Persistent effects of acute stress on fear and drug-seeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction

Abstract

Even following long periods of abstinence, individuals with anxiety disorders have high rates of relapse to drugs of abuse. Although many current models of relapse demonstrate effects of acute stress on drug-seeking, most of these studies examine stressful experiences that occur in close temporal and physical proximity to the reinstatement test. Here, we assess the effects of a stressful experience in one context on fear and drug-seeking in a different context. We adapt the stress-enhanced fear learning procedure to examine impacts on drug-seeking long after the stressful experience occurred. We find massive footshock in a distinct environment produced an acute increase in corticosterone, long-term hyper-responsivity to a single shock in different contexts with extensive histories of drug-seeking behaviors, enhancements in cocaineinduced conditioned place preference in mice, and persistent enhancements in cue-induced reinstatement of methamphetamine-seeking behavior in rats. Together, these experiments demonstrate that an acute trauma causes persistent changes in responsivity to mild stressors and drug-seeking behavior in other contexts, which mirrors aspects of the comorbidity between post-traumatic stress disorder and substance use disorders. These behavioral approaches provide novel procedures for investigating basic mechanisms underlying this comorbidity and they provide powerful tools for testing preclinical pharmacological and behavioral interventions. [Supplemental material is available for this article.]Compared with the general population, individuals diagnosed with post-traumatic stress disorder (PTSD) have higher rates of substance use disorders (SUDs) (Stewart 1996;McFarlane 1998;Ouimette et al. 1998;Back et al. 2000;Sonne et al. 2003;McCauley et al. 2012;Tipps et al. 2014;Roberts et al. 2015) and are twice as likely to use methamphetamine (METH) than are individuals with trauma exposure that does not lead to PTSD (Smith et al. 2010). Individuals with PTSD are also more likely to relapse to drugs of abuse when cues associated with drug-seeking are encountered, even long after periods of acute stress have ended (Bradizza et al. 2006), suggesting stressors that are temporally and contextually dissociated from drug-seeking may induce longterm changes that contribute to an increased risk for relapse.It has long been observed that stress is a potent inducer of reinstatement (an animal model of relapse) in rodents (e.g., Shaham et al. 2000;Erb et al. 2001;Sanchez and Sorg 2001;Boutrel et al. 2005;Redila and Chavkin 2008;Schindler et al. 2010). Although the ability of stress to induce reinstatement has been well established in the literature, most studies have focused on effects when the organism is tested in a state of acute stress within the drug-seeking context; few studies have evaluated the persistent effects of an acute stressor long after the stress has ended. Individuals with PTSD have traumatic experiences long before relapse and are unlikely to use drugs in the trauma-associated context; avoiding ...

Non-pharmacological factors that determine drug use and addiction

“…Acute severe stress causes an enhanced responsiveness to mild stressors at endocrine and behavioral level. It enhances the reinforcing action of psychostimulant drugs, alcohol and opiates, and their selfadministration and resistance to extinction acutely, as well as long after the stress has ended (Piazza et al, 1989;Pizzimenti et al, 2017;Logrip et al, 2012). In most cases, a PTSD emerges first and triggers development of drug abuse and addiction.…”

N‐Acetylcysteine treatment during acute stress prevents stress‐induced augmentation of addictive drug use and relapse

“…relatively intense acute footshock leads to persistent enhancements in cue-induced reinstatement of methamphetamine seeking, as well as facilitating cocaine conditioned place preference (29). Furthermore, a history of exposure to a predator odor exposure enhances the reinstatement of methamphetamine seeking and exposure to stress odor also increases responding in a stress-induced reinstatement procedure (30).…”

Context-Dependent and Context-Independent Effects of D1 Receptor Antagonism in the Basolateral and Central Amygdala during Cocaine Self-Administration

“…The gradual effect that emerged over days is consistent with other studies of the BLA, which have found a delayed effect of BLA lesions on cue-induced reinstatement with no immediate effect on maintained cocaine self-administration (Meil and See, 1997). These and other findings suggest the importance of multiple long-term behavioral tests to reveal amygdala function in drug reward (Baxter and Murray, 2002; Pizzimenti et al, 2017).…”