Anti-stress neuropharmacological mechanisms and targets for addiction treatment: A translational framework

Abstract

Stress-related substance use is a major challenge for treating substance use disorders. This selective review focuses on emerging pharmacotherapies with potential for reducing stress-potentiated seeking and consumption of nicotine, alcohol, marijuana, cocaine, and opioids (i.e., key phenotypes for the most commonly abused substances). I evaluate neuropharmacological mechanisms in experimental models of drug-maintenance and relapse, which translate more readily to individuals presenting for treatment (who have initiated and progressed). An affective/motivational systems model (three dimensions: valence, arousal, control) is mapped onto a systems biology of addiction approach for addressing this problem. Based on quality of evidence to date, promising first-tier neurochemical receptor targets include: noradrenergic (α1 and β antagonist, α2 agonist), kappa-opioid antagonist, nociceptin antagonist, orexin-1 antagonist, and endocannabinoid modulation (e.g., cannabidiol, FAAH inhibition); second-tier candidates may include corticotropin releasing factor-1 antagonists, serotonergic agents (e.g., 5-HT reuptake inhibitors, 5-HT3 antagonists), glutamatergic agents (e.g., mGluR2/3 agonist/positive allosteric modulator, mGluR5 antagonist/negative allosteric modulator), GABA-promoters (e.g., pregabalin, tiagabine), vasopressin 1b antagonist, NK-1 antagonist, and PPAR-γ agonist (e.g., pioglitazone). To address affective/motivational mechanisms of stress-related substance use, it may be advisable to combine agents with actions at complementary targets for greater efficacy but systematic studies are lacking except for interactions with the noradrenergic system. I note clinically-relevant factors that could mediate/moderate the efficacy of anti-stress therapeutics and identify research gaps that should be pursued. Finally, progress in developing anti-stress medications will depend on use of reliable CNS biomarkers to validate exposure-response relationships.

Drug-induced stress responses and addiction risk and relapse

“…Despite the gaps in the literature, these findings collectively suggest that dysregulation of the stress responses may serve as potential markers for prevention efforts and a target for the development of therapeutic interventions ( Greenwald, 2018 ; Milivojevic and Sinha, 2018 ). Prevention efforts that target individuals with certain risk factors known to impact the stress system (e.g., early life adversity, genetic, family history) may reduce the likelihood that these individuals will develop a substance use disorder.…”

Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation

“…High-frequency repetitive transcranial magnetic stimulation and/or cognitive training may bolster one's resilience to acute stress effects. In addition, 'anti-stress' medications that block α 1 -and β 1 -noradrenergic receptor stimulation (prazosin + propranolol) may rescue dlPFC cognitive functions during acute stress (Greenwald, 2018). We believe this experimental approach -pharmacological stress-induction and task-induced 1 H fMRS glutamate modulation -has widespread applicability in the study of brain function in health and disorders (Stanley and Raz, 2018).…”

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

“…Stress is an environmental variable clearly associated with initiation, maintenance and relapse into drug abuse and is a challenge for the treatment of substance use disorders. According to Greenwald [117], CBD can be considered an emerging pharmacotherapy with the potential for reducing stress-potentiated seeking and consumption of several drugs of abuse, including cocaine. In laboratory rodents, acute and repeated treatment with CBD produced anxiolytic effects in the elevated plus-maze [54,57,59] and other behavioural paradigms [16].…”