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Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice

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Abstract

Rationale

Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF).

Objectives

The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement.

Methods

Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4 × 15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist antalarmin (10 mg/kg, i.p.) or the β2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history.

Results

Pretreatment with ICI-118,551 or antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed.

Conclusions

These findings indicate that, during stress, norepinephrine, via β2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward.

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Acknowledgments

This research was funded by the NIH grant DA15758 to JR Mantsch.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA

    Jayme R. McReynolds, Oliver Vranjkovic, Malia Thao, David A. Baker, Khadijah Makky, Yiwei Lim & John R. Mantsch

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  1. Jayme R. McReynolds
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  2. Oliver Vranjkovic
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  3. Malia Thao
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  4. David A. Baker
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  5. Khadijah Makky
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  6. Yiwei Lim
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  7. John R. Mantsch
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Correspondence to John R. Mantsch.

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McReynolds, J.R., Vranjkovic, O., Thao, M. et al. Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice. Psychopharmacology 231, 3953–3963 (2014). https://doi.org/10.1007/s00213-014-3535-0

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