Grant Kathleen A, Helms Christa M, Rogers Laura S M, Purdy Robert H
Department of Behavioral Neuroscience, Oregon Health and Science University, Beaverton, OR 97006-6448, USA.
J Pharmacol Exp Ther. 2008 Jul;326(1):354-61. doi: 10.1124/jpet.108.137315. Epub 2008 Apr 24.
Positive modulation of GABA(A) and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3alpha,5alpha-P), pregnanolone (3alpha,5beta-P), epiallopregnanolone (3beta,5alpha-P), and epipregnanolone (3beta,5beta-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3alpha,5beta-P HS)], and a structurally similar, adrenally derived steroid [3alpha-hydroxy-5-androstan-17-one (3alpha,5alpha-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3alpha-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3beta-hydroxysteroids and 3alpha,5beta-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3alpha,5beta-P and 3alpha,5alpha-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5beta-reduced isomer (3alpha,5beta-P), the 5alpha isomer of pregnanolone (3alpha,5alpha-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3alpha,5beta-P- and 3alpha,5alpha-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3alpha,5alpha-P.
γ-氨基丁酸A（GABA(A)）受体的正向调节和N-甲基-D-天冬氨酸受体的拮抗作用介导了乙醇的辨别刺激效应。内源性神经活性甾体产生与乙醇相似的效应，提示这些甾体可能调节乙醇成瘾。对4-孕烯-3,20-二酮（孕酮）的3-羟基代谢物C-3位的四种功能性酯异构体[别孕烷醇酮（3α,5α-P）、孕烷醇酮（3α,5β-P）、表别孕烷醇酮（3β,5α-P）和表孕烷醇酮（3β,5β-P）]、经内源性硫酸化修饰的甾体合成类似物[孕烷醇酮半琥珀酸酯（3α,5β-P HS）]以及一种结构相似的肾上腺源性甾体[3α-羟基-5-雄甾烷-17-酮（3α,5α-A，雄酮）]进行了评估，观察其在雄性（n = 9）和雌性（n = 8）食蟹猴（猕猴）中给药30或60分钟后是否具有类似乙醇的辨别刺激效应。这些食蟹猴经过训练，在30分钟预处理间隔后辨别1.0或2.0 g/kg乙醇（灌胃）。3α-羟基甾体完全替代了乙醇（80%的情况），而3β-羟基甾体和3α,5β-P HS很少替代乙醇（6%的情况）。不存在性别差异。与训练辨别2.0 g/kg乙醇的猴子相比，3α,5β-P和3α,5α-A在训练辨别1.0 g/kg乙醇的猴子中替代作用更强。与5β-还原异构体（3α,5β-P）相比，孕烷醇酮的5α异构体（3α,5α-P）替代乙醇的效力高3至40倍，但在训练辨别2.0 g/kg乙醇的雌性猴子中效力最低。数据表明，与较高剂量（2.0 g/kg）相比，较低剂量（1.0 g/kg）乙醇的辨别刺激效应在更大程度上由对3α,5β-P和3α,5α-A敏感的受体介导。此外，乙醇的辨别刺激效应似乎由对3α,5α-P特别敏感的结合位点的活性介导。
