Effects of pentylenetetrazole-induced kindling on thyrotropin-releasing hormone biosynthesis and receptors in rat brain

It has been postulated that changes in thyrotropin-releasing hormone biosyn thesis may be involved in the mechanism of kindling-an animal model of epil eptogenesis. To test this hypothesis, a time-course study was carried out t o investigate the effects of pentylenetetrazole kindling (40 mg/kg i.p., da iry for eight days) on the expression of gene coding for preprothyrotropin- releasing hormone, the thyrotropin-releasing hormone tissue level and thyro tropin-releasing hormone receptor parameters in rat brain. As shown by an i n situ hybridization study, a single, convulsant dose of pentylenetetrazole (70 mg/kg i.p.) increased the preprothyrotropin-releasing hormone messenge r RNA level in the dentate gyrus of the hippocampal formation and piriform cortex after 3 h and, to a greater extent, after 24 h. Those changes were a ccompanied with increases in the thyrotropin-releasing hormone level in the striatum, hippocampus, amygdala and piriform cortex. Seven days after sing le pentylenetetrazole administration, the thyrotropin-releasing hormone lev el was still significantly elevated in the piriform cortex and striatum. Ac ute pentylenetetrazole decreased the density (B-max) of thyrotropin-releasi ng hormone receptors in the striatum after 3 and 24 h, and increased that d ensity in the piriform cortex and amygdala after 24 h and seven days, respe ctively. The thyrotropin-releasing hormone receptor affinity (K-d) was decr eased in the striatum and increased in the amygdala after only 3 h. Kindled rats showed a moderate increase in the preprothyrotropin-releasing hormone messenger RNA content in the dentate gyrus of the hippocampal formation an d piriform cortex after 3 and 24 h; however, a significant decrease in thos e parameters was found after 14 days. After 3 and 24 h, pentylenetetrazole kindling also elevated the thyrotropin-releasing hormone content in the hip pocampus, piriform cortex, and striatum (in the latter structure after 24 h only), whereas in the septum the thyrotropin-releasing hormone level was d ecreased. After seven days, the thyrotropin-releasing hormone level was sti ll elevated in the hippocampus and piriform cortex of kindled rats, but aft er 14 days it was significantly lowered in the hippocampus. The kindled rat s also showed a significant decrease in the density (B-max) of thyrotropin- releasing hormone receptors in the striatum (after 24 h, seven and 14 days) , and an increase in the piriform cortex (after seven days). The thyrotropi n-releasing hormone receptor affinity (K-d) value was increased in the hipp ocampus after seven and 14 days, and in the piriform cortex after seven day s. These results indicate that pentylenetetrazole kindling induces long-lastin g alterations in the thyrotropin-releasing hormone biosynthesis and thyrotr opin-releasing hormone receptor affinity in discrete regions of rat brain. These region-specific changes, in particular down-regulation of the thyrotr opin-releasing hormone biosynthesis in the hippocampus, may be involved in chronic neuronal hyperexcitability associated with kindling. (C) 1999 IBRO. Published by Elsevier Science Ltd.