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.
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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky Medical Center, 800 Rose Street, MN 225 Chandler Medical Center, Lexington, KY 40536-0298, USA. mjdunc0@uky.edu
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Duncan
authors.forename: Karrie E
authors.initials: KE
authors.lastname: Grear
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hoskins
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008647:Mesocricetus; D008845:Microinjections; D010636:Phenols / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D010636:Phenols; C404922:SB 269970; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D013449:Sulfonamides; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C047087:5-carboxamidotryptamine