Affiliations: [a] Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Pamplona, Spain | [b] Neurology & GI – Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex CM19 5AW, UK | [c] Department of Neurology, Singapore General Hospital, Singapore | [d] Department of Clinical Research, Singapore General Hospital, Singapore
Correspondence:
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Corresponding author: Dr. María J. Ramírez, Department of Pharmacology, School of Medicine, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain. Tel.: +34 948425600; Fax: +34 948425649; E-mail: [email protected].
Note: [] Communicated by Edna Grünblatt.
Abstract: We studied the hypothesis that disturbances in 5-HT6 receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer’s disease (AD). 5-HT6 density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT6 receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02±27.53 pmol/mg prot.) compared to controls (823.33±196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT6 receptor density was significantly lower (p<0.01) in AD (6.67±0.83) compared to controls (16.67±3.33). Splitting these results by sex, 5-HT6 receptor activation was significantly lower (p<0.01) in AD females compared to males (21.67±30.02 vs. 231.67±34.17 pmol/mg prot). 5-HT6 density and 5-HT levels were significantly correlated (p⩽0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT6 activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.
