Thyrotropin-releasing hormone reversal of ethanol-induced decreases in cerebellar cGMP

Abstract

THYROTROPIN-RELEASING hormone (TRH) has been shown to produce marked changes in the central nervous system unrelated to its actions on the anterior pituitary which result in the release of thyrotropin and prolactin¹. The first evidence for central effects of TRH were provided by observations that TRH potentiated L-dihydroxyphenylalanine-induced excitation in pargyline pretreated, hypophysectomised animals². Subsequently, TRH was found to antagonise the sedative and hypothermie effects of ethanol and pento-barbital^3–5. These results of TRH administration may depend upon many factors, including dose, time after administration and presence of other pharmacological agents, as well as on the parameters being measured. Although the effects of TRH have been shown to be extra-pituitary in nature⁵, biochemical and neural mechanisms that might account for its pharmacological actions have not been elucidated. Redos et al.⁶ recently reported that ethanol causes a dose-dependent decline in cerebellar guanosine-3′,5′-monophosphate (cGMP) without significantly altering adenosine-3′,5′-monophosphate (cAMP). As blood ethanol content inversely paralleled cGMP levels, they postulated that the ataxia produced by ethanol may be due to alterations in cGMP in the cerebellum. Though these changes may also reflect a feedback mechanism in response to the drug, it was of some interest to determine if these ethanol actions on cGMP were affected by TRH. We report here that decreases in cerebellar cGMP induced by ethanol are antagonised by administration of TRH and that administration of TRH itself results in significant elevation in cerebellar cGMP. These alterations in cerebellar cGMP provide the first biochemical evidence of non-hormonal actions of this tripeptide.