Enhanced Sensitivity to Stress and Drug/Alcohol Craving in Abstinent Cocaine-Dependent Individuals Compared to Social Drinkers

Abstract

Chronic exposure to cocaine is associated with neuroadaptions in stress and reward circuits that may increase susceptibility to relapse. We examined whether there are alterations in stress response and craving in abstinent cocaine-dependent individuals compared with a demographically matched group of non-addicted socially drinking community controls. Forty treatment-engaged abstinent cocaine patients (17F/23M) and 40 controls (19F/21M) were exposed to a brief 5 min guided imagery of individually calibrated stressful situations, personal drug/alcohol-related situation and a neutral-relaxing situation, one imagery per session, presented in random order. Craving, anxiety, emotion rating scales, and physiological measures were assessed. Cocaine patients reported significantly higher and more persistent stress-and cue-induced drug/alcohol craving, negative emotions, and physiological responses compared with social drinkers. In cocaine patients, stress-and cue-induced drug craving was accompanied by increased anger, fear, sadness, heart rate, and SBP. Controls reported minimal stress-induced craving and only increases in anxiety and SBP during stress exposure. Cue-induced alcohol craving was accompanied only by an increase in relaxed state. Females reported increased stress-induced anxiety and sadness compared with males, while males were emotionally and physiologically more reactive in the cue condition. These findings are the first to document functional alterations in stress-and reward-related affect and physiology in recently abstinent cocaine patients that is marked by an enhanced sensitivity to stress-and drug-related cue exposure. These data suggest that recovery from chronic cocaine abuse could be hampered by a hyper-responsive stress-and drug-craving state that increases cocaine relapse susceptibility.

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics

“…The importance of the alteration of such mechanisms is reinforced by the evidence that all these alterations occurred without changes in the circulating levels of glucocorticoids, although we cannot exclude that the hormonal levels might have been altered at different time points. Of note, the effects produced by short withdrawal wane in animals abstinent for 48 days, indicating that they are peculiar of the short-term withdrawal, an observation that might be of functional relevance given the altered response to stress observed in cocaine users during early abstinence (Fox et al, 2008;Sinha et al, 2003). Further, since we have previously shown that short-term withdrawal from developmental cocaine exposure causes an abnormal response to a stress challenge leading to pro-depressive symptoms (Caffino et al, 2015), we suggest that the herein shown dysregulation of the GR system may contribute to the negative emotional state observed in humans during early periods of abstinence (Gould, 2010;Koob, 2013).…”

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

“…Craving has become a subject of great interest as it is a reliable intermediate phenotype of relapse and the most distressing and long-lasting symptom experienced by dependent individuals between uses. Indeed, even after a period of abstinence, dependent individuals remain vulnerable to stress and other craving-inducing stimuli [10], which, in turn, leads to intense physiological responses and various negative feelings such as anger and sadness [11]. Real-time daily monitoring of craving and drug use has shown that craving reliably predicts relapse among dependent individuals [9,[12][13][14][15].…”

“…It remains to be determined if these properties translate in the attenuation of symptoms for other anxiety disorders than social phobia (e.g., post-traumatic stress disorder, panic disorder) [66]. There are contradictory results as to CBD's effect on sleep (similar to results from animal studies) as it has been associated with both wake-inducing and hypnotic properties in humans [11,67,68]. Altogether, many pharmacological, preclinical, and clinical properties (e.g., antipsychotic, anxiolytic) of CBD that had been demonstrated over roughly the last decade all point towards a potential role for CBD in alleviating behaviors relevant to addiction disorder.…”

Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

“…mGluR 2/3 are located pre-, peri-, and post-synaptically (Benarroch, 2008), and negatively modulate glutamate transmission by inhibiting glutamate release and reducing neural excitability at the postsynaptic level (Ferraguti and Shigemoto, 2006;Pinheiro and Mulle, 2008;Schoepp, 2001). mGluR 2/3 are widely expressed throughout brain circuits that mediate ethanolassociated conditioned reinforcement, incentive motivation and reward (Dayas et al, 2007;Kenny and Markou, 2004;Tzschentke and Schmidt, 2003;Zhao et al, 2006), as well as circuits mediating stress and anxiety responses (Benarroch, 2008;Dayas et al, 2007;Zhao et al, 2006), the latter representing important risk factors for ethanol abuse and relapse (Brown et al, 1995;Fox et al, 2007Fox et al, , 2008; Kreek and Koob, 1998;Sinha, 2000Sinha, , 2001Sinha et al, 2009). Recent findings provide strong evidence that mGluR 2/3 participate in mediating many addiction-relevant actions of ethanol.…”