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Role of 5-HT2C receptors in the control of central dopamine function

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Abstract

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT2C receptor subtypes. Indeed, electrophysiological and biochemical data demonstrate that 5-HT2C receptor agonists decrease, whereas 5-HT2C receptor antagonists enhance, mesocorticolimbic DA function. However, 5-HT2C receptors do not appear to play a relevant role in the control of the nigrostriatal DA system originating in the substantia nigra pars compacta. In this article, the role of 5-HT2C receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.

Section snippets

Distribution of 5-HT receptor subtypes in the basal ganglia

Several 5-HT receptor subtypes have been shown to be present in the basal ganglia. A high density of 5-HT1B receptors has been found in the SN, VTA, globus pallidus and entopeduncular nucleus 4, 5, although 5-HT1A binding sites and mRNA encoding the 5-HT1A receptor are barely detectable in these nuclei 5. High to moderate levels of 5-HT2A and 5-HT2C receptor binding sites and the corresponding mRNA are present in several forebrain areas including the basal ganglia and the limbic system. Thus,

5-HT and the electrical activity of DA neurons in the SNc and VTA

Acute administration of the selective 5-HT reuptake inhibitor (SSRI) fluoxetine causes a dose-dependent inhibition of the firing rate of VTA DA-containing neurons, but it does not affect the activity of DA-containing cells in the SNc (Ref. 12). A similar effect, although less pronounced, has been observed following administration of the SSRI citalopram 12. Furthermore, mesulergine, a nonselective 5-HT2C receptor antagonist 13, or the destruction of 5-HT-containing neurons by the neurotoxin

Effects of 5-HT2C receptor agonists and antagonists on DA-mediated function

A series of studies carried out in our laboratory has clearly shown that 5-HT2C receptors play a prominent role in the control of mesocorticolimbic DA-mediated function. Initially, it was found that the firing rate of DA-containing neurons in the VTA was reduced by mCPP and trifluoromethylphenylpiperazine (TFMPP) (a mixed 5-HT2A/2B/2C receptor agonist) 14, whereas these neurons were stimulated by mesulergine 10. Although, on the basis of these findings, it was suggested that 5-HT could exert an

Concluding remarks

In view of the hypothesis that disinhibition of the mesolimbic DA system underlies the mechanism of action of several antidepressant drugs 28, the disinhibitory effect of SB206553 and SB242084 on the mesolimbic DA system might open new possibilities for the employment of 5-HT2C receptor antagonists as antidepressants. This hypothesis is consistent with the suggestion that 5-HT2C receptor antagonists might exert antidepressant activity 29. In this respect, it is interesting to note that several

Acknowledgements

We would like to thank Daniela Sciarra and Sara Di Pierdomenico for their helpful assistance in the preparation of the manuscript. This work was supported by the CNR, Target Project on Biotechnology ctr. N. 990012549, the EC Biomed program-PL 963566 and the Associazione Italiana per la Ricerca sul Cancro (AIRC).

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