Regulation of cocaine-reinstated drug-seeking behavior by κ-opioid receptors in the ventral tegmental area of rats

Wen Lin Sun, YueQiang Xue, ZaiFang Huang, Jeffery Steketee

Research output: Contribution to journalArticle

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Abstract

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 anti-relapse therapies. Objectives Emerging evidence indicates that glutamatemediated 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 cocaineinduced 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.

Original languageEnglish (US)
Pages (from-to)179-188
Number of pages10
JournalPsychopharmacology
Volume209
Issue number2
DOIs
StatePublished - Apr 1 2010

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Drug-Seeking Behavior
Ventral Tegmental Area
Opioid Receptors
Cocaine
Dopaminergic Neurons
Prefrontal Cortex
Recurrence
Dopamine
Cocaine-Related Disorders
Dopamine Receptors
Amygdala
Opioid Analgesics
Acetylcholine
Neurotransmitter Agents
Serotonin
Appointments and Schedules

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Regulation of cocaine-reinstated drug-seeking behavior by κ-opioid receptors in the ventral tegmental area of rats. / Sun, Wen Lin; Xue, YueQiang; Huang, ZaiFang; Steketee, Jeffery.

In: Psychopharmacology, Vol. 209, No. 2, 01.04.2010, p. 179-188.

Research output: Contribution to journalArticle

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abstract = "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 anti-relapse therapies. Objectives Emerging evidence indicates that glutamatemediated 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 cocaineinduced 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.",
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