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

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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 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.

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Acknowledgements

The project described was supported by Grant numbers DA021278 (WLS) and DA023215 (JDS) from the National Institute on Drug Abuse, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIDA or NIH. All procedures followed the National Institute of Health Guidelines for the Care and Use of Laboratory Animals. There is no conflict of interest in relation to this article.

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Authors and Affiliations

  1. Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Crowe 115, Memphis, TN, 38163, USA

    WenLin Sun, YueQiang Xue, ZaiFang Huang & Jeffery D. Steketee

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  1. WenLin Sun
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  2. YueQiang Xue
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  3. ZaiFang Huang
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  4. Jeffery D. Steketee
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Correspondence to WenLin Sun.

Additional information

The project described was supported by Grant numbers DA021278 and DA023215 from the NIDA/NIH, and the contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIDA/NIH.

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Sun, W., Xue, Y., Huang, Z. et al. Regulation of cocaine-reinstated drug-seeking behavior by κ-opioid receptors in the ventral tegmental area of rats. Psychopharmacology 210, 179–188 (2010). https://doi.org/10.1007/s00213-010-1812-0

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