Distribution, level, pharmacology, regulation, and signaling of 5-HT6 receptors in rats and marmosets with special reference to an experimental model of parkinsonism

Serotonin 5-HT6 receptors have been implicated in the regulation of cognition, locomotion, and mood, but the elucidation of their functions is complicated by conflicting data using various animal models. Here, a systematic evaluation showed that autoradiographic binding with the selective 5-HT6 receptor antagonist [125I]SB-258585 was similar in marmosets and rats. In both species, [125I]SB-258585 binding was enriched in the caudate-putamen. Various recently developed agonists and antagonists toward 5-HT6 receptors exhibited similarities in their abilities to displace [125I]SB-258585 binding in marmosets and rats. The rank order of pEC50 values were as follows: (+)EMDT-CR = EMD386088>MS-245 = 5-HT>EMDT>>(−)EMDT-CR; and (+)EMDT-CR = EMD386088>5-HT = MS-245 = EMDT>>(−)EMDT-CR, in marmosets and rats, respectively. Unilateral 6-hydroxydopamine lesioning of dopaminergic axons caused a significant decrease of [125I]SB-258585 binding in the caudate-putamen of both marmosets and rats. Nonetheless, acute administration of the 5-HT6 receptor agonist EMDT to unilaterally 6-hydroxydopamine-lesioned rats, caused an induction of egr-1, homer, and enkephalin mRNAs in the dopamine-depleted hemisphere, indicating a supersensitization of 5-HT6 receptors following dopamine depletion. In conclusion, this study provides evidence for significant similarities in the distribution, level, pharmacology, and regulation of 5-HT6 receptors between rats and marmosets. J. Comp. Neurol. 519:1815–1827, 2011. © 2011 Wiley-Liss, Inc.