Effects of Chronic THC in Adolescence

一个人在青春期滥用药物，这是一个重要的成熟期，可能会增加他们的脆弱性 滥用药物对中枢神经系统(CNS)的影响。本申请汇集了一个多学科的 一组调查人员检查卵巢激素的存在是否会导致药效学变化 长期服用A9-THC改变了药物的主观效果，增加了女性患上 滥用药物，并改变他们的学习能力。长期接触A9-THG特别令人感兴趣，因为这是非法的 青少年普遍滥用药物，而卵巢激素的存在或不存在是一个令人感兴趣的辅助因素 因为：1)卵巢激素可能对成熟有独立或交互的影响；2)已公布的数据 由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的有害影响- THC对雌性大鼠学习的影响以及改变大脑中对学习至关重要的区域中大麻素配体的结合 比如海马体。出于同样的原因，也因为关于A9的影响的数据很少- 使用雌性模型，所有计划的行为实验都将使用雌性大鼠，并涉及存在或 接受A9-THC治疗的受试者缺乏卵巢激素。此外，每个行为组的受试者将被 以检测相关脑区大麻素受体和内源性大麻素水平的潜在变化 区域。更具体地说，这笔赠款的目的将决定：1)青春期前A9-THC是否在 与性腺完整的雌性大鼠相比，成年雌性大鼠对A9-THC的急性行为影响的敏感度会发生变化 在青春期接受药物治疗的性腺完整或卵巢切除的女性；2)青春期前的A9- 性腺完整的雌性大鼠给药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，成年后A9-THC的急性挑战 3)从青春期到成年期的性腺完整的A9-THC给药 雌性大鼠将对学习产生不同于性腺完整或 卵巢切除的女性，其长期服用A9-THC直到青春期后才开始；以及4)A9-THC 性腺完整雌性大鼠从青春期到成年期给药将改变内源性反应 与性腺完整或卵巢切除的女性相比，这些女性长期服用大麻 A9-THC直到青春期后才开始..总之，来自这些实验的数据将证明药物是如何 青春期的滥用和荷尔蒙状态可能会永久性地改变大脑功能和随后的 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.