Faculty Collaboration Database

Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex. Biol Psychiatry 2018 Jul 15;84(2):85-94

Date

11/05/2017

Pubmed ID

29100630

Pubmed Central ID

PMC5889367

DOI

10.1016/j.biopsych.2017.09.024

Scopus ID

2-s2.0-85033680278 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

BACKGROUND: Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL).

METHODS: We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons.

RESULTS: Corticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB₁R)- and 2-arachidonoylglycerol-dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB₁R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB₁R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34.

CONCLUSIONS: These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB₁R-mediated attenuation of inhibitory transmission in this brain region.

Author List

McReynolds JR, Doncheck EM, Li Y, Vranjkovic O, Graf EN, Ogasawara D, Cravatt BF, Baker DA, Liu QS, 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
Qing-song Liu PhD 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
Cocaine
Cocaine-Related Disorders
Drug-Seeking Behavior
Endocannabinoids
Extinction, Psychological
Glucocorticoids
Glycerides
Male
Piperidines
Prefrontal Cortex
Pyrazoles
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Self Administration
Stress, Psychological