Involvement of an Altered 5-HT 6 Receptor Function in Behavioral Symptoms of Alzheimer's Disease

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 ( $\mathit{p}\mathrm{<}0.01$ ) in AD ( $170.02\pm 27.53$ pmol/mg prot.) compared to controls ( $823.33\pm 196.67$ ). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT₆ receptor density was significantly lower ( $\mathit{p}\mathrm{<}0.01$ ) in AD ( $6.67\pm 0.83$ ) compared to controls ( $16.67\pm 3.33$ ). Splitting these results by sex, 5-HT₆ receptor activation was significantly lower ( $\mathit{p}\mathrm{<}0.01$ ) in AD females compared to males ( $21.67\pm 30.02$ vs. $231.67\pm 34.17$ pmol/mg prot). 5-HT₆ density and 5-HT levels were significantly correlated ( $\mathit{p}⩽0.01$ ) 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.