Sircar R, Kim D
Laboratory for Developmental Neuroscience, Department of Psychiatry, Albert Einstein College of Medicine, Bronx, New York, USA.
J Pharmacol Exp Ther. 1999 Apr;289(1):54-65.
Evidence suggests the existence of genetic differences in cocaine sensitization in male rats. The present study was undertaken to investigate cocaine sensitization in female rats of genetically distinct inbred (Fischer 344 and Lewis) and outbred (Sprague-Dawley) strains. All female rats were bilaterally ovariectomized and randomly assigned to one of four experimental groups: 1) estradiol benzoate group, 2) progesterone group, 3) estradiol benzoate-plus-progesterone group, and 4) ovariectomized group. Additional controls included sham-operated female rats, female rats that received a single oil injection, and female rats that received repeated oil injections. To determine gender-related differences in the acute and chronic effects of cocaine, data obtained from female rats were compared with those from strain- and weight-matched male rats. Estradiol benzoate-plus-progesterone female rats showed greater locomotor effect in response to an acute dose of cocaine and had more robust sensitization in response to repeated cocaine than did male rats. The bilateral removal of ovaries abolished cocaine sensitization. In all strains of rats studied, progesterone alone did not alter the ovariectomy-induced attenuation of cocaine behavior, but estrogen alone restored cocaine-induced behavioral sensitization. There were significant strain effects on the degree of gonadal hormonal-induced modulation of cocaine sensitization in female rats. Female Lewis rats were extremely sensitive to repeated-cocaine effects, whereas the Fischer 344 female rats showed only marginal effects. The Sprague-Dawley rats ranked intermediate in their behavioral sensitivity. The present study strongly supports the hypothesis that female rats are more sensitive to both acute and chronic behavioral effects of cocaine than are male rats and that the effects are strain dependent. It also shows that estrogen plays an important role in the increased sensitivity of female rats to cocaine sensitization. Together, these data indicate significant interactions between ovarian steroid hormones and genetic factors in cocaine-induced behavioral effects.
有证据表明雄性大鼠在可卡因敏感化方面存在基因差异。本研究旨在调查基因不同的近交系（Fischer 344和Lewis）和远交系（Sprague-Dawley）雌性大鼠的可卡因敏感化情况。所有雌性大鼠均双侧卵巢切除，并随机分配到四个实验组之一：1）苯甲酸雌二醇组，2）孕酮组，3）苯甲酸雌二醇加孕酮组，4）卵巢切除组。额外的对照组包括假手术雌性大鼠、接受单次油注射的雌性大鼠和接受重复油注射的雌性大鼠。为了确定可卡因急性和慢性作用中的性别相关差异，将雌性大鼠获得的数据与品系和体重匹配的雄性大鼠的数据进行比较。与雄性大鼠相比，苯甲酸雌二醇加孕酮的雌性大鼠对急性剂量可卡因的运动反应更大，对重复给予可卡因的敏感化更强。双侧卵巢切除消除了可卡因敏感化。在所有研究的大鼠品系中，单独使用孕酮不会改变卵巢切除引起的可卡因行为减弱，但单独使用雌激素可恢复可卡因诱导的行为敏感化。性腺激素对雌性大鼠可卡因敏感化的调节程度存在显著的品系效应。雌性Lewis大鼠对重复给予可卡因的效应极其敏感，而Fischer 344雌性大鼠仅表现出轻微效应。Sprague-Dawley大鼠的行为敏感性居中。本研究有力地支持了以下假设：雌性大鼠对可卡因的急性和慢性行为效应比雄性大鼠更敏感，且这些效应取决于品系。研究还表明，雌激素在雌性大鼠对可卡因敏感化的敏感性增加中起重要作用。总之，这些数据表明卵巢甾体激素与基因因素在可卡因诱导的行为效应中存在显著相互作用。
