Reinstatement of drug-maintained behavior suppressed by extinction or an availabl

描述（由申请人提供）：只有理解复吸背后的行为和神经生物学机制，我们才能降低高患病率的复吸。为了研究这些机制，复发的恢复模型已经被开发出来，在这个模型中，动物学会自我给药，然后对药物的反应被灭绝所抑制：反应不再提供对药物的获取。一旦反应被抑制，暴露于药物、药物相关刺激或信号药物可用性的刺激会导致对药物的反应恢复，尽管药物持续缺乏。同样的情况也会促使戒毒者复发。此外，在自我报告的渴望中活跃的大脑区域的失活减少了恢复行为。然而，在人类中，禁欲很少是被迫的；成瘾者选择减少或停止使用药物，用其他适应性行为取代不适应的药物使用。此外，在动物模型中，增加强制禁欲的时间会增加随后的恢复；然而，在人类中，较长时间的禁欲减少了复发的可能性。因此，在行为和神经生物学机制上可能存在根本的差异，这是药物自我给药行为被灭绝所抑制的基础，而行为被强化的替代行为所抑制。在这个提议中，(1)建立了在食物和乙醇强化同时固定比例的情况下导致乙醇优势或乙醇抑制选择的条件。然后，在几种已知的恢复灭绝抑制反应和沉淀复发的治疗方法之后，比较恢复灭绝抑制反应或选择抑制反应。(2)比较了消除抑制和选择抑制反应下多个脑区可逆失活对恢复反应的影响。(3)确定了各工序反应抑制期的长短对恢复反应的影响。最后，(4)在两种方法下，分别在30天和60天的酒精自我给药或抑制酒精自我给药后建立刺激泛化曲线。这种方法提供了有关行为刺激控制的信息，可以帮助我们了解增加复发脆弱性或促进恢复的条件。这些研究将开始在选择决定因素和恢复行为的研究之间建立一个整合的关系。该项目通过加强替代行为而不是完全去除药物来抑制药物服用，从而增强了一种常用的复发行为动物模型。这更类似于戒除毒瘾者所需要的决定。将测试大脑区域和禁欲时间的影响。

DESCRIPTION (provided by applicant): Only by understanding behavioral and neurobiological mechanisms that underlie relapse can we reduce the high prevalence of relapse to drug addiction. To study these mechanisms, the reinstatement model of relapse has been developed, where animals learn to self-administer a drug, and then responding for the drug is suppressed by extinction: responses no longer provide access to the drug. Once responding is suppressed, exposure to the drug, drug-associated stimuli, or stimuli signaling drug availability result in a resumption of responding for the drug, despite its continuing absence. These same conditions promote relapse in recovering addicts. Also, inactivating brain regions that are active during self-reported craving reduce reinstatement behavior. However, in humans, abstinence is rarely forced; addicts choose to reduce or stop drug use, replacing maladaptive drug use with other, adaptive behaviors. Additionally, in the animal model, increasing the period of forced abstinence increases subsequent reinstatement; yet in humans longer periods of abstinence reduce the likelihood of relapse. Thus there could be a fundamental difference in the behavioral and neurobiological mechanisms that underlie drug self-administration behavior that has been suppressed by extinction verses behavior suppressed by reinforcing an alternative behavior. In this proposal, (1) conditions are established that result in ethanol-predominant or ethanol-suppressed choices under a concurrent fixed-ratio schedule of food and ethanol reinforcement. Then, reinstatement of extinction-suppressed or choice-suppressed responding is compared following several treatments known to reinstate extinction-suppressed responding and precipitate relapse. (2) The impact of reversible inactivation of several brain regions on reinstatement responding under extinction-suppressed and choice-suppressed responding is compared. (3) The impact of the length of the period of response suppression on reinstatement responding in each procedure is determined. Finally, (4) stimulus generalization curves are established following 30 or 60 days of ethanol self-administration or suppressed ethanol-self-administration under both procedures. This method provides information about the stimulus control of a behavior and could help us understand conditions that increase vulnerability to relapse or promote recovery. These studies will begin to build an integrative relationship between studies on the determinates of choice and reinstatement behaviors. PUBLIC HEALTH RELEVANCE This project enhances a commonly used animal model of relapse behavior by suppressing drug taking by reinforcing an alternative behavior rather than removing drug altogether. This is more similar to the decisions required of recovering addicts. The influence of brain regions and abstinence period will be tested.