Effect of Various 5HT2C Agents in the Control of Fos Expression in Basal Ganglia

The use of anatomo-functional markers, without precisely addressing cellular mechanisms of action of pharmacological compounds, gives a picture of the effects of drugs in a tissue. It is interesting to look at the data concerning 5-HT2C receptors in the basal ganglia where all modalities of interaction of 5-HT2C receptors may occur.

Several studies have reported that 5-HT2C receptor stimulation may affect the expression of the proto-oncogene c-Fos in the brain. In basal ganglia, the effect is noticeable in the medial STR, the subthalamic nucleus, and with lower magnitudes of effects, in the lateral striatum, the entopeduncular nucleus and the substantia nigra pars reticulata (De Deurwaerdere and Chesselet 2000; Cook and Whirtshafter 1995; Stark et al. 2006). Numerous studies have failed to report substantial effect of 5-HT2C antagonists on indirect cellular markers of neuronal activity (Moorman and Leslie 1996; Rouillard et al. 1996; Javed et al. 1998; Gardier et al. 2000; Stark et al. 2008). Again, this might be due to the lack of selectivity of the antagonists for 5-HT2C receptors (mianserin, ritanserin, metergoline), to the low tone of endogenous 5-HT in subcortical regions or to the pharmacological profile of these antagonists. In a series of experiments, we have observed with (1 mg/kg) the mixed 5-HT2B/2C antagonist SDZ SER082 and the 5-HT2C antagonist SB 243213 a Fos labeling in striatal and subthalamic regions (De Deurwaerdere et al. 2010). A high dose of SB 206553 (10 mg/kg) also enhanced Fos in the entopeduncular nucleus and the substantia nigra pars reticulata (De Deurwaerdere et al. 2008). Increase in Fos expression or other neuronal markers have not been observed in other brain areas suggesting that the link between 5-HT2C receptors and subcortical DA transmission is strong in basal ganglia.

The expression of Fos in basal ganglia after 5-HT2C agonists or antagonists suggests that all these class of drugs affect cellular activity in basal ganglia. The distribution of the effects elicited by these drugs is similar in medial sectors of basal ganglia but seems to be higher with antagonists in lateral sectors. The effects associated with antagonists can not be clearly associated with a specific pharmacological interaction of the drugs with the receptor. Nevertheless, the distinct pattern of their effects suggests mechanisms more complex than a simple blockade of endogenous 5-HT at 5-HT2C receptors. Interestingly, if part of the effects of the antagonists is related to the removal of a tonic inhibitory influence exerted by 5-HT2C receptors on gene expression, this would suggest that 5-HT2C receptors are able to exert an opposite role in the control of gene expression in the striatum and the subthalamic nucleus.

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