. However, the effect of SB 206553 on DA release remains insensitive to the decrease

SB 206553 1 SB 242084 1 SB 243213 1

10 10 10

Fig. 10.2 Dose-dependent differences in the magnitude of the increase in basal accumbal (NAc) and striatal (STR) dopamine release induced by the 5-HT2C inverse agonist SB 206553 and the 5-HT2C antagonists SB 242084 and SB 243213. Data are averaged over 2.5 h monitoring and expressed as the mean ± Standard Error Mean (SEM) percentages of baseline corresponding to the area under the curve (AUC). The 5-HT2C compounds were administered intraperitoneally (doses in mg/kg) (n = 5-7 animals) (Adapted from De Deurwaerdere et al. 2004. Copyright permission from The Society for Neuroscience)

SB 206553 1 SB 242084 1 SB 243213 1

10 10 10

Fig. 10.2 Dose-dependent differences in the magnitude of the increase in basal accumbal (NAc) and striatal (STR) dopamine release induced by the 5-HT2C inverse agonist SB 206553 and the 5-HT2C antagonists SB 242084 and SB 243213. Data are averaged over 2.5 h monitoring and expressed as the mean ± Standard Error Mean (SEM) percentages of baseline corresponding to the area under the curve (AUC). The 5-HT2C compounds were administered intraperitoneally (doses in mg/kg) (n = 5-7 animals) (Adapted from De Deurwaerdere et al. 2004. Copyright permission from The Society for Neuroscience)

in 5-HT terminal activity induced by either peripheral administration of the 5-HT1A autoreceptor agonist 8-OH-DPAT or by intra-raphe injections of the neurotoxin 5,7-dihydroxytryptamine (De Deurwaerdere et al. 2004). Therefore, the difference between SB 206553 and SB 242084 or SB 243213 may be a consequence of their distinct intrinsic pharmacological properties and suggest that the constitutive activity of the 5-HT2C receptor participates in the regulation of DA release in vivo. The parallel pharmacological effects of 5-HT2C compounds on IP accumulation and DA release suggest that the marked increase in DA release produced by SB 206553 may involve its inverse agonist property toward the PLC effector pathway (De Deurwaerdere et al. 2004).

The small increase in basal DA release induced by SB 242084 and SB 243213 could be consequent to either their full inverse agonist activity at the PLA2 and Gai pathways or the selective blockade of a small endogenous inhibitory tone exerted by 5-HT itself at 5-HT2C receptors (De Deurwaerdere et al. 2004; Berg et al. 2006). Recently, it has been proposed that SB 243213 behaves as a partial inverse agonist with a weaker efficacy compared with SB 206553 on DA release (Berg et al. 2006). Indeed, SB 243213 produces a small increase in DA release by itself and antagonizes both the agonist- (Ro 60-0175) and inverse agonist- (SB 206553) induced changes in DA release in the NAc (Berg et al. 2006). The small excitatory effect of SB 242084 was also insensitive to a pretreatment with 8-OH-DPAT (Navailles et al. unpublished data) suggesting that its effect is not related to the level of 5-HT extracellular levels. Like SB 243213, the effect of SB 242084 on basal DA release could result from a partial inverse agonism with a weaker efficacy than SB 206553. These results may also illustrate the protean agonism property of SB 242084 and SB 243213 (Arrang et al. 2008).

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