Effects of Chronic THC in Adolescence

描述（由申请人提供）：一个人在青春期，一个重要的成熟时期滥用药物，可能会增加他们对滥用药物的中枢神经系统（CNS）影响的脆弱性。目前的申请汇集了一个多学科的研究小组，以检查卵巢激素和慢性A9-THC给药是否会改变药物的主观效果，增加女性对药物滥用的脆弱性，并改变她们的学习能力。长期接触a9 -四氢大麻酚是特别有趣的，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缺乏作为一个辅助因素是有趣的，因为：1)卵巢激素可能对成熟有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中对学习至关重要的区域（如海马）的结合。出于同样的原因，由于缺乏关于A9-四氢大麻酚对雌性模型的影响的数据，所有计划的行为实验都将使用雌性大鼠，并涉及A9-四氢大麻酚治疗对象卵巢激素的存在或缺乏。此外，每个行为组的受试者将被处死，以检测大麻素受体和内源性大麻素在相关脑区水平的潜在变化。更具体地说，这项资助的目的将确定：1)与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在青春期前后给予a9 -四氢大麻酚是否会改变它们成年后对a9 -四氢大麻酚急性行为影响的敏感性；2)青春期前后性腺完整的雌性大鼠与性腺完整或卵巢切除的青春期未用药的雌性大鼠相比，青春期前后给药A9-THC会改变成年后大麻素系统对A9-THC急性刺激的药效学反应；3)性腺完整的雌性大鼠从青春期到成年期服用A9-THC对学习的影响不同于性腺完整或去卵巢的雌性大鼠，后者直到青春期后才开始长期服用A9-THC；4)与性腺完整或卵巢切除的雌性大鼠相比，从青春期到成年期给药A9-THC会改变大麻素系统的内源性反应，而雌性大鼠直到青春期后才开始长期给药A9-THC。综上所述，这些实验的数据将证明青少年时期的药物滥用和激素状况如何永久性地改变大脑功能和随后滥用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.