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  • Title: 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.
    Author: Duncan MJ, Grear KE, Hoskins MA.
    Journal: Brain Res; 2004 May 15; 1008(1):40-8. PubMed ID: 15081380.
    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.
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