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Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

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Abstract

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.

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Acknowledgments

This research was supported by National Institute on Drug Abuse grants DA16511 and DA21690 (RES), 1F32 DA025411-01 (DMB), and NIH grant C06 RR015455. The authors thank Shannon Ghee and Bernard Smalls for technical assistance and data collection.

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Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Deanne M. Buffalari

  2. Department of Neurosciences, Medical University of South Carolina, BSB416B, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Chelsey K. Baldwin & Ronald E. See

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  1. Deanne M. Buffalari
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  2. Chelsey K. Baldwin
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  3. Ronald E. See
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Correspondence to Ronald E. See.

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Buffalari, D.M., Baldwin, C.K. & See, R.E. Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats. Psychopharmacology 223, 179–190 (2012). https://doi.org/10.1007/s00213-012-2705-1

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