Resurgence of Punishment-Suppressed Cocaine Seeking

描述（由申请人提供）：戒断一段时间后的复吸是药物成瘾的典型特征。在复发的标准动物模型中，操作性反应（如杠杆按压）通过给药得到加强。然后通过不使用药物来消除药物寻求，并且由于暴露于药物、药物线索/环境或压力而诱发复发。已知药物和非药物强化物在行为控制中相互作用，可替代的非药物强化物可减少药物服用。安排非药物强化剂的行为干预非常成功，但当这种治疗结束时，替代强化剂的停止通常与复发有关。此外，一些潜在的与压力有关的复发来源（例如，家庭或职业环境的变化）可能被描述为涉及替代非药物强化物的丧失。复发的标准动物模型没有检查这种由丧失替代非药物强化引起的复发。我们的实验室开发了一种复苏模型，在这种模型中，当非药物强化的替代来源随后被移除时，已消失的药物寻求会增加（即复发）。然而，长期以来对动物复发模型（包括复发范式）的批评是，它们通过在复发测试之前消除药物寻求来实现对药物寻求的抑制。对使用灭绝的关注在于，人类停止寻求药物显然不是寻求药物消失的结果。相反，相当多的证据表明，吸毒带来的负面后果是一个促成因素。这项R21探索性/发展性资助的目标是开发一种复苏模型，以检查在抑制可卡因寻求后，由于替代强化的丧失而导致的复发，并产生负面后果，而不是消失。该项目解决了在该领域取得进展的一个长期障碍，该障碍是由于使用灭绝作为在复发之前抑制寻求药物的手段而造成的。通过开发一种使用负面后果来抑制药物寻求的复发程序，该研究可能会产生一个更合适的模型，用于检查由非药物强化丧失引起的复发的行为和神经生物学机制。

DESCRIPTION (provided by applicant): Relapse following periods of abstinence is a defining feature of drug addiction. In standard animal models of relapse, an operant response (e.g., lever press) is reinforced by drug delivery. Drug seeking is then extinguished by withholding the drug, and relapse is induced by exposure to drugs, drug-cues/contexts, or stress. Drug and non-drug reinforcers are known to interact in the control of behavior, and availability of alternative non-drug reinforcers decreases drug taking. Behavioral interventions arranging non-drug reinforcers have been very successful, but when such treatment ends, the discontinuation of alternative reinforcement is often associated with relapse. In addition, some potentially stress-related sources of relapse (e.g., changes in familial or vocational circumstances) might be characterized as involving the loss of alternative non-drug reinforcers. Standard animal models of relapse do not examine such relapse induced by loss of alternative non-drug reinforcement. Our laboratory has developed the resurgence model in which extinguished drug seeking increases (i.e., relapses) when an alternative source of non- drug reinforcement is subsequently removed. However, a long-standing criticism of animal models of relapse, including the resurgence paradigm, is that they achieve suppression of drug seeking by extinguishing drug seeking prior to relapse testing. The concern with the use of extinction is that cessation of drug seeking by humans is clearly not the result of extinction of drug seeking. Instead, considerable evidence suggests that the experience of negative consequences as a result of drug use is a contributing factor. The goal of this R21 Exploratory/Developmental grant is to develop a version of the resurgence model to examine relapse induced by loss of alternative reinforcement following suppression of cocaine seeking with negative consequences, rather than extinction. The project addresses a long-standing barrier to progress in the field resulting from the use of extinction as the means to suppress drug- seeking prior to relapse. By developing a version of the resurgence procedure using negative consequences to suppress drug seeking, the proposed research could result in a more appropriate model for examining the behavioral and neurobiological mechanisms of relapse induced by loss of non-drug reinforcement.