Petralia S M, Jahagirdar V, Frye C A
Department of Psychology, The University at Albany, SUNY, Albany, NY 12222, USA.
J Neuroendocrinol. 2005 Sep;17(9):545-52. doi: 10.1111/j.1365-2826.2005.01342.x.
In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Central 3alpha,5alpha-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3beta-hydroxysteroid dehydrogenase, and subsequently reduced to 3alpha,5alpha-THP. We hypothesize that, in the VTA, formation of 3alpha,5alpha-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin+finasteride, or vehicle on lordosis and midbrain and plasma 3alpha,5alpha-THP levels were examined. In Experiment 3, we investigated whether infusions of 3alpha,5alpha-THP to the VTA reinstated lordosis and midbrain 3alpha,5alpha-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin+finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3alpha,5alpha-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3alpha,5alpha-THP to the VTA restored lordosis and midbrain 3alpha,5alpha-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3alpha,5alpha-THP are important for mediating lordosis of rats.
在腹侧被盖区（VTA），5α-孕烷-3α-醇-20-酮（3α,5α-四氢孕酮）可促进大鼠的脊柱前凸。中枢3α,5α-四氢孕酮是由外周孕酮（来自卵巢和/或肾上腺）通过5α-还原酶和3α-羟基类固醇氧化还原酶（3α-HSOR）的顺序酶活性代谢产生的。此外，在神经胶质细胞中，胆固醇通过细胞色素P450侧链裂解酶（P450scc）转化为孕烯醇酮，然后通过3β-羟基类固醇脱氢酶代谢为孕酮，随后还原为3α,5α-四氢孕酮。我们假设，在VTA中，通过代谢和生物合成形成3α,5α-四氢孕酮对于促进雌性大鼠的脊柱前凸是必要的。在实验1中，自然接受交配的大鼠双侧VTA注射细胞色素P450侧链裂解酶抑制剂地高辛（1微克/侧）、5α-还原酶抑制剂非那雄胺（10微克/侧）、地高辛（1微克/侧）+非那雄胺（10微克/侧）或溶剂，3小时后测试其脊柱前凸情况。在实验2中，研究了VTA注射地高辛、非那雄胺、地高辛+非那雄胺或溶剂对脊柱前凸以及中脑和血浆3α,5α-四氢孕酮水平的影响。在实验3中，我们研究了向VTA注射3α,5α-四氢孕酮是否能在给予抑制剂后恢复脊柱前凸和中脑3α,5α-四氢孕酮水平。与溶剂相比，VTA注射地高辛、非那雄胺或地高辛+非那雄胺显著且相似地降低了脊柱前凸和中脑3α,5α-四氢孕酮水平，但未降低血浆3α,5α-四氢孕酮水平。在接受抑制剂注射后，向VTA注射3α,5α-四氢孕酮恢复了脊柱前凸和中脑3α,5α-四氢孕酮水平。这些数据表明，在VTA中，孕酮的中枢生物合成以及孕酮（来自中枢和/或外周来源）代谢为3α,5α-四氢孕酮对于介导大鼠的脊柱前凸都很重要。
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