Aging and SB-269970-A, a selective 5-HT7 receptor antagonist, attenuate circadian phase advances induced by microinjections of serotonergic drugs in the hamster dorsal raphe nucleus

Abstract

Aging leads to many changes in the circadian timekeeping system, including reduced sensitivity to phase-resetting signals such as systemic administration of the serotonergic agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In previous studies, we observed an age-related decrease in 5-HT7 receptor binding sites, one of the receptor subtypes that is activated by 8-OH-DPAT, in the dorsal raphe nucleus. In this study, we tested the hypotheses that (1) aging reduces circadian phase shifts induced by local administration of 8-OH-DPAT (30 microM, i.e., 1.97 ng) or 5-carboxamidotryptamine (5-CT, 100 nM, i.e., 6.39 pg), another serotonin agonist, into the dorsal raphe and (2) 5-HT7 receptors mediate the phase shifts induced by administration of 5-CT and 8-OH-DPAT into the dorsal raphe. Young (3-5 months), middle-aged (12-13 months) and old hamsters (17-19 months) were surgically implanted with chronic guide cannulae aimed at the dorsal raphe, and were housed in cages equipped with running wheels. Aging significantly inhibited (P<0.01) the phase advances in running-wheel rhythms induced by 8-OH-DPAT microinjected during the midsubjective day. 5-CT induced phase advances tended to decrease with aging, but this effect was not significant (P<0.12). Microinjection of the selective 5-HT7 receptor antagonist, SB-269970-A (50-5000 nM, i.e., 0.39-390 pg), 15 min before microinjection of 5-CT or 8-OH-DPAT into the dorsal raphe of young hamsters, significantly inhibited phase shifts. In conjunction with our previous study, these findings indicate that an age-related reduction in 5-HT7 receptors in the dorsal raphe nucleus is an important neurochemical mechanism leading to aging deficits in the circadian timekeeping system.