Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell

Abstract

Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and therefore amplifying the reward changes in the neuronal activity induced by METH. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) is unknown. Herein, we provide direct evidence that METH creates neuroinflammation, at least in part, via the activation of the innate immune Toll-like receptor 4 (TLR4). Biophysical studies revealed that METH bound to MD-2, the key coreceptor of TLR4. Molecular dynamics simulations showed METH binding stabilized the active heterotetramer (TLR4/MD-2)2 conformation. Classic TLR4 antagonists LPS-RS and TAK-242 attenuated METH induced NF-κB activation of microglia, whereas added MD-2 protein boosted METH-induced NF-κB activation. Systemically administered METH (1 mg/kg) was found to specifically up-regulate expression of both CD11b (microglial activation marker) and the proinflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), but not in either the nucleus accumbens shell (NAc) or prefrontal cortex (PFC). Systemic administration of a nonopioid, blood–brain barrier permeable TLR4 antagonist (+)-naloxone inhibited METH-induced activation of microglia and IL-6 mRNA overexpression in VTA. METH was found to increase conditioned place preference (CPP) as well as extracellular dopamine concentrations in the NAc, with both effects suppressed by the nonopioid TLR4 antagonist (+)-naloxone. Furthermore, intra-VTA injection of LPS-RS or IL-6 neutralizing antibody suppressed METH-induced elevation of extracellular NAc dopamine. Taken together, this series of studies demonstrate that METH-induced neuroinflammation is, at least in part, mediated by TLR4-IL6 signaling within the VTA, which has the downstream effect of elevating dopamine in the NAc shell. These results provide a novel understanding of the neurobiological mechanisms underlying acute METH reward that includes a critical role for central immune signaling and offers a new target for medication development for treating drug abuse.

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

“…Indeed, a recent report examining METH's effects on TLR4 signaling and VTA-NAc dopamine transmission provides convincing evidence of this fact. In this study, Wang X. et al (2019) report that METH can bind to lymphocyte antigen 96 (i.e., MD-2), which interacts directly with TLR4 to confer receptor responsiveness to LPS, and that inhibition of TLR4 attenuated METH-induced NF-κB activation in microglia. In addition, this study also showed that METH upregulates IL-6 within the VTA and that this is associated with enhanced extracellular dopamine within the NAc, and treatment with the TLR4 inhibitor (+) naloxone or an intra-VTA IL-6 antibody reduces METH-induced increases in NAc dopamine (Wang X. et al, 2019).…”

“…In this study, Wang X. et al (2019) report that METH can bind to lymphocyte antigen 96 (i.e., MD-2), which interacts directly with TLR4 to confer receptor responsiveness to LPS, and that inhibition of TLR4 attenuated METH-induced NF-κB activation in microglia. In addition, this study also showed that METH upregulates IL-6 within the VTA and that this is associated with enhanced extracellular dopamine within the NAc, and treatment with the TLR4 inhibitor (+) naloxone or an intra-VTA IL-6 antibody reduces METH-induced increases in NAc dopamine (Wang X. et al, 2019). This study parallels findings described above by Brown et al (2018), which demonstrated reduced cocaine-primed reinstatement following intra-VTA treatment with a TLR4 antagonist.…”

A “Drug-Dependent” Immune System Can Compromise Protection against Infection: The Relationships between Psychostimulants and HIV

“…administration of only one dose, five days before splenocyte culture [ 66 ]. These data suggest that similar pathways may be triggered by amphetamine and Con A in immune cells, which could be explained by recent evidence that methamphetamine is a TLR4 agonist (see below) [ 168 ]. As far as we know, the simultaneous enkephalinergic activation in immunocytes and in the brain following exposure to amphetamine is the only evidence of a drug of abuse inducing similar biological changes in both systems.…”

Hippocampal blood–brain barrier of methamphetamine self‐administering HIV‐1 transgenic rats

“…This observation complements the observation of Zhang and colleagues who showed a meth‐induced increase in NF‐κB activation in cultured astrocytic cells (Zhang et al., 2015). Meth increases TNF‐α receptor expression (Park et al., 2017) and activates TLR4 (Wang et al., 2019). These actions of meth may underlie the increased NF‐κB activation observed in the non‐Tg rats.…”