The goal of the proposed research is to delineate a mechanistic role for the neurosteroid allopregnanolone (ALLOP) at the level of the ventral tegmental area (VTA) on ethanol self-administration patterns and brain reward pathway activation. Gamma-aminobutyric acid type A (GABA-A) receptors in the VTA are thought to mediate, in part, ethanol's subjective and motivational effects; presumably via modulation of the mesolimbic dopaminergic projection from the VTA to the nucleus accumbens (NAc). The neurosteroid ALLOP, an endogenous positive modulator of GABA-A receptors, has been demonstrated to potentiate maintained and reinstated operant responding for ethanol as well as augment ethanol self-administration. The first specific aim will determine the effects of manipulating the levels and metabolism (sulfonation) of ALLOP within the VTA on established ethanol consumption patterns in mice. Studies in the second research aim will assess the impact of VTA-applied ALLOP on NAc DA and will evaluate ALLOP's interaction with ethanol-stimulated changes in extracellular NAc DA levels. Results from these experiments will provide valuable insights into the mechanisms underlying neurosteroid modulation of ethanol intake and reward.
