Environmental Influences on Cocaine Self-Administration

描述（由申请人提供）：这是竞争性继续申请的第一次修订，以继续研究环境应激和随后激活促肾上腺皮质激素释放激素（CRH）和下丘脑-垂体-肾上腺（HPA）轴对大鼠静脉注射可卡因自我给药的影响。这些实验背后的主要假设是，可卡因的强化至少部分是通过与常见的神经生物学效应系统的相互作用而介导的，这些系统也被压力激活。迄今为止，通过该项目收集的数据表明，CRH和皮质酮在可卡因奖励中都起着重要作用。抑制可卡因诱导的CRH或血浆皮质酮增加的化合物，或阻断暴露于压力源后激活的生理过程的化合物，被证明可以显著减弱正在进行的可卡因自我给药，以及恢复已消失的可卡因寻求行为。在本项目所要求的期间内，研究将继续集中于这些化合物，进一步澄清它们对可卡因强化的急性作用。研究还将集中于这些化合物的合理组合对可卡因自我给药的影响，以期利用这些化合物的潜在有益影响，同时尽量减少其不利影响。初步数据表明，这种组合在减少可卡因自我给药剂量方面是有效的，单独给药时没有明显效果。此外，治疗可卡因成瘾的药物疗法不太可能经常采用“灵丹妙药”的方法，即服用一次药物，成瘾者就永远“治愈”了。相反，未来治疗成瘾的药物可能会继续需要长期给药。然而，大多数研究药物滥用潜在治疗药物的临床前实验室，包括我们的实验室，通常只在急性给药后评估几种剂量的试验化合物。更有效的方法是在更类似于临床使用的条件下测试这些化合物。因此，我们建议也研究这些化合物在不同条件下的慢性给药。本修订后的申请中描述的实验是根据这些规定设计的，并考虑了以前提交的审稿人的建议。

DESCRIPTION (provided by applicant): This is the first revision of a competing continuation application to proceed with investigations of the effects of environmental stress and the subsequent activation of corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal (HPA) axis on intravenous cocaine self-administration in rats. The primary hypothesis underlying these experiments is that cocaine reinforcement is mediated, at least in part, through interactions with common neurobiological effector systems also activated by stress. Data collected through this project to date have demonstrated an important role for both CRH and corticosterone in cocaine reward. Compounds that suppress cocaine-induced increases in CRH or plasma corticosterone, or those that block physiological processes activated following exposure to stressors were shown to significantly attenuate ongoing cocaine self-administration as well as the reinstatement of extinguished cocaine-seeking behavior. During the requested period of this project, research will continue to focus on such compounds, further clarifying their acute effects on cocaine reinforcement. Research also will focus on the effects of rational combinations of these compounds on cocaine self-administration in an attempt to capitalize on the potential beneficial effects of these compounds while minimizing their adverse effects. Preliminary data suggest that such combinations are effective in reducing cocaine self-administration at doses that produce no apparent effects when administered separately. In addition, pharmacotherapies for the treatment of cocaine addiction are unlikely to ever routinely involve a "magic bullet" approach, whereby a drug is administered once and the addict is "cured" forever. Rather, future medications for the treatment of addiction will likely continue to require chronic dosing. However, most preclinical laboratories investigating potential therapeutic agents for drug abuse, including ours, typically evaluate several doses of the test compound following its acute administration only. A more valid approach would be to test these compounds under conditions more analogous to how they would be used in the clinic. Therefore, we propose to also investigate the chronic administration of these compounds under different conditions. The experiments described in this revised application were designed with these stipulations in mind, taking into consideration the recommendations of the reviewers of the previous submission.