Treatment of rats with the TRH analog MK-771. Down-regulation of TRH receptors and behavioral tolerance.

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)