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CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats

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Abstract

Rationale

Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Objectives

The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.

Methods

Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement.

Results

Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher dose (i.e., 3 mg/kg) and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 h access/day) was affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex.

Conclusions

These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related.

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Acknowledgments

This research was funded by NIH grant DA015758 to JR Mantsch and NIH grant DA038663 to JR Mantsch and CJ Hillard and by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

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

    Jayme R. McReynolds, Elizabeth M. Doncheck, Oliver Vranjkovic, Geoffrey S. Ganzman, David A. Baker & John R. Mantsch

  2. Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Cecilia J. Hillard

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  1. Jayme R. McReynolds
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  2. Elizabeth M. Doncheck
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  3. Oliver Vranjkovic
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  4. Geoffrey S. Ganzman
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  5. David A. Baker
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  6. Cecilia J. Hillard
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  7. John R. Mantsch
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Correspondence to John R. Mantsch.

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McReynolds, J.R., Doncheck, E.M., Vranjkovic, O. et al. CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. Psychopharmacology 233, 99–109 (2016). https://doi.org/10.1007/s00213-015-4092-x

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