title: Treatment of rats with the TRH analog MK-771. Down-regulation of TRH receptors and behavioral tolerance.
abstract: The regulation of receptors for thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) was studied by administering the TRH analog, MK-771 to rats by three different schedules and then measuring changes in the binding of [3H](3MeHis2) TRH and behavioral responses to a challenge with MK-771. The behavioral responses monitored were wet-dog shakes, large motor movements, small motor movements and forepaw tremor. Temperature changes were also monitored. The first schedule consisted of intracerebroventricular (i.c.v.) administration of MK-771 for seven days (5 micrograms/microliter per hr) via a mini-osmotic pump. At the end of the treatment, rats showed no shaking or large motor movements typically induced by TRH, in response to a 5 mg/kg (i.p.) challenge of MK-771. Receptors were found to be 50% of control levels in the three areas of brain examined. The second schedule consisted of the administration of MK-771 (5 micrograms/2 microliters, i.c.v., once a day and 2 mg/kg, i.p., once a day). It was found that the number of receptors decreased on about the same time course as development of tolerance to wet-dog shakes and large motor movements. The third schedule consisted of the administration of MK-771 (5 micrograms/2 microliters, i.c.v.) once every 2 hr to a total of four doses. These animals eventually developed tolerance to the wet-dog shakes produced by the subsequent challenge with MK-771 and also showed a 50% decrease in receptor binding after the fourth exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: S M
authors.initials: SM
authors.lastname: Simasko
authors.forename: A
authors.initials: A
authors.lastname: Horita
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D003864:Depression, Chemical; D004361:Drug Tolerance; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018025:Receptors, Thyrotropin-Releasing Hormone; D053778:Thiazolidines; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D011956:Receptors, Cell Surface; D018025:Receptors, Thyrotropin-Releasing Hormone; D053778:Thiazolidines; D013973:Thyrotropin-Releasing Hormone; C021597:pyro(l-alpha-aminoadipyl)-L-histidyl-L-thiazolidine-4-carboxamide