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

• DOI: 10.1016/j.biopsych.2017.09.024
• Publication Date: 2017-10-12T01:31:11Z
• Authors: Jayme R. McReynolds; Elizabeth M. Donc...; Yan Li; Oliver Vranjkovic; Evan N. Graf; Daisuke Ogasawara; Benjamin F. Cravatt; David A. Baker; Qing-Song Liu; Cecilia J. Hillard; John R. Mantsch
• Keywords: Male; 0301 basic medicine; 571; Drug-Seeking Behavior; Addiction; Prefrontal Cortex; Self Administration; Prelimbic cortex; Arachidonic Acids; Extinction, Psychological; Glycerides; Rats, Sprague-Dawley; Cocaine-Related Disorders; 03 medical and health sciences; 0302 clinical medicine; Cocaine; Piperidines; Receptor, Cannabinoid, CB1; Animals; Biology; Glucocorticoids; Self-administration; 16. Peace & justice; Rats; 3. Good health; Pyrazoles; Corticosterone; Stress, Psychological; Endocannabinoids

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).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.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.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.