Diversity of thyrotropin-releasing hormone receptors in the pituitary and discrete brain regions of rats

In order to analyze the receptor properties of central nervous system (CNS) -stimulant thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-proli namide TRH), we evaluated the binding of TRH and its analog taltirelin hydr ate ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-L-histi dyl-L-prolinamide tetrahydrate; taltirelin, TA-0910) in rat anterior pituit ary and several brain regions. There was a specific binding of [H-3]methyl TRH (MeTRH) in the anterior pituitary, hypothalamus, brain stem, cerebral c ortex and cerebellum with Kd values of 1.0-1.6 nM. The inhibition of [H-3]M eTRH binding by TRH and taltirelin was monophasic in the anterior pituitary , hypothalamus and brain stem with Ki values of 6.3-8.0 nM and 145.5-170.4 nM for TRH and taltirelin, respectively. In contrast, the biphasic inhibiti on was revealed in the cerebral cortex and cerebellum. The K-i values for T RH and taltirelin were 4.1-4.3 nM and 67.8-73.4 nM for the high affinity bi nding site and 3.6-4.2 mu M and 82.3-197.5 mu M for the low affinity bindin g site, respectively. Addition of 100 mu M GTP or its analog 5'-guanylylimi dodiphosphate (Gpp[NH]p) affected neither the biphasic inhibition by TRH no r that by taltirelin. Thus the results suggest the presence of distinct hig h and low affinity TRH receptors in the CNS in contrast to the pituitary.