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](3MeHis 2)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 μg/μl 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 μg/2μl, 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 ( 5μg 2μl , i.c.v.) once every 2hr 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. The conclusions from these data are that receptors for TRH down-regulate in response to constant agonist stimulation and that the decrease in the number of receptors is accompanied by a decreased behavioral sensitivity to TRH agonists. These results suggest that tolerance to the action of TRH in the CNS may be due to down-regulations receptors and demonstrate that a putative peptide neuromodulatory system is highly adaptable to receptor stimulation.