GLUCOCORTICOID FUNCTION IN SUBJECTIVE/BEHAVIORAL/NEUROCHEMICAL EFFECT OF COCAINE

当前研究提案的主要目标是检查 改变糖皮质激素(GC)水平的药物干预 会影响可卡因在人体内的行为和神经化学效应。 有三个具体目标：#1)对15种可卡因进行受试者内研究 吸毒者及其对固定顺序递增剂量的行为反应 急性(&lt；12hr)给药后鼻腔注射可卡因的方案 合成GC强的松、皮质醇合成抑制剂和GC受体 拮抗剂、酮康唑和安慰剂；#2)受试者间随机 45例可卡因依赖者(均为HIV感染者)及其行为研究 慢性(7天)前后对相同可卡因方案的反应 用泼尼松(n=15)、酮康唑(n=15)或 安慰剂(n=15)和；#3)相同的平行临床前研究 对清醒恒河猴的药物干预，包括可卡因诱导 精神运动功能与体内同步微透析措施 基础和可卡因诱导的脑双胺和5-羟色胺水平。我们 假设增加GC(泼尼松)水平会增加可卡因- 诱发的兴奋和神经化学影响，以及抑制GC 合成(酮唑类)会减弱可卡因的作用。如果确认为 人类，我们的发现将提供强有力的证据支持初级 GC在可卡因滥用中的病理生理学作用并导致新的 可卡因依赖的药物治疗。7中的初步数据 作为第一项研究的可卡因成瘾者目前正在接受分析。

The primary goal of the current research proposal is to examine whether pharmacological interventions which alter glucocorticoids (GC ) levels will influence cocaine's behavioral and neurochemical effects in humans. There are three specific aims: #1) a within-subjects study of 15 cocaine addicts and their behavioral responses to a fixed-order, ascending dose regimen of intranasal cocaine after acute (<12hr) pretreatment with the synthetic GC prednisone, the cortisol synthesis inhibitor and GC receptor antagonist, ketoconazole, and placebo; # 2) a between-subjects randomized study of 45 cocaine dependent subjects (all HIV) and their behavioral responses to the same cocaine regimen before and after chronic (7 days) pretreamtent with either prednisone (n=15), ketoconazole (n=15), or placebo (n=15) and; # 3) parallel preclinical studies of the identical drug interventions in awake rhesus monkeys, including cocaine-induced psychomotor activity and concurrent in vivo microdialysis measures of basal and cocaine-induced brain dipamine and serotonin levels. We hypothesize that increasing GC (prednisone) levels will enhance cocaine- induced euphoria and neurochemical impact, and that inhibiting GC synthesis (ketocoazole) will diminish cocaine's effects. If confirmed in humans, our findings would provide strong evidence in support of a primary pathophyisiological role for GC in cocaine abuse and lead to novel pharmacotherapies for cocaine dependence. Peliminary data from in 7 cocaine addicts studied as part of # 1 are currently being analyzed.