Adaptations in 5-HT Receptor Expression and Function: Implications for Treatment of Cognitive Impairment in Aging

Malfunction of the serotonin system may contribute to memory deficits during aging. We evaluated the 5-HT6 antagonist RO4368554 in two models of learning and memory in aged rats. Male rats (18 months) were assigned to two groups of equal cognitive performance. After 2 weeks of 5-HT6 antagonist RO4368554 (5 mg/kg, i.p.) treatment, rats showed significant improvement in object recognition and social discrimination compared with rats given chronic vehicle. Brains from these animals were examined for changes in plasticity-associated proteins Ki-67 and PCNA. No differences were seen between groups in any of these markers. We also measured mRNA expression of 5-HT6, along with 5-HT1A, 5-HT1B, and tryptophan hydroxylase-2 mRNAs in 4-month-old and 24-month-old F344 rats. Decreases in 5-HT1B expression were observed in several forebrain regions in the old rats. These results demonstrate that 5-HT6 and 5-HT1B receptors are potential targets for treatment of age-related memory disorders. (C) 2009 Wiley-Liss, Inc.