Sex Differences and Incubation of Cocaine Craving

描述（由申请方提供）：先前在可卡因滥用的临床前和临床研究中报告了性别差异。虽然戒毒后可卡因复吸是治疗依赖性的最大障碍，但对长期戒毒后可卡因复吸是否存在性别差异的关注有限。与临床证据一致，实验室动物研究表明，可卡因自我给药和可卡因寻求行为的恢复存在性别差异。据报道，相对于男性，女性对可卡因的反应水平更高，消退反应水平更高，重新暴露于少量可卡因后恢复水平更高，但暴露于与可卡因摄入相关的线索后恢复水平相同或更低。此外，女性表现出较高水平的初始和致敏可卡因诱导的运动比男性。最近的研究越来越多地集中在神经系统的时间依赖性变化后，证明可卡因寻求增加在戒毒。这种“渴望的孵化”效应也在临床人群中观察到，并被认为会促使吸毒复发。考虑到在其他易复发动物模型中的性别差异，性别差异可能有助于潜伏药物渴望的神经适应。因此，拟议的项目将调查雄性和雌性大鼠在可卡因自我给药戒断期间寻求可卡因的时间进程。据预测，女性将表现出增强孵化。这些发现将进一步加深我们对性别差异与药物成瘾行为可塑性之间关系的理解。这些初步的实验将形成后续研究的基础，研究性腺激素的组织和激活作用，以及时间依赖性神经适应的性别差异的神经内分泌基础。

DESCRIPTION (provided by applicant): Sex differences have been previously reported in preclinical and clinical studies of cocaine abuse. While relapse to cocaine use following abstinence is the most significant impediment in the treatment of dependence, limited attention has been given as to whether sex differences exist in relapse to cocaine seeking after prolonged abstinence. Consistent with clinical evidence, laboratory animal studies have demonstrated that there are sex differences in cocaine self-administration and in the reinstatement of cocaine-seeking behavior. Relative to males, females have been reported to exhibit higher levels of responding for cocaine, higher levels of extinction responding, higher levels of reinstatement following reexposure to small amounts of cocaine but either the same or lower levels reinstatement following exposure to cues associated with cocaine intake. Further, females show higher levels of initial and sensitized cocaine-induced locomotion than do males. Recent research has increasingly focused on time-dependent changes in the nervous system following demonstrations that cocaine-seeking increases during drug abstinence. This "incubation of craving" effect has also been observed in clinical populations and is thought to precipitate relapse to drug taking. Given the sex differences in other animal models of relapse vulnerability, it is likely that sex differences contribute to the neuroadaptations underlying the incubation of drug craving. Accordingly, the proposed project will investigate the time course of cocaine-seeking during abstinence from cocaine self-administration in male and female rats. It is predicted that females will exhibit enhanced incubation. These findings will further our understanding of the relation between sex differences and behavioral plasticity involved in drug addiction. These initial experiments will form the bases of subsequent studies examining the organizational and activational effects of gonadal hormones and the neuroendocrine bases of sex differences in time-dependent neuroadaptations.