Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

Abstract

During the past two decades, there has been a tremendous expansion of knowledge regarding the neurobiological effects of substance abuse and how these effects impact behavior. At the same time, there has been a profound change in our understanding of the way in which the central nervous system responds to noxious stimuli. Most often referred to as the innate immune response (IIR), this defense mechanism is activated by a number of agents (toxic, microbial, ischemic) and has been implicated in the progression of a number of neurodegenerative diseases. We review evidence that psychostimulants of abuse (cocaine, methamphetamine, ecstasy) are associated with activation of the IIR. We first present background on what is currently known about the IIR including some of the cellular elements involved (microglia, astrocytes, vascular endothelial cells), key receptor pathways, and primary inflammatory cytokines (IL-1β, IL-6, TNF-α). We then present a variety of protein and gene expression data taken from animal studies that show increased expression of various components of the IIR following acute or repeated psychostimulant administration. Collectively the data indicate an association of psychostimulant use with IIR activation in the brain even at exposures not traditionally associated with neurotoxicity. Thus, the gradually escalating deleterious effects of psychostimulant use could in part involve neuroinflammatory mechanisms. Finally, we offer one hypothesis of a possible mechanism by which psychostimulants result in IIR activation and discuss the potential therapeutic implications of these findings for treatment of the recovering addict.

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…1 It is also evident that chronic abuse of psychostimulants (such as methamphetamine (METH) and cocaine) causes significant level of neurotoxicity and inflammation leading to persistent neurochemical abnormalities and loss of synaptic integrity. [2][3][4][5] Pronounced levels of oxidative stress and mitochondrial dysfunction, due to uncontrolled increase in cellular reactive oxygen (ROS) and nitrogen species (RNS), were identified as major pathological mechanisms underlying psychostimulant or smoking-induced neurodegeneration. [6][7][8][9][10][11][12] In fact, clinical studies suggest a diminished anti-oxidative stress response in cocaine or methamphetamine abusers compared with normal subjects.…”

Cocaine counteracts LPS-induced hypolocomotion and triggers locomotor sensitization expression

“…Clinical observations indicate that infections and chronic lesions are more frequent in drug users and elevated inflammatory states are evident in cocaine dependents (Clark, et al, 2013;Kousik et al, 2012). Additionally, some research groups have addressed the hypothesis of the involvement of lipopolysaccharide (LPS) and inflammatory cytokines in depressive illness and addiction behaviour (Breese et al, 2008;Dantzer et al, 2008;Leclercq et al, 2012;Maes et al, 2012).…”

“…There is evidence to suggest that the gut-brain axis may play a role in the pathogenesis of alcohol-dependence (Leclercq et al, 2012). Cytokines have also been shown to be involved in the neural disruption of addictive behaviors induced by psychostimulants (Clark et al, 2013;Kousik et al, 2012). Exposure to LPS, during late pregnancy, affects the development of the brain's dopaminergic system and predisposes to enhanced locomotor response following amphetamine challenge (Zager et al, 2012).…”

Sex differences in impulsivity and brain volumes in methamphetamine users

“…Larger right superior frontal volumes observed in the male METH users could be due to neuroinflammation caused by METH, possibly due to increased water content and cell volumes (Chang et al, 2007) and reactive gliosis and increases in gene and protein expression of factors associated with the innate immune response (Clark et al, 2013). Greater activated microglial density and glial proliferation could be contributing to the neuroinflammatory effects, previously shown in frontal gray matter in METH users (Chang et al, 2005b;Ernst et al, 2000).…”