COCAINE ABUSE: EFFECTS ON BRAIN SEXUAL DIFFERENTIATION

在过去几年中，可卡因的滥用急剧增加， 多年来，导致越来越多的成瘾婴儿出生 在怀孕期间使用可卡因的母亲 现有证据表明， 长期的行为影响将在这些孩子身上变得明显， 变老 动物研究的初步证据表明， 在暴露于辐射的男性中，相关行为可能在某种程度上女性化。 药物在围产期的发展。 我们建议进行的研究，将设法确定 生殖和非生殖的性二态行为， 在产前暴露于可卡因的雄性大鼠中雌性化，和/或 出生后神经行为性别分化的关键时期。 将研究的行为将包括男性和女性生殖 行为潜力、气味标记和糖精偏好。 长期 可卡因对下丘脑-垂体-性腺轴的影响将是 通过研究LH的脉冲式释放、LH的正反馈来检验 对雌激素和孕激素的反应，精子的形态学研究， 出生前后睾丸激素的激增 我们和其他人以前的研究表明，去甲肾上腺素能 系统是大脑性别分化的重要调节器。 在某种程度上，这是由于去甲肾上腺素抑制雌二醇的能力 下丘脑核的掺入。 可可碱增强去甲肾上腺素能 通过其阻止突触再摄取的能力来抑制活性。 初步 申请中描述的数据表明，可卡因可以显著地 第1天抑制雌二醇下丘脑核掺入 出生后 这种影响似乎是负责不完整的 行为的男性化，我们已经观察到n名男性在产前暴露于 可卡因 本研究的中长期目标是 可卡因改变HPG轴的程度的表征， 女性化男性行为以及开始定义的机制， 这一点已经实现了。 预计这些信息将 重要的是制定最终的治疗策略，以克服这种 对产前接触可卡因的儿童的影响。

Recreational use of cocaine has increased dramatically in the past few years, resulting in a an increasing number of addicted infants being born to mothers using cocaine during pregnancy. Present evidence indicates that long-term behavioral effects will become evident in these children as they grow older. Preliminary evidence from animal studies indicated that sex related behaviors may be feminized to some degree in males exposed to the drug during perinatal development. The studies we have proposed will seek to determine the extent to which reproductive and non-reproductive sexually dimorphic behaviors are feminized in male rats exposed to cocaine during the prenatal and/or postnatal critical periods for neurobehavioral sexual differentiation. Behaviors to be studied will include masculine and feminine reproductive behavior potentials, scent marking and saccharin preference. The long-term effect of cocaine on the hypothalamic-pituitary-gonadal axis will be examined by studying the pulsatile release of LH, the positive LH feedback response to estrogen and progesterone, morphological studies of sperm, and the pre- and postnatal surge of testosterone. Previous work by ourselves and others has shown that the noradrenergic system is an important modulator of sexual differentiation of the brain. In part, this is due to the ability of norepinephrine to inhibit estradiol incorporation if hypothalamic nuclei. Cocaine enhances noradrenergic activity through its ability to block reuptake at the synapse. Preliminary data described in the application indicate that cocaine can significantly inhibit hypothalamic nuclear incorporation of estradiol on day 1 postnatally. Such an effect appears to be responsible for the incomplete masculinization of behavior we have observed n males exposed prenatally to cocaine. The intermediate and long-term goals of this study are the characterization of the extent to which cocaine will alter the HPG axis and feminize male behavior as well as to begin to define the mechanisms through which this accomplished. It is expected that such information will be of importance in devising eventual treatment strategies to overcome such effects in children prenatally exposed to cocaine.