Effects of Chronic THC in Adolescence

青少年时期是一个重要的成熟时期，如果在这一时期滥用药物， 滥用药物对中枢神经系统的影响。本申请汇集了多学科、多领域的技术人员。 一组研究人员检查卵巢激素的存在是否导致药效学变化， 长期服用A9-THC改变了药物的主观效果，增加了女性对药物的脆弱性。 药物滥用，改变他们的学习能力。长期暴露于A9-THG是特别令人感兴趣的，因为这是非法的。 药物被青少年广泛滥用，而卵巢激素的存在或缺乏是一个辅助因素 因为：1）卵巢激素可能对成熟产生独立或相互作用的影响; 2）已发表的数据 这些研究人员产生的结果表明，卵巢激素雌激素可以减弱A9- THC对雌性大鼠学习的影响，并改变对学习至关重要的大脑区域中大麻素配体的结合 比如海马体。由于这些相同的原因，并且因为关于A9的影响的数据很少， THC使用雌性模型，所有计划的行为实验将使用雌性大鼠，并涉及存在或 在A9-THC治疗的受试者中不存在卵巢激素。此外，每个行为组的受试者将被 处死以检查相关脑中大麻素受体和内源性大麻素水平的潜在变化 地区更具体地说，这笔赠款的目的将决定：1）青少年期A9-THC管理， 性腺完整的雌性大鼠将改变它们作为成年人对A9-THC的急性行为效应的敏感性， 对青春期未用药的性腺完整或卵巢切除的女性; 2）青春期前后的A9- 在性腺完整的雌性大鼠中给予THC将改变大麻素系统的药效学反应 与性腺完整或卵巢切除的雌性相比， 3）在性腺完整的人中，从青春期到成年期施用A9-THC， 雌性大鼠对学习的影响不同于性腺完整或 卵巢切除的女性，其A9-THC的长期施用直到青春期后才开始;和4）A9-THC 在性腺完整的雌性大鼠中，从青春期到成年期的给药将改变 与性腺完整或卵巢切除的女性相比， 的A9-THC没有-直到青春期后才开始。总之，这些实验的数据将证明药物如何 青少年时期的滥用和激素状态可能会永久改变大脑功能， 滥用A9-THC。

Drug abuse by an individual during adolescence, a significant period of maturation, may enhance their vulnerability to the central nervous system (CNS) effects of abused drugs. The present application brings together a multidisciplinary team of investigators to examine whether pharmacodynamic changes resulting from the presence of ovarian hormones and chronic A9-THC administration alters the subjective effects of the drug, increases the vulnerability of females to drug abuse, and changes their ability to learn. Chronic exposure to A9-THG is of particular interest because this illicit drug is widely abused by adolescents, while the presence or absence of ovarian hormones is of interest as a cofactor because: 1) ovarian hormones may have independent or interactive influences on maturation and 2) published data generated by these investigators indicate that the ovarian hormone estrogen can attenuate the detrimental effects of A9- THC on learning in female rats and alter the binding of cannabinoid ligands in brain areas that are critical for learning such as the hippocampus. For these same reasons, and because there is a paucity of data regarding the effects of A9- THC using female models, all of the planned behavioral experiments will use female rats and involve the presence or absence of ovarian hormones in A9-THC-treated subjects. In addition, subjects in each behavioral group will be sacrificed to examine potential changes in cannabinoid receptors and endogenous cannabinoid levels in relevant brain areas. More specifically, the aims of this grant will determine whether: 1) peri-adolescent A9-THC administration in gonadally intact female rats will alter their sensitivity as adults to the acute behavioral effects of A9-THC when compared to either gonadally intact or ovariectomized females that were drug-naTve during adolescence; 2) peri-adolescent A9- THC administration in gonadally intact female rats will alter the pharmacodynamic response of the cannabinoid system to acute challenge with A9-THC as an adult when compared to either gonadally intact or ovariectomized females that were drug-naTve during adolescence; 3) A9-THC administration from adolescence to adulthood in gonadally intact female rats will produce effects on learning that are different from those produced in either gonadally intact or ovariectomized females whose chronic administration of A9-THC did not start until post adolescence; and 4) A9-THC administration from adolescence to adulthood in gonadally intact female rats will alter the endogenous response of the cannabinoid system when compared to either gonadally intact or ovariectomized females whose chronic administration of A9-THC did-not start until post adolescence.. Together, data from these experiments will demonstrate how drug abuse and hormonal status during adolescence may permanently alter brain function and the liability of subsequent abuse of A9-THC.