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使用毒品的能力，并降低治疗干预措施的有效性。女性与可卡因相关的脑功能障碍的严重程度低于男性。此外，可卡因滥用治疗似乎对女性比男性更有利。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）可能具有预防脑血管功能障碍的治疗作用。

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.