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Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures

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Abstract

Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [3H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [3H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

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Acknowledgments

The authors wish to acknowledge Susan Nader and Tonya Calhoun for their assistance in conducting the self-administration studies.

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The authors declare that they have no conflicts of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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  1. Department of Physiology and Pharmacology, Center for the Neurobiology of Addiction Treatment, One Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC, 27157-1083, USA

    Hilary R. Smith, Michael A. Nader & Linda J. Porrino

  2. Ferring Pharmaceuticals, Clinical Sciences, Medical Affairs, 100 Interpace Parkway, Parsippany, NJ, 07054, USA

    Thomas J. R. Beveridge

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  1. Hilary R. Smith
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Smith, H.R., Beveridge, T.J.R., Nader, M.A. et al. Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures. Brain Struct Funct 221, 2703–2715 (2016). https://doi.org/10.1007/s00429-015-1066-z

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