Mechanistic and functional divergence between thyrotropin-releasing hormone and RO 15-4513 interactions with ethanol

Abstract

Both thyrotropin-releasing hormone (TRH) and RO 15-4513 antagonize ethanol-induced depression, but this common property does not infer that both compounds share similar mechanisms of action. In the present studies, both TRH (30 mg/kg, i.p.) and RO 15-4513 (10 mg/kg, i.p.) reversed ethanol-induced depression of locomotor activity, in accord with previous reports. However, the benzodiazepine antagonist, RO 15-1788, blocked this action of RO 15-4513, while exerting no effect on the analeptic action of TRH. Using a model of seizure activity electrically elicited from the inferior colliculus, ethanol exerted a dose-related attenuation of seizure activity. This anticonvulsant action of ethanol was not altered by TRH (30 mg/kg, i.p.), but RO 15-4513 (3 mg/kg) reversed the effect of the 0.5, but not the 1.0 g/kg, dose of ethanol. In addition, pretreatment with RO 15-4513 (1 or 3 mg/kg, i.p.), but not TRH (30 mg/kg, i.p.), caused seizure generalization into the forebrain following inferior collicular stimulation, further verifying the proconvulsant properties of RO 15-4513. In conclusion, the analeptic action of TRH appears independent of benzodiazepine activity, and in contrast to RO 15-4513, TRH does not exhibit proconvulsant properties. Furthermore, because TRH did not antagonize both depressant actions of ethanol studied, it appears unlikely that TRH directly interacts with the molecular basis of ethanol action.

Fig. 1

Effects of TRH and RO 15-4513 alone and in combination with RO 15-1788 on the depression of locomotor activity (± SEM) induced by a 2.0 g/kg i.p. dose of ethanol (ETOH). All animals were treated with ETOH and 1 min later received either TRH (30 mg/kg, i.p.), or RO 15-4513 (10 mg/kg, i.p). For RO 15-1788 studies, 10 mg/kg of this compound was administered, i.p., 1-min post-ETOH, while the TRH or RO 15-4513 was administered 2-min post-ETOH. *p < 0.05 versus saline control; **p < 0.05 versus ETOH control.

Fig. 2

The time course of both the TRH and RO 15-4513 antagonism of ethanol sedation depicted in Fig. 1, as compared to ETOH or saline alone. The activity counts (±SEM) were measured within each 10-min interval.