Rationale-Relapse is one of the main challenges facing the current treatment of cocaine addiction. Understanding its neurobiological mechanism is a critical step toward developing effective antirelapse therapies.Objectives-Emerging evidence indicates that glutamate-mediated activation of dopamine (DA) neurons in the ventral tegmental area (VTA) may be critically involved in cocaine-induced relapse to drug-seeking behavior. Activity of VTA DA neurons is modulated by multiple neurotransmitter systems including opioids, serotonin, dopamine, and acetylcholine. Recent studies demonstrated that activation of κ-opioid receptors (κORs) in the rat VTA directly inhibits the activity of a subpopulation of DA neurons projecting to the prefrontal cortex (PFC) and amygdala. Because we previously showed that blockade of DA receptors in the dorsal PFC inhibits cocaine-induced reinstatement of extinguished cocaine-seeking behavior suggesting a critical role of the VTA-PFC DA circuit in this process, we tested the hypothesis that activation of κORs in the VTA will block cocaine-induced reinstatement in rats.Methods-Rats were trained to self-administer intravenous cocaine (0.125 mg/infusion) under a modified fixed-ratio five schedule. After extinction of the learned behavior, the effects of activation of VTA κORs on cocaine-induced reinstatement were studied.Results-The κOR agonist U50 488 (0-5.6 μg/side) microinjected into the VTA dose-dependently decreased cocaine-induced reinstatement. The effects could not be explained by either a disruption of operant behavior or diffusion of the drug to the areas surrounding the VTA. Moreover, the effect was reversed by norbinaltorphimine.Conclusions-The VTA DA neurons expressing functional κORs are critically involved in cocaine-induced reinstatement in rats.
for their support and friendship throughout the project. At last, I also would like to gratefully acknowledge the care and support of my husband and parents, who always encouraged me on the way along.
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