The regulation of TRH and serotonin receptors: chronic TRH and analog administration in the rat.

Thyrotropin releasing hormone (TRH) and serotonin (5-HT) are co-transmitters in spinal and medullary neurons. To study the functional significance of this relationship and the regulation of TRH receptors, we chronically administered TRH and analogs MK-771 and CG-3509 to rats at a dose which evoked behavioral abnormalities. TRH reduced specific binding at spinal (24%) and hypothalamic (31%) TRH receptors and decreased TRH stimulated motor behaviors, such as rearing and cage crossing (locomotion). 5-HT1 and 5-HT2 receptors were unaffected except for an 11% increase in specific binding at spinal 5-HT1 sites. 5-HT and NE concentrations measured by HPLC were not altered in brainstem or hippocampus. In contrast, spinal TRH receptor specific binding increased 11% in rats treated intracisternally with 5,7-dihydroxytryptamine, but the effect was not significant. In competition studies in vitro, MK-771, TRH, and CG-3509 had no activity at 5-HT2 receptors in neocortex, brainstem, or spinal cord, and little activity at 5-HT1 sites (IC 50s greater than 100 uM). A mixed competitive and non-competitive binding profile at 5-HT1 sites resulted in the presence of 100 uM TRH. Conversely, 5-HT agonists had minimal effect at TRH receptors in spinal cord. These data suggest reciprocal or independent regulation of 5-HT1 and TRH receptors in co-transmitter and non-cotransmitter regions, respectively, in response to chronic TRH administration.