Thyrotropin releasing hormone (TRH; pGlu-His-Pro-NH2) has multiple but transient homeostatic functions in brain. It is hydrolyzed in vitro by pyroglutamyl peptidase II (PPII), a narrow specificity ectoenzyme with a preferential localization in brain, but evidence that PPII controls TRH communication in the brain in vivo is scarce. We therefore studied in male Wistar rats the distribution of PPII mRNA in the septum and the consequence of PPII inhibition on the analeptic effect of TRH injected into the medial septum. Twelve-fourteen % of cell profiles expressed PPII mRNA in the medial septum-diagonal band of Broca; in this region the specific activity of PPII was relatively high. Twenty-thirty five percent of PPII mRNA labeled profiles were positive for TRH-R1 receptor mRNA. The intra medial septum injection of TRH reduced, in a dose dependent manner, the duration of ethanol-induced loss of righting reflex (LORR). Injection of the PPII inhibitor pGlu-Asn-Pro-MCA into the medial septum enhanced the effect of TRH. The injection of a phosphinic TRH analog, a higher affinity inhibitor of PPII, diminished the duration of LORR by itself. In contrast, the intraseptal injection of pGlu-Asp-Pro-NH2, a peptide that did not inhibit PPII activity, or of an inhibitor of prolyl oligopeptidase, did not change the duration of LORR. We conclude that in the medial septum, PPII activity may limit TRH action, presumably by reducing the concentration of TRH in the extracellular fluid around cells co-expressing PPII and TRH-R1.
- Received January 20, 2012.
- Revision received April 19, 2012.
- Accepted April 20, 2012.
- The American Society for Pharmacology and Experimental Therapeutics