Stuber Garret D, Roitman Mitchell F, Phillips Paul E M, Carelli Regina M, Wightman R Mark
Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Neuropsychopharmacology. 2005 May;30(5):853-63. doi: 10.1038/sj.npp.1300619.
Cocaine acts as a reinforcer through its pharmacological effects on brain monoaminergic systems, which, through repeated pairings with environmental stimuli, lead to the development of conditioned effects of the drug. Both the pharmacological and conditioned aspects of cocaine are implicated in several facets of acquisition and maintenance of addiction, including drug craving. Here, we compare the effects of contingent (response dependent) and noncontingent (response independent) cocaine on rapid dopaminergic signaling in the core of the nucleus accumbens. Dopamine was monitored using fast-scan cyclic voltammetry. Noncontingent cocaine administered to both naive and animals with a history of self-administration resulted in a profound increase in the frequency of transient dopamine release events that are not time-locked to any specific environmental stimuli. Pharmacological effects were detectable approximately 40 s after cocaine administration. In contrast, when animals where allowed to self-administer cocaine on an FR-1 schedule, dopamine transients (69+/-12 nM) were consistently observed time-locked to each reinforced response (peaking approximately 1.5 s after response completion). Importantly, no pharmacological effect of cocaine was observed within the 10 s following noncontingent cocaine administration, indicating that dopamine signals time-locked to the reinforced response are a result of the pairing of the operant behavior, the drug-associated cues, and cocaine. These data demonstrate that this pharmacological action of cocaine occurs for an extended period following either contingent or noncontingent administration, but is distinct from those dopamine transients that are time-locked to each lever-press in self-administering animals.
可卡因通过其对脑单胺能系统的药理作用发挥强化剂的作用，通过与环境刺激的反复配对，导致药物条件性效应的形成。可卡因的药理和条件性方面都与成瘾的获得和维持的几个方面有关，包括药物渴望。在这里，我们比较了偶然（反应依赖性）和非偶然（反应独立性）可卡因对伏隔核核心快速多巴胺能信号传导的影响。使用快速扫描循环伏安法监测多巴胺。对未接触过可卡因的动物和有自我给药史的动物给予非偶然的可卡因，导致瞬态多巴胺释放事件的频率大幅增加，这些事件与任何特定环境刺激无时间锁定关系。给药后约40秒可检测到药理作用。相比之下，当动物按照FR-1程序自我给药可卡因时，始终观察到多巴胺瞬变（69±12 nM）与每次强化反应时间锁定（在反应完成后约1.5秒达到峰值）。重要的是，在非偶然给予可卡因后的10秒内未观察到可卡因的药理作用，这表明与强化反应时间锁定的多巴胺信号是操作性行为、药物相关线索和可卡因配对的结果。这些数据表明，可卡因给药后，无论偶然给药还是非偶然给药，其药理作用都会持续较长时间，但与自我给药动物中与每次杠杆按压时间锁定的多巴胺瞬变不同。
