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

Authors
  • Greenwald, Mark K1
  • 1 Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA.
Type
Published Article
Journal
Neurobiology of stress
Publication Date
Nov 01, 2018
Volume
9
Pages
84–104
Identifiers
DOI: 10.1016/j.ynstr.2018.08.003
PMID: 30238023
Source
Medline
Keywords
Language
English
License
Unknown

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.

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