Translational and reverse translational research on the role of stress in drug craving and relapse

Abstract

Rationale and background High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown. Objectives and highlights Here, we address this topic by discussing recent results on the effect of alpha-2 adreno-ceptors and substance P-NK1 receptor antagonists on stress-induced reinstatement in mice and rats and stress-induced craving and potentially stress-induced relapse in humans. We also discuss brain sites and circuits involved in stress-induced reinstatement of drug seeking in rats and those activated during stress-induced craving in humans. Conclusions There is evidence that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced drug seeking in rats and stress-induced craving in humans. Whether these drugs would also prevent stress-induced drug relapse in humans and whether similar or different brain mechanisms are involved in stress-induced reinstatement in non-humans and stress-induced drug craving and relapse in humans are subjects for future research.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects

“…In a heterogeneous condition such as AD, characteristics of study participants may be decisive in determining whether an efficacy signal will be detected (Heilig et al, 2011;Litten et al, 2012;Sinha et al, 2011b). Whether craving and relapse are primarily driven by stress-or alcohol-associated stimuli, respectively, is a patient characteristic that has been suggested to predict treatment responses to different pharmacological mechanisms (Heinz et al, 2003).…”

Role of Bed Nucleus of the Stria Terminalis Corticotrophin-Releasing Factor Receptors in Frustration Stress-Induced Binge-Like Palatable Food Consumption in Female Rats with a History of Food Restriction

“…We found previously that the anticonvulsant drug topiramate (which showed some efficacy in the treatment of binge-eating disorders in patients (McElroy et al, 2004) and orexin-1 receptor antagonists decrease stress-induced binge eating Piccoli et al, 2012). Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in food restriction/frustration stress-induced binge eating in our model.…”

Sex Differences in Guanfacine Effects on Drug Craving and Stress Arousal in Cocaine-Dependent Individuals

“…Guanfacine also promotes a downregulation of sympathomimetic outflow from the vasomotor center of the brain to the heart (Sica, 2007). Notably, extensive preclinical and clinical research has shown that both of these central and peripheral mechanisms may have a salient role in the reduction of cocaine craving, owing to the fact that activation of the lateral tegmental NE system Erb, 2010;Sinha et al, 2011;Mantsch et al, 2013) and autonomic peripheral arousal (Sinha et al, 2003;Fox et al, 2008b) are implicated in stress-induced motivation for, and relapse to, cocaine during early recovery.…”

“…These adaptations include the desensitization of alpha2-adrenoceptors in the mediobasal hypothalamus (Baumann et al, 2004), increased activation of corticotrophin releasing hormone and NE in the central nucleus of the amygdala (CeA) and BNST (Shalev et al, 2002;Shaham et al, 2003), and heightened NE responsivity to stress in humans (Fox et al, 2005). Most notably, these withdrawal-related alterations have been shown to underpin stress-induced reinstatement of cocaine in rats Sinha et al, 2011), as well as the negative reinforcing effects of cocaine such as depressive-like symptoms (Siever and Uhde, 1984) and elevated anxiety and panic attacks (McDougle et al, 1994;Smith and Aston-Jones, 2008). As enhanced negative affect and sympathetic sensitivity to stress and drug cues during early withdrawal have been associated with elevated craving and relapse vulnerability (Sinha et al, 2003;Fox et al, 2005Fox et al, , 2008b, centrally mediated inhibition of NE, via functional antagonism of noradrenergic signaling, may provide a salient mechanism for medications development.…”