Kim Joseph A, Pollak Kelly A, Hjelmstad Gregory O, Fields Howard L
Ernest Gallo Clinic and Research Center, Wheeler Center for the Neurobiology of Addiction and Department of Neurology, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5664-9. doi: 10.1073/pnas.0401373101. Epub 2004 Apr 2.
Repeated exposure to drugs of abuse produces forms of experience-dependent plasticity including behavioral sensitization. Although a single exposure to many addicting substances elicits locomotor sensitization, there is little information regarding the motivational effects of such single exposures. This study demonstrates that a single cocaine exposure enhances both rewarding and aversive forms of opioid place conditioning. Rats were given a single injection of cocaine (15 mg/kg i.p.) in their home cage at different times before conditioning. This treatment enhanced conditioned place preference (CPP) to morphine (2 x 10 mg/kg s.c.) if training began 1 or 5 but not 10 days after the cocaine injection. A single cocaine exposure also enhanced conditioned place aversion (CPA) to the kappa-opioid receptor agonist U69593 (2 x 0.16 mg/kg s.c.). Compared to morphine CPP, U69593 CPA was delayed and persistent. It was not observed at 1 day but appeared if the conditioning began 5 or 10 days after the cocaine injection. Although the cocaine-induced enhancements of both morphine CPP and U69593 CPA followed different time courses, suggesting different mechanisms, both effects were blocked by injection of the N-methyl-d-aspartate receptor antagonist MK-801 (0.5 nmol bilaterally) into the ventral tegmental area, immediately before the cocaine injection. Thus, through a circuit involving the ventral tegmental area, a single cocaine exposure enhanced both micro-opioid receptor reward and kappa-opioid receptor aversion.
反复接触滥用药物会产生包括行为敏化在内的经验依赖性可塑性形式。尽管单次接触许多成瘾物质会引发运动敏化，但关于这种单次接触的动机效应的信息却很少。本研究表明，单次接触可卡因会增强阿片类药物位置条件反射的奖赏性和厌恶性形式。在条件反射训练前的不同时间，给大鼠在其饲养笼中单次注射可卡因（15毫克/千克，腹腔注射）。如果在可卡因注射后1天或5天而非10天开始训练，这种处理会增强对吗啡（2×10毫克/千克，皮下注射）的条件性位置偏爱（CPP）。单次接触可卡因还会增强对κ-阿片受体激动剂U69593（2×0.16毫克/千克，皮下注射）的条件性位置厌恶（CPA）。与吗啡CPP相比，U69593 CPA出现延迟且持续存在。在注射后1天未观察到，但如果在可卡因注射后5天或10天开始条件反射训练则会出现。尽管可卡因诱导的吗啡CPP和U69593 CPA增强遵循不同的时间进程，表明机制不同，但在可卡因注射前立即向腹侧被盖区双侧注射N-甲基-D-天冬氨酸受体拮抗剂MK-801（0.5纳摩尔）可阻断这两种效应。因此，通过涉及腹侧被盖区的神经回路，单次接触可卡因增强了μ-阿片受体奖赏和κ-阿片受体厌恶。
