Sex Differences and Incubation of Cocaine Craving

描述（由申请人提供）：性别差异先前在可卡因滥用的临床前和临床研究中有报道。虽然戒断后再次使用可卡因是治疗依赖的最大障碍，但对于长期戒断后再次使用可卡因是否存在性别差异，人们的关注有限。与临床证据一致，实验动物研究表明，在可卡因自我给药和恢复可卡因寻求行为方面存在性别差异。据报道，与男性相比，女性对可卡因的反应水平更高，消失反应水平更高，在再次接触少量可卡因后恢复的水平更高，但在接触与可卡因摄入有关的线索后恢复的水平相同或更低。此外，与男性相比，女性表现出更高水平的初始和致敏的可卡因诱导运动。最近的研究越来越关注神经系统的时间依赖性变化，因为有证据表明，在戒断毒品期间，可卡因的寻求会增加。这种“渴望的潜伏期”效应也在临床人群中观察到，并被认为会促使吸毒复发。鉴于其他易复发动物模型的性别差异，性别差异很可能有助于药物渴望潜伏的神经适应。因此，本项目将研究雄性和雌性大鼠在戒断可卡因自我给药期间寻求可卡因的时间过程。预计雌性会表现出更强的孵化能力。这些发现将进一步加深我们对药物成瘾中性别差异与行为可塑性之间关系的理解。这些初步的实验将构成后续研究的基础，以检验性腺激素的组织和激活效应，以及时间依赖性神经适应中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.