Toll-Like Receptor 4 Signaling and Drug Addiction

Abstract

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

“…Nevertheless, neuroinflammation markers have not been documented after MDPV in vivo administration. Accordingly, we aimed to characterize if PRR innate immune modulators, particularly the TLRs and RAGE may be altered, as both have been implied in microglia induced neurotoxicity and neuroinflammation in drug addiction [ 25 , 36 , 40 , 42 , 43 , 45 , 46 , 79 ]. Unique attention has been given to TLR4 signaling: this is seemingly associated with METH induced activation of glial cells in hippocampus [ 44 ], increased DA in the NAc shell [ 36 ], enhanced cytokine expression in the cortex [ 37 ], and reduced pro-inflammatory mediators in microglia-like cells upon LPS stimulation [ 38 ].…”

“…Accordingly, new avenues are being explored. There is a growing body of evidence showing that a group of pattern recognition receptors (PRRs) that detect and respond to exogenous pathogen associated molecular patterns (PAMPs) and endogenous danger associated molecular patterns (DAMPs), the toll-like receptors (TLRs), may be implicated in psychostimulant induced innate neuroimmune responses [ 36 , 40 , 42 , 43 ]. TLR4 signaling seems to be involved in drug reward-associated behaviors and proinflammatory responses, contributing to the development of drug addiction [ 36 , 43 ].…”

“…There is a growing body of evidence showing that a group of pattern recognition receptors (PRRs) that detect and respond to exogenous pathogen associated molecular patterns (PAMPs) and endogenous danger associated molecular patterns (DAMPs), the toll-like receptors (TLRs), may be implicated in psychostimulant induced innate neuroimmune responses [ 36 , 40 , 42 , 43 ]. TLR4 signaling seems to be involved in drug reward-associated behaviors and proinflammatory responses, contributing to the development of drug addiction [ 36 , 43 ]. Coherently, the TLR4/NFκB signaling pathway has been recently and increasingly reported to be associated with METH induced activation of glial cells in hippocampus [ 44 ], increased DA in the NAc shell [ 36 ], enhanced cytokine expression in the cortex [ 37 ], and reduced pro-inflammatory mediators in microglia-like cells upon LPS stimulation [ 38 ].…”

The Decrease In The Anxiolytic Effect of Morphine After Repeated Use of The Drug In Rats is Associated With Inflammatory Cytokine Signaling Pathways In The Prefrontal Cortex

“…Therefore, further analyses of molecular pathways in the PFC are important to understand the mechanisms resulting in the development of morphine dependence and the decrease in its anxiolytic-like effects after prolonged use of the drug. Activation of glia by morphine via binding to tolllike receptors has attracted considerable attention to explain, at least partly, non-neuronal mechanisms of the induction of tolerance and dependence to morphine (Eidson and Murphy 2013; Eidson and Murphy 2019; Hutchinson et al 2011;Wu and Li 2020). However, little is known about the involvement of neuroin ammation pathways upon activation of toll-like receptors and production of in ammatory cytokines in anxiety-like behaviors after repeated injection of morphine.…”

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

“…Some TSRs were regulated in multiple comparisons, including several near Hif3a and Fkbp5 loci. Moreover, differential TSRs were also enriched near genes that have been previously linked to addiction processes (Foxo3 (Ferguson et al, 2015), Tlr4 (Wu and Li, 2020)) or addiction vulnerability (Nat1 (Comings et al, 2000), Ppm1k (Carr et al, 2007;Liang et al, 2010), Pknox2 (Zuo et al, 2014)).…”