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（申请人提供）：最近的调查表明，普通人群吸食大麻的比例已增至 7%，此外，大麻现已在 18 个州和哥伦比亚特区实现医疗用途合法化。这使得人们认为这种非法药物可能造成的健康相关风险最小，但这尚未得到证实，并且确实需要了解大麻素使用和滥用的所有生物医学后果。多学科结合在一起研究小组检查卵巢激素的存在以及急性或慢性 9-四氢大麻酚 (9-THC) 给药是否会减少女性的记忆缺陷，因为这种非法药物长期被广泛滥用，因此长期服用 9-THC 是否会减少女性的记忆缺陷。潜在的治疗用途可能还需要长期给药，卵巢激素的存在或不存在作为辅助因子很重要，因为：1）卵巢激素对认知功能有直接和间接的影响，2）已发表。这些研究人员产生的数据表明，卵巢激素雌二醇可以拮抗 9-THC 对雌性大鼠学习的不良影响，并改变对学习至关重要的大脑区域（例如海马体）中大麻素配体的结合。由于关于 9-THC 对雌性动物的影响的数据仍然很少，所有计划的行为实验都将使用雌性大鼠，并涉及 9-THC 处理的卵巢激素的存在或不存在此外，每个治疗组中的受试者将被牺牲以检查潜力。 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力的急性和慢性影响，并且海马体也会发生类似的减弱，从而影响其记忆力。为了解决这一假设，特定目标 1 中的实验将确定卵巢激素是否会以类似的方式减弱 9-THC 对记忆的急性破坏作用。 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 完成后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。 ，这些数据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，并且雌激素受体 (ER) 信号传导大麻素受体 (CBR) 信号传导对记忆编码至关重要的大脑区域。