GABAergic neuroactive steroids contribute to ethanol action in the CNS

The mechanisms of ethanol action and tolerance that involve GABA-A receptors are not completely understood. Our group has delineated a specific effect of ethanol on the synthesis and translocation of steroidogenic acute regulatoryoprotein and the affinity constant of the biosynthetic enzyme 3alpha-hydroxysteroid dehydrogenase that result in dramatic elevations in GABAergic neuroactive steroids in rodent plasma and brain. These steroids modulate specific ethanol actions including electrophysiological responses in the medial septum and pyramidal cells, anticonvulsion, hypnosis and the impairment of spatial learning. The effect of ethanol on allopregnanolone levels can be attenuated by pre-administration of finasteride and eliminated by adrenalectomy. In both cases, the behavioral effects of ethanol are attenuated. Administration of the immediate precursor of allopregnanolone to adrenalectomized rats restores the hypnotic effects of ethanol. These studies clearly support a role for neuroactive steroids in the GABAmimetic effects of ethanol in rodents. Studies in human and non-human primates are needed to establish the role of neurosteroids in these species, since primate steroid pathways differ from rodents.