Chemokines, cytokines and substance use disorders

Abstract

Efficacious pharmacotherapies for the treatment of substance use disorders need to be expanded and improved. Non-neuronal cells, particularly astrocytes and microglia, have emerged as therapeutic targets for the development of pharmacotherapies to treat dependence and relapse that accompanies chronic drug use. Cytokines and chemokines are neuroimmune factors expressed in neurons, astrocytes, and microglia that demonstrate promising clinical utility as therapeutic targets for substance use disorders. In this review, we describe a role for cytokines and chemokines in the rewarding and reinforcing effects of alcohol, opioids, and psychostimulants. We also discuss emerging cytokine- and chemokine-based therapeutic strategies that differ from conventional strategies directed toward transporters and receptors within the dopamine, glutamate, GABA, serotonin, and GABA systems.

Keywords: Alcohol; Chemokines; Cocaine; Cytokines; Methamphetamine; Opioids.

Fig. 1.

Model demonstrating potential interactions between drugs of abuse and cytokine/chemokine systems and putative therapeutic targets for substance use disorders (green lines = increase, red lines = decrease, MOR = μ-opioid receptor). (A) Exposure to different classes of drugs of abuse (psychostimulants, alcohol, opioids) causes an increase in brain levels of pro-inflammatory cytokines and chemokines (e.g. TNFα, IL-1β, CCL2, CCL5, and CXCL12). This leads to activation of specific receptors (e.g. CCR2, CCR5, and CXCR4) that enhances dopamine transmission in the limbic system, which exacerbates rewarding and reinforcing effects of drugs of abuse and relapse to drug seeking, and, in the case of opioids, reduces analgesic efficacy. (B) Cytokine and chemokine receptor antagonists (CRA) block the enhancement in dopamine transmission, thereby reducing drug reward, reinforcement and relapse, but enhance the analgesic efficacy of opioids by preventing desensitization of μ-opioid receptors (MOR).