Cocaine & Steroids: Brain Vascular & Behavioral Effects

可卡因

• 批准号: 6933127
• 负责人: Marc J Kaufman
• 金额: $ 36.82万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933127
• 关键词: behavioral /social science research tag; bioimaging /biomedical imaging; brain circulation; cerebrovascular imaging /visualization; clinical research; cocaine; cognition disorders; dosage; drug abuse; estrogens; functional magnetic resonance imaging; gender difference; hormone regulation /control mechanism; human subject; pharmacokinetics; progesterone; sex hormones; testosterone; vasoconstriction; young adult human (21-34)

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.

描述（由申请人提供）：慢性可卡因使用会导致脑部异常和认知功能障碍，这既可能损害吸毒者抵抗进一步使用药物使用的能力，并降低治疗干预措施的功效。与男性相关的可卡因相关脑功能障碍的严重程度少于男性。此外，可卡因滥用治疗似乎比男性受益更多。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）可能具有治疗用途，可防止脑血管功能障碍。 可卡因降低脑血流的能力可能在脑功能障碍的发展中起关键作用。雌激素已显示出急性改善，而孕酮和睾丸激素急性降解血管功能。因此，激素的血管影响可能解释可卡因大脑作用的性别差异。我们试图确定雌激素，孕酮和睾丸激素是否改变可卡因药代动力学以及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，并在静脉内可卡因（0.4 mg/kg）和雌激素（男性），孕酮或睾丸激素（女性）治疗后表征心血管反应。随后，我们将使用称为动态敏感性对比度MRI（DSC MRI）的无创功能性MRI技术来评估这些激素是否改变可卡因的急性脑血管作用。 DSC MRI测量脑血容量（CBV）和血流（CBF）。研究对象将包括具有偶尔可卡因使用历史的健康男人和女性，他们将每个人都参加一项随机的，安慰剂对照，双盲研究。 与天然激素相比，制药行业正在积极开发具有更大受体选择性的新型类固醇受体剂，这可能会提高选择性调节对可卡因的血管反应的能力。因此，如果我们对可卡因引起的血管收缩的荷尔蒙作用的假设得到了验证，则将增强在慢性治疗试验中鉴定有效研究的有效疗法的潜力。

项目成果

Antiandrogen pretreatment alters cocaine pharmacokinetics in men.

抗雄激素预处理改变可卡因在男性中的药代动力学。

• DOI: 10.1097/adm.0b013e31815a137c
• 发表时间: 2007
• 期刊: Journal of addiction medicine
• 影响因子: 5.5
• 作者: Yamamoto,RinahT;Teter,ChristianJ;Barros,TanyaL;McCarthy,Elissa;Mileti,Crystal;Juliano,Trisha;Medeiros,CarissaL;Looby,Alison;Maywalt,MelissaA;McNeil,JaneF;Olson,David;Mallya,Gopinath;Lukas,ScottE;Renshaw,PerryF;Kaufman,
• 通讯作者: Kaufman,