Toll-Like Receptor 4 Signaling and Drug Addiction.

Ruyan Wu,Jun-Xu Li

doi:10.3389/fphar.2020.603445

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.

Highlights

Neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction (Kalivas and O’Brien, 2008; Otis and Mueller, 2017)
Different classes of drugs including opioids, alcohol and psychostimulants will be reviewed to discuss whether toll-like receptor 4 (TLR4) signaling can be used as a potential therapeutic target for the treatment of drug addiction
Specific Tlr4 knockdown in mouse nucleus accumbens (NAc) did not alter ethanol intake and preference for ethanol in the 24 h continuous access two-bottle test. These results suggest that TLR4 was not important to the excessive drinking behavior and subsequently question the hypothesis that TLR4 is a critical component in mediating alcohol response

Summary

INTRODUCTION

Neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction (Kalivas and O’Brien, 2008; Otis and Mueller, 2017). Evidence of a Role of Toll-Like Receptor 4 in Alcohol Addiction Studies have suggested that TLR4 affects some behavioral effects of ethanol (Pandey, 2012; Wu et al, 2012; Pascual et al, 2015; Blednov et al, 2017a) Both pharmacological inhibition of TLR4 and genetic deficiency of TLR4 or MyD88 significantly decreased the duration of loss of righting reflex (LORR) and reduced recovery time in motor impairment (rotarod test). Another study showed that TLR4 knockout (KO) mice had a deficit in low-frequency stimulation-induced NMDAR-dependent long-term depression (LTD) in NAc core, which contributed to an attenuation in drug reward learning (Kashima and Grueter, 2017) These mixed results about the role of TLR4 in psychostimulants action make it difficult to draw specific conclusions here. These results are encouraging, though more studies are needed to examine the long-term effect of ibudilast on both peripheral and central neuroinflammation markers and how these modulations link to clinical outcomes

FUTURE DIRECTIONS

SUMMARY