HT2C Receptors and Basal Ganglia Function

How does the stimulation of 5-HT2C receptors control basal ganglia function? As noted earlier, the basal ganglia consist of highly interconnected regions, each characterized by a specific organization and neuronal circuits. The influence of 5-HT2C receptors on this network will depend on the electrophysiological and metabolic features of each group of neurons. For example, it is likely that 5-HT2C receptors will differentially affect silent striatal neurons compared to tonically active SNr neurons. The challenge is to understand how the role of 5-HT2C receptors in one region will eventually impact the whole network and to determine whether common rules govern the effect of their stimulation.

A first evidence that the control exerted by 5-HT2C receptors in the basal ganglia depends on network information comes from the control they exert on the activity of mesencephalic DA neuron. 5-HT2C agonists and antagonists inhibit and enhance, respectively, the activity of DA neurons and the release of DA from striatal nerve terminals in rats (Di Giovanni et al., Chap. 11). It is noteworthy that the effects of 5-HT2C compounds vary with the state of the animal (anesthesia, awake) and are greater in the VTA than in the SNc (Navailles and De Deurwaerdere, Chap. 10). Few studies have been devoted to the brain regions involved in this regulation. Intrastriatal or intraccumbal administration of 5-HT2C antagonists may enhance DA release (Alex et al. 2005; Alex and Pehek 2007; Navailles et al. 2006a). Conversely, administration of these antagonists into the VTA does not affect DA release in the nucleus accumbens (Navailles et al. 2006a). Strikingly, neither intra-VTA nor intraaccumbal administrations of Ro-60-0175 inhibit DA release in the nucleus accumbens, but these regions may become involved when the agonist is administered systemically (Navailles et al. 2006a). Altogether, these results suggest that the tonic inhibitory control exerted by 5-HT2C receptors involves receptors located in terminal areas of DA neurons. This is consistent with the data mentioned earlier showing that 5-HT2C receptors are involved in the tonic inhibition of neuronal excitability in the striatum (Rueter et al. 2000). Thus, this phasic inhibitory control likely involves 5-HT2C receptors located in areas containing cell bodies and terminals of DA neurons but depends on information provided by other brain regions.

The second evidence for a role of neuronal circuits in the effects resulting from 5-HT2C receptor stimulation comes from Fos studies that revealed a greater effect of systemic injections of mCPP in the striatum and the STN than in the EPN or SNr. The mixed 5-HT2C/2B antagonist SDZ SER-082 and the selective 5-HT2C antagonist SB 243213 increased Fos expression only in the STN and the striatum (De Deurwaerdere et al. 2010). Thus, 5-HT2C receptors appear to exert a tonic (perhaps constitutive) influence in the striatum and the STN cells. In both regions, the

5-HT2C receptors could, in addition, mediate phasic responses. It is interesting that the higher responsiveness of basal ganglia structures to 5-HT2C receptor modulation occurs in the two regions receiving direct inputs from the cerebral cortex (De Deurwaerdere and Chesselet 2000a, b; De Deurwaerdere et al. 2010).

A third evidence comes from behavioral experiments reporting that alterations in 5-HT2C transmission in the STN or the striatum lead to rotational behavior in rats. Thus, unilateral injection of 5-HT, quipazine (a nonselective 5-HT2C agonist), or MK 212 (a preferential 5-HT2C agonist) into the STN induced a contralateral and dose-dependent turning behavior (Belforte and Pazo 2004). The contraversive turning behavior induced by 5-HT, blocked by the nonselective 5-HT2 antagonist mianserine, is attributed to a decreased excitatory input from the STN to the SNr, which in turn enhances the activity of the ipsilateral motor thalamus. Indeed, kainic acid lesion of the SNr suppressed the contralateral rotations elicited by the stimulation of STN 5-HT2B/2C receptors (Belforte and Pazo 2004). Other data, however, indicate that blockade of subthalamic 5-HT2C receptors suppresses the stereotypic behavior induced by apomorphine administration (Barwick et al. 2000), which would support the opposite idea that 5-HT2C receptors activate subthalamonigral activity. In the striatum, local injections of 5-HT provoked contraversive turning, while the nonselective 5-HT1/2 antagonist methysergide induced ipsiversive circling (James and Starr 1980). Although these data favor the existence of both tonic and phasic controls exerted by the 5-HT system on striatal cells, the interpretation of these data is limited by the lack of specificity of the pharmacological tools employed in these studies.

Altogether, the in vivo data support the idea that 5-HT2C transmission is hetero-geneously organized in the basal ganglia. The main areas under the control of 5-HT2C receptors are the striatum and the STN, the two entries of cortical inputs to the basal ganglia. In contrast, the output regions of basal ganglia are less sensitive to 5-HT2C modulation in naive rats (Di Matteo et al. 2008). In addition, both tonic and phasic controls coexist in the STN and the striatum.

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