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.

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

“…The findings described here provide critical new insight into the long-lasting impact of immune-related signaling on gene expression in the brain. Understanding the acute and longlasting contributions of neuroimmune signaling to neuromodulation and plasticity is particularly important given the growing recognition that many environmental events, including stress (Frank et al, 2017;McKim et al, 2016;Serrats et al, 2017;Weber et al, 2015;Wohleb et al, 2015) and drugs of abuse (Crews et al, 2015;Hofford et al, 2018), recruit neuroimmune signaling pathways. Here we demonstrated sex-specific patterns of gene expression months after a subchronic immune challenge, where males showed a persistent shift in baseline gene expression and females showed a markedly different response to subsequent stimulation.…”

“…These findings provide critical new insight into the long-lasting impact of immune-related signaling on gene expression in the brain. Understanding the long-lasting contributions of neuroimmune signaling to neuromodulation and plasticity is particularly important given the growing recognition that many environmental events, including stress (Weber et al, 2015;Wohleb et al, 2015;McKim et al, 2016;Frank et al, 2017;Serrats et al, 2017) and drugs of abuse (Crews et al, 2015;Hofford et al, 2018) both recruit neuroimmune signaling pathways.…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…Indeed, immunological changes are seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Hofford and colleagues highlight mechanistic findings showing causal roles for central and peripheral immune mediators in substance use disorder and appropriate animal models (Hofford et al ., ). Another avenue for enhancing specificity derives from accumulating knowledge of the effects of oxidative stress in the nervous system, evolving from strictly neurotoxic to including a more nuanced role in redox‐sensitive signalling.…”

Granulocyte-Colony Stimulating Factor reduces cocaine-seeking and downregulates glutamatergic synaptic proteins in medial prefrontal cortex

“…In recent years, there has been increased interest in non-traditional pharmacological approaches to treat cocaine addiction. There is growing evidence for neuroimmune interactions in multiple neuropsychiatric disorders including schizophrenia, depression, and addiction (Hodes et al, 2015;Lacagnina et al, 2017;Miller and Goldsmith, 2017;Hofford et al, 2019). This has led to an emerging body of research targeting neuroimmune interactions as possible translational research targets in addiction and other neuropsychiatric diseases.…”