Involvement of an altered 5-HT -{6} receptor function in behavioral symptoms of Alzheimer's disease.
We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} 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-HT_{6} 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-HT_{6} 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-HT_{6} receptor activation was significantly lower (p< 0.01) in AD females compared to males (121.67 +/- 30.02 vs. 231.67 +/- 34.17 pmol/mg prot). 5-HT_{6} density and 5-HT levels were significantly correlated (p < or = 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-HT_{6} 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.
Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Beatriz
B
Marcos
Mónica
M
García-Alloza
Francisco J
FJ
Gil-Bea
Tsu T
TT
Chuang
Paul T
PT
Francis
Christopher P
CP
Chen
Shirley W T Y
SW
Tsang
Mitchell K P
MK
Lai
María J
MJ
Ramirez
D000262:Adenylyl Cyclases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000473:pathology / Q000503:physiopathology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D011446:Prospective Studies; D011618:Psychotic Disorders / Q000473:pathology / Q000503:physiopathology*; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D012737:Sex Factors; D013702:Temporal Lobe / Q000473:pathology / Q000503:physiopathology
D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; D012701:Serotonin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases