Effects of Chronic THC in Adolescence

描述（由申请人提供）：个体在青春期（成熟的重要时期）滥用药物可能会增加他们对滥用药物对中枢神经系统（CNS）影响的脆弱性。本申请汇集了多学科研究人员小组，以检查卵巢激素的存在和长期 A9-THC 给药引起的药效学变化是否会改变药物的主观效果，增加女性滥用药物的脆弱性，并改变她们的学习能力。长期暴露于 A9-THC 是特别令人感兴趣的，因为这种非法药物被青少年广泛滥用，而卵巢激素的存在或不存在作为辅助因子也令人感兴趣，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）这些研究人员发表的数据表明，卵巢激素雌激素可以减轻 A9-THC 对雌性大鼠学习的有害影响，并改变大麻素配体在大脑区域的结合。对于学习至关重要，例如海马体。出于这些相同的原因，并且由于关于 A9-THC 使用雌性模型的影响的数据很少，所有计划的行为实验都将使用雌性大鼠，并涉及 A9-THC 治疗受试者中是否存在卵巢激素。此外，每个行为组的受试者将被牺牲，以检查相关大脑区域大麻素受体和内源性大麻素水平的潜在变化。更具体地说，这笔拨款的目的将确定：1）与青春期未接受药物的性腺完整或卵巢切除的雌性大鼠相比，在性腺完整的雌性大鼠中进行青春期 A9-THC 给药会改变成年后对 A9-THC 急性行为影响的敏感性； 2) 与青春期未曾接受药物的性腺完整或卵巢切除的雌性大鼠相比，性腺完整的雌性大鼠青春期前后的 A9-THC 给药将改变成年后大麻素系统对 A9-THC 急性攻击的药效反应； 3) 性腺完整的雌性大鼠从青春期到成年期的 A9-THC 给药会对学习产生影响，这与性腺完整或卵巢切除的雌性大鼠所产生的效果不同，后者直到青春期后才开​​始长期给药 A9-THC； 4) 与性腺完整或卵巢切除的雌性大鼠（其直到青春期后才开​​始长期施用 A9-THC）相比，从青春期到成年期对性腺完整的雌性大鼠施用 A9-THC 将改变大麻素系统的内源性反应。这些实验的数据将共同证明青春期期间的药物滥用和荷尔蒙状态如何可能永久改变大脑功能以及随后滥用 A9-THC 的可能性。

DESCRIPTION (provided by applicant): 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-THC 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-naive 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-naive 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.