Interactive Effects of Cannabinoids and Sex Hormones in Females

大麻素和性激素对女性的相互作用

• 批准号: 8827986
• 负责人: PETER J WINSAUER
• 金额: $ 32.04万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827986
• 关键词: ATP phosphohydrolase; Acquired Immunodeficiency Syndrome; Acute; Address; Adolescence; Adult; Affect; Age; Animals; Area; Attenuated; Behavioral; Binding; Brain; Brain-Derived Neurotrophic Factor; CREB-binding protein; CREB1 gene; Cachexia; Cannabinoids; Chronic; Complex; Complication; Corpus striatum structure; Cyclic AMP; Data; Development; Disease; District of Columbia; Estradiol; Estrogen Receptors; Estrogens; Female; General Population; Genetic Transcription; Glaucoma; Goals; Gonadal Steroid Hormones; Grant; Health; Heat-Shock Response; Hippocampus (Brain); Homologous Gene; Hormones; Illicit Drugs; Learning; Ligands; Long-Term Effects; Malignant Neoplasms; Marijuana; Marijuana Smoking; Medical; Memory; Memory impairment; Molecular; Molecular Chaperones; Multiple Sclerosis; Neuronal Plasticity; Ovarian hormone; Pharmaceutical Preparations; Play; Process; Proteins; Proteomics; Publishing; Rattus; Receptor Signaling; Reporting; Research; Research Personnel; Response Elements; Risk; Role; Signal Transduction; Signaling Protein; Site; Surveys; Synapses; Synaptic plasticity; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Uses; Time; Work; attenuation; behavioral study; cannabinoid receptor; cofactor; cognitive function; critical period; drug of abuse; human CREBBP protein; interest; marijuana use; memory encoding; memory process; multidisciplinary; palliative; public health relevance; receptor; receptor sensitivity; research study; restoration; sex

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.

描述（由申请人提供）：最近的调查表明，普通人群中大麻的使用率已高达7%。此外，大麻现已在18个州和哥伦比亚特区合法化，用于医疗目的，这促使人们认为这种非法药物可能造成最小的健康风险。然而，这一点尚未得到证实，而且真实的需要了解大麻素使用和滥用的所有生物医学后果。本申请汇集了多学科的研究人员团队，以检查卵巢激素和急性或慢性9-四氢大麻酚（9-THC）施用的存在是否减少女性的记忆缺陷。9-THC的长期给药是特别令人感兴趣的，因为这种非法药物被广泛长期滥用，并且大多数潜在的治疗用途也可能需要长期给药。卵巢激素的存在或不存在作为辅助因子是令人感兴趣的，因为：1）卵巢激素对认知功能有直接和间接的影响，和2）由这些研究人员产生的公开数据表明，卵巢激素雌二醇可以拮抗9-羟色胺的有害作用，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，并且由于仍然缺乏关于9-THC对雌性动物的影响的数据，所有计划的行为实验都将使用雌性大鼠，并涉及9-THC治疗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处死，以检查潜在的 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 β-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，并且在海马中发生类似的衰减，以影响其在记忆中的活性和作用。为了解决这个假设，具体目标1中的实验将确定卵巢激素是否减弱9-THC对记忆的急性破坏作用。以类似的方式，具体目标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，具体目标3将确定雌二醇是否可以减弱9- THC对海马活动的破坏性影响。完成后，这些数据将证明女性中的雌激素可以减弱9-THC对记忆的急性和慢性影响，并且雌激素受体（ER）信号传导减少了对记忆编码至关重要的大脑区域中的大麻素受体（CBR）信号传导。