The International Journal of Neuropsychopharmacology

Research Article

Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects

Beatriz Marcosa1, Maria Caberoa1, Maite Solasa1, Bárbara Aisaa1 and Maria J. Ramireza1 c1

a1 Department of Pharmacology, University of Navarra, Pamplona, Spain


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.

(Received May 06 2009)

(Reviewed June 14 2009)

(Revised June 22 2009)

(Accepted July 31 2009)

(Online publication September 09 2009)


c1 Address for correspondence: Dr M. J. Ramírez, Department of Pharmacology, School of Medicine, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain. Tel.: +34 948425600 Fax: +34 948425649 Email: