Effects of Chronic THC in Adolescence

描述(申请人提供)：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团队，以检查卵巢激素和长期服用A9-THC引起的药效学变化是否改变了药物的主观效果，增加了女性对药物滥用的易感性，并改变了她们的学习能力。人们特别感兴趣的是长期接触A9-THC，因为这种非法药物在青少年中广泛滥用，而卵巢激素的存在或不存在是令人感兴趣的辅因，因为：1)卵巢激素对成熟期可能有独立或交互的影响；2)这些研究人员发表的数据表明，卵巢激素雌激素可以减弱A9-THC对雌性大鼠学习的不利影响，并改变大脑中对学习至关重要的区域，如海马区的大麻素配体的结合。由于同样的原因，而且由于缺乏关于A9-THC在雌性模型中的影响的数据，所有计划中的行为实验都将使用雌性大鼠，并涉及A9-THC治疗对象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牺牲，以检查相关脑区大麻素受体和内源性大麻素水平的潜在变化。更具体地说，这笔赠款的目的将决定：1)与青春期性腺完整或摘除卵巢的青春期未服药的雌性大鼠相比，青春期前后性腺完整的雌性大鼠服用A9-THC是否会改变它们成年后对A9-THC急性行为影响的敏感性；2)与青春期未服药的性腺完整或卵巢切除的雌性大鼠相比，青春期性腺未受损的雌性大鼠服用A9-THC是否会改变大麻系统对A9-THC急性挑战的药效反应；3)性腺完整的雌性大鼠从青春期到成年期给予A9-THC对学习产生的影响与性腺完整或卵巢切除的雌性大鼠不同，后者的长期给予A9-THC直到青春期后才开始；4)性腺完整的雌性大鼠从青春期到成年期给予A9-THC将改变大麻系统的内源性反应，与性腺完整或卵巢切除的雌性大鼠相比，后者的长期给予A9-THC直到青春期后才开始。总之，这些实验的数据将展示青春期药物滥用和荷尔蒙状态如何永久改变大脑功能和随后滥用A9-THC的易感性。

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.