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

• Published in: Journal of comparative neurology (1911) 2011-06, Vol.519 (9), p.1816-1827
• Main Authors: Zhang, Xiaoqun, Andren, Per E., Glennon, Richard A., Svenningsson, Per
• Format: Article
• Language: English
• Subjects: 6-hydroxydopamine; Animals; Brain Chemistry - drug effects; Brain Chemistry - physiology; Callithrix; caudate-putamen; Disease Models, Animal; EMDT; FARMACI; GPCR; Male; Medicin och hälsovetenskap; Parkinsonian Disorders - metabolism; PHARMACY; Protein Binding - drug effects; Protein Binding - physiology; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - biosynthesis; Receptors, Serotonin - metabolism; Receptors, Serotonin - physiology; SB-258585; serotonin; Serotonin Antagonists - metabolism; Serotonin Receptor Agonists - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0021-9967; 1096-9861; 1096-9861
• DOI: 10.1002/cne.22605

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.