Interactive Effects of Cannabinoids and Sex Hormones in Females

描述(申请人提供)：最近的调查表明，普通人群中大麻的使用率已高达7%。此外，出于医疗目的，大麻现在已在18个州和哥伦比亚特区合法化，这导致了人们认为这种非法药物对健康的风险可能是最小的。然而，这一点尚未得到证实，确实需要了解使用和滥用大麻类药物的所有生物医学后果。本申请汇集了一个多学科的研究团队，以检查卵巢激素的存在和急性或慢性9-四氢大麻酚(9-THC)的给药是否减少了女性的记忆缺陷。长期服用9-THC特别令人感兴趣，因为这种伊利西药物被广泛长期滥用，而且大多数潜在的治疗用途也可能需要长期服用。卵巢激素的存在或不存在是一个令人感兴趣的辅助因素，因为：1)卵巢激素对认知功能有直接和间接的影响，以及2)这些研究人员发表的数据表明，卵巢激素雌二醇可以对抗9-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(如海马体)中大麻素配体的结合。由于同样的原因，而且关于9-THC对雌性动物的影响的数据仍然很少，所有计划中的行为实验都将使用雌性大鼠，并涉及9-THC处理的受试者中卵巢激素的存在或不存在。此外，每个治疗组的受试者将被牺牲以检查潜力 相关脑区大麻素或雌激素受体的变化。我们的总体假设是，17�-雌二醇可以减弱9-THC对成年雌性大鼠记忆的急性和慢性影响，海马区也存在类似的衰减，以影响其在记忆中的活动和作用。为了解决这一假设，特定目标1的实验将确定卵巢激素是否减弱9-THC对记忆的急性干扰效应。以类似的方式，特定的目标2将确定雌二醇是否可以减弱9-THC对记忆的慢性影响，并促进对这些影响的耐受性的发展。最后，特定的目标3将确定雌二醇是否可以减弱9-THC对海马区活动的干扰效应。这些数据完成后，将证明女性体内的雌激素可以减弱�9-THC对记忆的急性和慢性影响，以及雌激素受体(ER)信号减少大脑中对记忆编码至关重要的区域的大麻素受体(CBR)信号。

DESCRIPTION (provided by applicant): Recent surveys have indicated that the rate of use of marijuana among the general population has increased to as high as 7%. Moreover, marijuana has now been legalized in 18 states and the District of Columbia for medical purposes, which has contributed to the notion that this illicit drug may pose the least health-related risks. This has not been verified, however, and there is a real need to understand all of the biomedical consequences of cannabinoid use and abuse. The present application brings together a multidisciplinary team of investigators to examine whether the presence of ovarian hormones and acute or chronic 9- tetrahydrocannabinol ( 9-THC) administration reduces memory deficits in females. Chronic administration of 9-THC is of particular interest because this illici drug is widely abused chronically and most of the potential therapeutic uses may also require chronic administration. The presence or absence of ovarian hormones is of interest as a cofactor because: 1) ovarian hormones have direct and indirect influences on cognitive function, and 2) published data generated by these investigators indicate that the ovarian hormone estradiol can antagonize the detrimental effects of 9-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 still a paucity of data regarding the effects of 9-THC on female animals, all of the planned behavioral experiments will use female rats and involve the presence or absence of ovarian hormones in 9- THC-treated subjects. In addition, the subjects in each treatment group will be sacrificed to examine potential changes in cannabinoid or estrogen receptors in relevant brain areas. Our overall hypothesis is that 17 �- estradiol can attenuate both the acute and chronic effects of 9-THC on memory in adult female rats and that a similar attenuation occurs in the hippocampus to affect its activity and role in memory. To address this hypothesis, experiments in Specific Aim 1 will determine whether ovarian hormones attenuate the acute disruptive effects of 9-THC on memory. In a similar manner, Specific Aim 2 will determine whether estradiol can attenuate the chronic effects of 9-THC on memory and facilitate the development of tolerance to those effects. Finally, Specific Aim 3 will determine whether estradiol can attenuate the disruptive effects of 9- THC on hippocampal activity. When completed, these data will demonstrate that estrogens in females can attenuate both the acute and chronic effects of �9-THC on memory, and that estrogen receptor (ER) signaling reduces cannabinoid receptor (CBR) signaling in brain areas critical for memory encoding.