Elsevier

Biological Psychiatry

Volume 84, Issue 2, 15 July 2018, Pages 85-94
Biological Psychiatry

Priority Communication
Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex

https://doi.org/10.1016/j.biopsych.2017.09.024Get rights and content

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.

Section snippets

Subjects

A total of 102 male Sprague Dawley rats (275 to 300 g at arrival; Envigo RMS, Inc., Indianapolis, IN), were individually housed in a 12-hour reverse light/dark cycle (7 am to 7 pm lights off) as described in the Supplement. All behavioral procedures were conducted in the dark phase. Of the rats designated for behavioral testing, 14 were excluded from the study because of misplaced cannulation or because they did not complete all behavioral testing.

Surgery

For intravenous self-administration and

Corticosterone Acts in the PL to Potentiate Reinstatement

After 14 days of stable cocaine self-administration, responding was extinguished and rats were tested for reinstatement of cocaine seeking. All self-administration and extinction data are displayed in Supplemental Table S1. As previously reported under these conditions 8, 10, electric footshock stress (3 × 0.5 mA, 200-ms duration, mean intershock interval 40 seconds, range 10 to 70 seconds over a 15-minute period) alone did not induce reinstatement, but rather potentiated cocaine seeking in

Discussion

Stress is a powerful determinant of drug seeking in individuals with SUDs. This is problematic for relapse prevention, as stress is prevalent and unavoidable in the daily lives of drug addicts. Although the general idea that stress contributes to drug seeking is well established 22, 23, 24, the nature of this contribution appears to be more complex than previously thought. While it is true that in some cases, stress can serve as a direct trigger for drug craving 2, 11, supported by findings in

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. DA015758 (to JRM), DA038663 (to JRM, CJH, Q-SL), and DA035217 (to Q-SL).

JRM and DAB are consultants for and stakeholders in Promentis Pharmaceuticals Inc. CJH is on the Scientific Advisory Board for Phytecs, Inc. The other authors report no biomedical financial interests or potential conflicts of interest.

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