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.

Keywords: alcohol; drug reward; opioids; psychostimulants; reinstatement; toll-like receptor 4; withdrawal.

FIGURE 1

The Toll-like receptor 4 (TLR4) signaling pathway. TLR4 and its co-receptor MD-2 can signal through two different pathways, the myeloid differentiation primary response protein 88 (MyD88)-dependent and MyD88-independent pathway. In MyD88-dependent pathway, the signal transduces through Interleukin 1 receptor associated kinase 4 and 1 (IRAK4 and IRAK1) and the following TNF receptor associated factor 6 (TRAF6). The activation of TRAF6 leads to phosphorylation of inhibitors of nuclear factor κB Kinases (IKKs), which in turn activates the IκB. The activation of IκB leads to its degradation and the initiation of activation of NFκB and the production of proinflammatory cytokines, for example, Tumor Necrosis Factor (TNF), IL-1β and IL-6 (Kawai and Akira, 2007). In contrast, MyD88-independent pathway adopts the adaptor protein TRIF and transduces the signal through TRAF3, TBK1 and IKKε, which then phosphorylates interferon regulatory factor 3 (IRF3). IRF3 then translocates to the nucleus and promotes the transcription of type 1 interferons. Drugs of abuse like opioids, alcohol and psychostimulants may activate TLR4 signaling and induce pro-inflammatory responses.