The Role of Allopregnanolone and Ethanol in Brain

University Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

The objective of this research proposal is to examine the role of allopregnanolone in ethanol action in the brain. This proposal builds on previous work that establishes allopregnanolone as a modulator of some behavioral and electrophysiological effects of ethanol. Acute ethanol exposure has the ability to induce physiologically relevant allopregnanolone levels in rat cortex. In vivo and in vitro models will be used to test ethanol's effect on peripheral steroid sources as well as central glial neurosteroid sources. Glia are the main site of neurosteroid biosynthesis in the brain. Furthermore, cloned steroid biosynthetic enzymes will be used to test directly the effect of ethanol on the neurosteroid biosynthetic pathway. In combination, these studies will determine the source of ethanol-induced neurosteroids as well as indicate the mechanism used to induce neurosteroid levels. There is evidence to suggest that the GABAergic neurosteroid allopregnanolone is important in modulating the acquisition of ethanol drinking behavior, tolerance to ethanol, and some ethanol induced behaviors. By uncovering the mechanism through which ethanol influences cortical allopregnanolone levels, the field will gain a greater understanding of the underlying biological basis of alcoholism and its related disorders. Also, because allopregnanolone is an endogenous compound, it is a very viable target for therapeutic intervention without the plethora of side effects the characterize many psychoactive drug treatments.