, Volume 218, Issue 1, pp 69-82

First online:

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

  • Rajita SinhaAffiliated withDepartment of Psychiatry, Yale University
  • , Yavin ShahamAffiliated withBehavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS Email author 
  • , Markus HeiligAffiliated withLaboratory of Clinical and Translational Studies, IRP/NIAAA/NIH/DHHS

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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 adrenoceptors 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.


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.


Corticotropin-releasing factor Craving Extinction NK1 receptor Noradrenaline Reinstatement Relapse Reverse translational research Stress Substance P Translational research Yohimbine