Janis G C, Devaud L L, Mitsuyama H, Morrow A L
Bowles Center for Alcohol Studies, Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill 27599-7178, USA.
Alcohol Clin Exp Res. 1998 Dec;22(9):2055-61.
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 anticonvulsant effects of the endogenous GABA(A) receptor modulator, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP). Alterations in endogenous, cerebral cortical levels of 3alpha,5alpha-THP during alcohol withdrawal could contribute to the observed sensitization to 3alpha,5alpha-THP. Therefore, this study investigated plasma and brain levels of 3alpha,5alpha-THP, progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3alpha,5alpha-THP) and 3alpha,5alpha-THP levels were unchanged in alcohol-dependent animals. Cerebral cortical levels of 3alpha,5alpha-THP decreased in dependent male animals, but not in dependent female rats. During alcohol withdrawal, plasma corticosterone and progesterone levels increased in male, but not female rats. However, neither plasma nor cerebral cortical 3alpha,5alpha-THP levels were altered from control levels in male or female rats during alcohol withdrawal. Plasma and brain levels of 3alpha,5alpha-THP were markedly higher in female compared with male rats. Cerebral cortical levels of 3alpha,5alpha-THP during the diestrus phase of the estrus cycle were approximately 4 to 6 ng/g, a concentration that may approach physiological relevance. These findings suggest that sensitization to 3alpha,5alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3alpha,5alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdrawal in male rats may underlie gender differences in allopregnanolone sensitivity during ethanol withdrawal.
长期饮酒（乙醇）会导致酒精耐受性的发展以及对某些苯二氮䓬类药物和巴比妥类药物的交叉耐受性。相比之下，经历酒精戒断的大鼠对内源性GABA(A)受体调节剂3α-羟基-5α-孕烷-20-酮（3α,5α-THP）的抗惊厥作用敏感。酒精戒断期间内源性大脑皮质3α,5α-THP水平的变化可能导致对3α,5α-THP的敏感性增加。因此，本研究调查了大鼠酒精依赖和戒断期间血浆和大脑中3α,5α-THP、孕酮和皮质酮的水平。酒精依赖动物的血浆皮质酮、孕酮（3α,5α-THP的前体）和3α,5α-THP水平没有变化。依赖酒精的雄性动物大脑皮质3α,5α-THP水平降低，但依赖酒精的雌性大鼠没有降低。在酒精戒断期间，雄性大鼠的血浆皮质酮和孕酮水平升高，而雌性大鼠没有。然而，在酒精戒断期间，雄性或雌性大鼠的血浆和大脑皮质3α,5α-THP水平与对照水平相比均未改变。雌性大鼠的血浆和大脑3α,5α-THP水平明显高于雄性大鼠。发情周期间情期大脑皮质3α,5α-THP水平约为4至6 ng/g，这一浓度可能接近生理相关性。这些发现表明，酒精戒断期间对3α,5α-THP的敏感性增加并非由雄性或雌性大鼠大脑中内源性3α,5α-THP水平升高介导。然而，雄性大鼠酒精戒断期间循环皮质酮和孕酮水平的升高可能是酒精戒断期间别孕烷醇酮敏感性性别差异的基础。
