Effects of Chronic THC in Adolescence

描述（由申请人提供）：个体在青春期（一个重要的成熟期）滥用药物，可能会增加其对滥用药物的中枢神经系统（CNS）影响的脆弱性。本申请汇集了一个多学科的研究人员团队，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影响，增加女性对药物滥用的脆弱性，并改变她们的能力学习。长期暴露于A9-THC特别令人感兴趣，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素是令人感兴趣的，因为：1）卵巢激素可能对成熟具有独立或交互影响，2）这些研究人员产生的公开数据表明，卵巢激素雌激素可以减弱A9- 10的不利影响。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（如海马体）中大麻素配体的结合。由于这些相同的原因，并且由于使用雌性模型的A9- THC的影响的数据缺乏，所有计划的行为实验将使用雌性大鼠，并且涉及A9-THC治疗的受试者中卵巢激素的存在或不存在。此外，每个行为组的受试者将被处死，以检查大麻素受体和相关脑区内源性大麻素水平的潜在变化。更具体地说，该资助的目的将确定：1）与青春期未用药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给予青春期前后的A9-THC是否会改变它们作为成年人对A9-THC的急性行为效应的敏感性; 2）在性腺完整的雌性大鼠中给予青春期前后的A9- THC将改变大麻素系统对A9- THC的急性攻击的药效学反应。与青春期未接受过药物治疗的性腺完整或卵巢切除女性相比，成年时的THC; 3）A9-在性腺完整的雌性大鼠中，从青春期到成年期给予THC将对学习产生与在性腺完整或卵巢切除的雌性大鼠中产生的那些不同的影响，A9-THC直到青春期后才开始;和4）当与性腺完整或卵巢切除的雌性大鼠（其A9-THC的长期施用直到青春期后才开始）相比时，在性腺完整的雌性大鼠中从青春期到成年的A9-THC施用将改变大麻素系统的内源性反应。总之，这些实验的数据将证明青春期的药物滥用和激素状态如何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.