Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

Abstract

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…There are several recent reviews from 2016-2018 providing the details of other important stress responsive systems (like Corticotrophin Releasing Factor, Neuropeptide Y, and glucocorticoid receptor, etc.) from preclinical evidence to the recent clinical trials [Koob and Mason, 2016;Mantsch et al, 2016;Blaine and Sinha, 2017;Mason, 2017;Robinson and Thiele, 2017;Spierling and Zorrilla, 2017;Tunstall et al, 2017;Pomrenze et al, 2017]. The main focus in this mini-review is several other important stress responsive systems, which recently has not been reviewed, like arginine vasopressin/V1b receptors (Part I), and proopiomelanocortin/β-endorphin (Part II).…”

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

“…One of the conclusions that have emerged from this research is that type 1 receptors for corticotropin-releasing factor 1 (CRF1) are key mediators of stress-induced alcohol seeking. Accordingly, in rodents, systemic administration of brain penetrant CRF1 antagonists consistently blocks relapse-like behavior triggered by stress (reviewed, e.g., in Heilig and Koob, 2007;Le and Shaham, 2002a;Mantsch et al, 2016;Zorrilla et al, 2013).…”

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

“…TAAR1 has been implicated as a modulator of the dopaminergic system Miller, 2007, 2009a). TAAR1 knock-out mice showed augmented amphetamine-induced striatal release of dopamine (DA) (Lindemann et al, 2008). Moreover, transgenic mice that overexpress TAAR1 specifically in the brain showed decreased sensitivity to amphetamine (Revel et al, 2012a).…”