Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects.
A growing body of evidence supports the use of serotonin 5-HT6 receptor antagonists as a promising mechanism for treating cognitive dysfunction. We evaluated 5-HT6 receptor expression and associated biochemical mechanisms in the hippocampus of rats that had been trained in the Morris water maze (MWM), a spatial learning task. Training in the MWM induces a down-regulation of 5-HT6 receptor protein and mRNA receptor expression. The learning procedure or the administration of the selective 5-HT6 receptor antagonist SB-271046 induced an increase in pCREB1 levels while CREB2 levels were significantly reduced. However, although SB-271046 was able to improve retention in the MWM, no further changes in pCREB1 or CREB2 levels were found to be associated with the presence of the 5-HT6 receptor antagonist during the learning procedure. The MWM procedure significantly increased pERK1/2 levels and interestingly, further increases were seen when treating with SB-271046 during the MWM. These results suggest that, in the hippocampus, biochemical pathways associated with pERK1/2 expression, and not with the CREB family of transcription factors, seem to be related to the cognitive-enhancing properties of 5-HT6 receptor antagonists.
Marcos
Beatriz
B
Department of Pharmacology, University of Navarra, Pamplona, Spain.
Cabero
Maria
M
Solas
Maite
M
Aisa
Bárbara
B
Ramirez
Maria J
MJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D050882:CREB-Binding Protein / Q000378:metabolism; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D007456:Iodine Isotopes; D010879:Piperazines; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C418570:SB 258585; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D050882:CREB-Binding Protein; D000262:Adenylyl Cyclases; C117443:SB 271046