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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

An assessment of the effects of serotonin 6 ( 5-HT6) receptor antagonists in rodent models of learning.

Antagonists of serotonin 6 ( 5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.[1]


  1. An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. Lindner, M.D., Hodges, D.B., Hogan, J.B., Orie, A.F., Corsa, J.A., Barten, D.M., Polson, C., Robertson, B.J., Guss, V.L., Gillman, K.W., Starrett, J.E., Gribkoff, V.K. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
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