Stress sets the stage for cocaine cravings in the brain, study finds

A new study published in Biological Psychology sheds light on the neurobiological processes that link stress to cravings for cocaine.

“Despite intensive research efforts, drug addiction persists as one of society’s most significant health-related issues, and treatment options are limited,” explained study author John R. Mantsch, the chair of the Biomedical Sciences Department at Marquette University.

“The development of interventions aimed at relapse prevention is particularly important for improved outcomes in patients with substance use disorders. Much evidence suggests that stress is a critical contributor to drug use and relapse. While it is clear that there is a relationship between stress and drug seeking, the exact nature of this relationship and the underlying mechanisms are unclear.”

“The goals of this study were to develop a new model for studying the contribution of stress to drug seeking and to examine the mechanisms in the prefrontal cortex through which stressful stimuli promote drug seeking,” Mantsch said.

Previous research has established a link between stress and drug cravings, and some studies indicate that stress can act as trigger for cravings.

The findings from new study, which was conducted on rats, suggests that stress can set the stage for — but not necessarily directly trigger — cocaine-seeking behavior. Stress appears to set the stage for cravings through its actions on the medial prefrontal cortex, an area of the brain that plays a major role in executive functions such as planning.

“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,” Mantsch told PsyPost.

“In this paper, we use a preclinical rodent model to demonstrate that, during periods of stress, elevated glucocorticoids mobilize endocannabinoid signaling in the prelimbic prefrontal cortex to attenuate inhibitory transmission and promote cocaine seeking behavior.”

“Our findings establish a novel mechanism through which stress can promote susceptibility to relapse in individuals with substance use disorder and therefore may reveal opportunities for new and more effective treatment strategies aimed at relapse prevention,” Mantsch explained.

But there is still much that scientists don’t understand about the link between stress and drug abuse.

“There are several important questions yet to be addressed,” Mantsch told PsyPost. “First, the time-course of stress effects is suggestive of a glucocorticoid mechanism that this not mediated by the canonical glucocorticoid receptor, which typically functions by regulating gene transcription, resulting in effects that take time to develop.”

“Secondly, the output pathway from the prefrontal cortex that is regulated by stress and mediates drug seeking needs to be confirmed. Third, it is unclear if the effects of endocannabinoids on drug seeking can be reproduced by cannabis exposure. Such an observation could suggest that acute cannabis use can promote relapse.”

“However, it should be noted that in contrast to cannabis effects which will be exerted throughout the brain, the effects of stress on endocannabinoids are likely not uniform throughout the brain,” Mantsch said. “Moreover, THC (the primarily active cannabinoid constituent in cannabis products) and endocannabinoids have different actions at receptors that may predict distinct effects on cortical signaling and behavior.”

“Finally, we are in the process of determining if there are sex differences in the effects of stress and glucocorticoids on relapse susceptibility.”

The study, “Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex“, was co-authored by Jayme R. McReynolds, Elizabeth M. Doncheck, Yan Lib, Oliver Vranjkovic, Evan N.Graf, Daisuke Ogasawara, Benjamin F.Cravatt, David A.Baker, Qing-Song Liu, and Cecilia J.Hillard.