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CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 2016 Jan;233(1):99-109

Date

10/13/2015

Pubmed ID

26455361

Pubmed Central ID

PMC4703460

DOI

10.1007/s00213-015-4092-x

Scopus ID

2-s2.0-84953275278   25 Citations

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.

Author List

McReynolds JR, Doncheck EM, Vranjkovic O, Ganzman GS, Baker DA, Hillard CJ, Mantsch JR

Authors

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arachidonic Acids
Behavior, Addictive
Cocaine
Cocaine-Related Disorders
Endocannabinoids
Extinction, Psychological
Glycerides
Male
Piperidines
Pyrazoles
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Self Administration
Stress, Psychological