[Glu2]TRH dose-dependently attenuates TRH-evoked analeptic effect in mice

Abstract

Thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) and the structurally related [Glu(2)]TRH (pGlu-Glu-Pro-NH(2)) are endogenous peptides with a plethora of actions in the central nervous system. Many centrally-mediated effects of TRH are shared with those of [Glu(2)]TRH, although the involvement of different receptors is presumed. The analeptic action is the best-known TRH-related central nervous system effect. While [Glu(2)]TRH itself is analeptic, its co-administration with TRH into mice produced a dose-dependent attenuation of TRH-evoked reversal of barbiturate-induced sleeping time. This finding is in agreement with our previous observations that [Glu(2)]TRH significantly attenuates TRH-induced hippocampal extracellular acetylcholine release. Taken together, [Glu(2)]TRH may be considered as a negative modulator for the cholinergic effect of TRH in the mouse brain.

Fig. 1

Chemical structure of TRH and [Glu²]TRH.

Fig. 2

Sleeping time measured after i.v. administration of TRH (bars with hatch pattern of vertical lines) or [Glu²]TRH (bars with hatch pattern of horizontal lines) at equimolar dose (10 μmol/kg body weight) followed by injection of pentobarbital (60 mg/kg body weight, i.p.) 10 min later, as well as reversal of TRH-induced analeptic effect (10 μmol/kg body weight) by various doses of [Glu²]TRH upon co-administration with TRH (bars shaded with cross-hatch pattern). Open bar shows sleeping time measured for the control (saline) group. The sleeping time was recorded from the onset of the loss of the righting reflex until the reflex was regained. Data are shown as average ± SEM for n=12–18 at each doses. Statistical evaluation was done by analysis of variance (ANOVA) followed by post hoc Tukey test. Differences were considered significant with P<0.05; * indicates statistically significant differences from the control group (saline); ^† indicates statistically significant differences from the TRH group; ^# indicates statistically significant differences from the [Glu²]TRH group.