Effects of Chronic THC in Adolescence

个人在青春期（成熟的重要时期）滥用药物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。本申请汇集了多学科 研究小组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 会改变药物的主观效果，增加女性对药物的脆弱性 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，因为这种非法物质 该药物被青少年广泛滥用，而卵巢激素的存在与否作为辅助因子值得关注 因为：1）卵巢激素可能对成熟有独立或相互作用的影响，2）已发表的数据 这些研究人员得出的结果表明，卵巢激素雌激素可以减轻 A9- 的有害影响 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。出于同样的原因，并且由于缺乏有关 A9- 效果的数据 THC 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 A9-THC 治疗受试者缺乏卵巢激素。此外，每个行为组中的受试者将 牺牲以检查相关大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是否：1) 青春期前后的 A9-THC 管理 与相比，性腺完整的雌性大鼠成年后对 A9-THC 的急性行为影响的敏感性会发生变化 青春期未曾接触过药物的性腺完整或卵巢切除的女性； 2) 青春期A9- 在性腺完整的雌性大鼠中施用 THC 将改变大麻素系统的药效反应 与性腺完整或卵巢切除的女性相比，成年后 A9-THC 的急性挑战 青春期未曾接触过药物； 3) 从青春期到成年，在性腺完整的情况下施用 A9-THC 雌性老鼠对学习的影响不同于性腺完整或性腺完整的老鼠。 直到青春期后才开始长期服用 A9-THC 的卵巢切除女性；和 4) A9-THC 对性腺完整的雌性大鼠从青春期到成年期的给药将改变性腺完整的雌性大鼠的内源性反应 与长期服用性腺完整或卵巢切除的女性相比，大麻素系统 A9-THC 直到青春期后才开始。总而言之，这些实验的数据将证明药物如何 青春期的滥用和荷尔蒙状态可能会永久改变大脑功能以及随后的后果 A9-THC 的滥用。

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.