Effects of chronic ethanol consumption and withdrawal on the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in male and female rats

Prolonged alcohol (ethanol) consumption leads to the development of alcohol tolerance and cross-tolerance to some benzodiazepines and barbiturates. In contrast, rats undergoing alcohol withdrawal are sensitized to the anticon vulsant effects of the endogenous GABA, receptor modulator, 3 alpha-hydroxy -5 alpha-pregnan-20-one (3 alpha,5 alpha-THP). Alterations in endogenous, c erebral cortical levels of 3 alpha,5 alpha-THP during alcohol withdrawal co uld contribute to the observed sensitization to 3 alpha,5 alpha-THP, Theref ore, this study investigated plasma and brain levels of 3 alpha,5 alpha-THP , progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3 alpha,5 alpha-THP) and 3 alpha,5 alpha-THP levels were unchanged in alcohol-depende nt animals. Cerebral cortical levels of 3 alpha,5 alpha-THP decreased in de pendent male animals, but not in dependent female rats. During alcohol with drawal, plasma corticosterone and progesterone levels increased in male, bu t not female rats, However, neither plasma nor cerebral cortical 3 alpha,5 alpha-THP levels were altered from control levels in male or female rats du ring alcohol withdrawal. Plasma and brain levels of 3 alpha,5 alpha-THP wer e markedly higher in female compared with male rats. Cerebral cortical leve ls of 3 alpha,5 alpha-THP during the diestrus phase of the estrus cycle wer e similar to 4 to 6 ng/g, a concentration that may approach physiological r elevance. These findings suggest that sensitization to 3 alpha,5 alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3 alpha,5 alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdr awal in male rats may underlie gender differences in allopregnanolone sensi tivity during ethanol withdrawal.