Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders

Abstract

Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the "dual-hit" hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.

Keywords: anti-inflamatory treatments; neuroinflammatory priming; stress; substance use disorder.

Fig. 1.

Neuroinflammatory Processes. Microglia, the resident macrophages of the brain that play a key role in modulating the brain’s immune response (Napoli & Neumann, 2009), express surface toll-like receptors (TLRs) such as TLR4 that mediate the immune response to address endogenous and exogenous insults (Jack et al., 2005). Intercellularly, the nuclear transcription factor kappa-B (NF-κB) and mitogen activated protein kinase (MAPK) signaling transduction pathways occur downstream of TLR4 and mediate the induction of proinflammatory genes (Dinarello, 2000; Zusso et al., 2019). Upon activation, microglia have the ability to release inflammatory factors such as inducible nitric oxide synthase (iNOS) and cyclooxegnase-2 (COX2) as well as initiate the transcription of chemokines and cytokines to mediate inflammatory responses (F. T. Crews et al., 2017; Liu, Zhang, Joo, & Sun, 2017; Munhoz et al., 2008). Chemokines are a family of small proteins that act through G-protein coupled receptors that stimulate the immune system (Rostene, Kitabgi, & Parsadaniantz, 2007) and include the CC, CXC, CX3C, and XC families of chemokines while the main cytokines involved in inflammatory responses in the brain include tumor necrosis factors (TNFs), interferons (IFNs), and interleukins (ILs) (Dinarello, 2000). Figure was created with BioRender.com.