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.
Lindner
Mark D
MD
Department of Neuroscience, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. mark.lindner@bms.com
Hodges
Donald B
DB
Hogan
John B
JB
Orie
Anitra F
AF
Corsa
Jason A
JA
Barten
Donna M
DM
Polson
Craig
C
Robertson
Barbara J
BJ
Guss
Valerie L
VL
Gillman
Kevin W
KW
Starrett
John E
JE
Gribkoff
Valentin K
VK
D000818:Animals; D001665:Binding Sites; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008409:Mastication / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015000:Yawning / Q000187:drug effects; D000096926:Benzenesulfonamides
D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C114163:Ro 4-6790; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor; C117443:SB 271046