Cocaine & Steroids: Brain Vascular & Behavioral Effects

描述（由申请人提供）：长期使用可卡因会导致大脑异常和认知功能障碍，这可能会损害吸毒者抵抗进一步吸毒的能力，并降低治疗干预的疗效。与可卡因相关的脑功能障碍的严重程度在女性中比男性要低。此外，可卡因滥用治疗对妇女的好处似乎多于男子。这些性别差异具有重要的治疗意义，因为它们表明雌激素具有保护作用。因此，雌激素（或相关化合物）可能具有治疗用途，以防止脑血管功能障碍。 皮质醇减少脑血流量的能力可能在脑功能障碍的发展中起关键作用。雌激素已被证明可以迅速改善血管功能，而孕酮和睾酮则会迅速降低血管功能。因此，激素对血管的影响可能是可卡因对大脑影响的性别差异的原因。我们试图确定是否雌激素，孕激素和睾酮改变可卡因的药代动力学和可卡因的急性脑血管收缩作用。 我们将测量可卡因和激素药代动力学，并描述静脉注射可卡因（0.4 mg/kg）和雌激素（男性）或孕酮或睾酮（女性）联合治疗后的心血管反应。随后，我们将评估这些激素是否改变可卡因的急性脑血管效应，使用非侵入性功能MRI技术称为动态磁敏感对比MRI（DSC MRI）。DSC MRI测量脑血容量（CBV）和血流量（CBF）。研究受试者将包括偶尔使用可卡因的健康男性和女性，他们将各自参加随机、安慰剂对照、双盲研究。 制药业正在积极开发新型类固醇受体药物，其受体选择性比天然激素更高，这可能会提高选择性调节血管对可卡因反应的能力。因此，如果我们关于激素对可卡因引起的血管收缩的影响的假设得到验证，将提高在慢性治疗试验中确定有效治疗方法的潜力。

DESCRIPTION (provided by applicant): Chronic cocaine use causes brain abnormalities and cognitive dysfunction, which may both impair a drug user's ability to resist further drug use and decrease the efficacy of treatment interventions. The severity of cocaine associated brain dysfunction is less in women than in men. Further, cocaine abuse treatment appears to benefit women more than men. These sex differences have important therapeutic implications, because they suggest a protective role for estrogen. Thus, estrogen (or a related compound) might be of therapeutic use to protect against brain vascular dysfunction. Cocaine's ability to reduce cerebral blood flow is likely to play a critical role in the development of brain dysfunction. Estrogen has been shown to acutely improve, while progesterone and testosterone acutely degrade vascular function. Consequently, vascular effects of hormones may account for sex differences in cocaine's brain effects. We seek to determine whether estrogen, progesterone, and testosterone alter cocaine pharmacokinetics and cocaine's acute cerebral vasoconstrictive effects. We will measure cocaine and hormone pharmacokinetics, and characterize cardiovascular responses after combined intravenous cocaine (0.4 mg/kg) and estrogen (men), or progesterone or testosterone (women) treatments. Subsequently, we will evaluate whether these hormones alter cocaine's acute cerebrovascular effects, using a noninvasive functional MRI technique called Dynamic Susceptibility Contrast MRI (DSC MRI). DSC MRI measures cerebral blood volume (CBV) and blood flow (CBF). Study subjects will include healthy men and women with histories of occasional cocaine use, who will each participate in a randomized, placebo-controlled, double-blind study. The pharmaceutical industry is actively developing novel steroid receptor agents with greater receptor selectivity than the natural hormones, which may improve the ability to selectively modulate vascular responses to cocaine. Thus, if our hypotheses regarding hormonal effects on cocaine-induced vasoconstriction are validated, the potential for identifying effective therapeutics for investigation in chronic treatment trials will be enhanced.