Environmental Influences on Cocaine Self-Administration

描述(由申请人提供)：这是一项竞争性的继续申请的第一次修订，以继续调查环境应激以及随后激活的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的影响。这些实验的基本假设是，可卡因的强化至少部分是通过与也被应激激活的常见神经生物学效应系统的相互作用来调节的。到目前为止，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发挥着重要作用。抑制可卡因诱导的CRH或血浆皮质酮增加的化合物，或那些阻止暴露于应激源后激活的生理过程的化合物，被证明显著减弱了正在进行的可卡因自我给药以及消除的可卡因寻找行为的恢复。在本项目所要求的期间，研究将继续集中在这些化合物上，进一步阐明它们对可卡因强化的严重影响。研究还将侧重于这些化合物的合理组合对可卡因自我给药的影响，试图利用这些化合物的潜在有益影响，同时将其不利影响降至最低。初步数据表明，在单独给药时不产生明显影响的剂量下，这种组合在减少可卡因自我给药方面是有效的。此外，治疗可卡因成瘾的药物疗法不太可能例行公事地涉及一次给药，而吸毒者就永远“治愈”的“灵丹妙药”。相反，未来治疗成瘾的药物可能会继续需要长期服用。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测试化合物。一种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，我们还建议调查这些化合物在不同条件下的长期给药情况。本修订申请中描述的实验是根据这些规定设计的，并考虑到了前一次提交的评审者的建议。

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.