Cocaine & Steroids: Brain Vascular & Behavioral Effects

描述(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，这可能会削弱吸毒者抵抗进一步药物使用的能力，并降低治疗干预的效果。可卡因相关的脑功能障碍在女性中的严重程度低于男性。此外，可卡因滥用治疗似乎使女性比男性受益更多。这些性别差异具有重要的治疗意义，因为它们暗示了雌激素的保护作用。因此，雌激素(或相关化合物)可能具有预防脑血管功能障碍的治疗作用。 可卡因减少脑血流量的能力可能在大脑功能障碍的发展中发挥关键作用。雌激素被证明可以显著改善血管功能，而黄体酮和睾丸素则会显著降低血管功能。因此，荷尔蒙的血管效应可能解释了可卡因对大脑影响的性别差异。我们试图确定雌激素、孕激素和睾酮是否会改变可卡因的药代动力学和可卡因的急性脑血管收缩效应。 我们将测量可卡因和激素的药代动力学，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，我们将使用一种名为动态磁敏对比磁共振成像(DSC MRI)的非侵入性功能磁共振成像技术，评估这些激素是否会改变可卡因的急性脑血管效应。DSC MRI测量脑血容量(CBV)和血流量(CBF)。研究对象将包括偶尔使用可卡因的健康男性和女性，他们每个人都将参加一项随机、安慰剂对照的双盲研究。 制药行业正在积极开发比天然激素具有更高受体选择性的新型类固醇受体药物，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，那么在慢性治疗试验中确定有效治疗药物的可能性将会增强。

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.