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.
Marcos
Beatriz
B
Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
García-Alloza
Mónica
M
Gil-Bea
Francisco J
FJ
Chuang
Tsu T
TT
Francis
Paul T
PT
Chen
Christopher P
CP
Tsang
Shirley W T Y
SW
Lai
Mitchell K P
MK
Ramirez
María J
MJ
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