Neuroimmune mechanisms of psychostimulant and opioid use disorders

Abstract

Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non-traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain-immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders.

Keywords: addiction; immune effects of drugs of abuse; inflammation; microbiome.

Fig. 1

Emerging synaptic mechanisms of inflammation and addiction in the nucleus accumbens. Recent evidence has demonstrated multiple potential mecha-nisms of inflammatory processes affecting synaptic function in models of substance use disorder. (1) Levels of G-CSF are increased by cocaine, and G-CSF enhances neuronal activation and production of immediate early gene c-Fos in response to cocaine. (2) Cocaine and potentially opioids lead to increases in microglial production of TNF-a which inhibit AMPA receptor function in D1-expressing medium spiny neurons. (3) Via direct action on the toll-like receptors cocaine and opioids increase levels of IL-1b, enhancing synaptic dopamine release. (4) The anti-inflammatory cytokine IL-10 is upregulated by opioids in rats with a history of stress. IL-10 inhibits production of pro-inflammatory mediators by toll-like receptors.