Abstract
BackgroundThe nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown.MethodsThe present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot.ResultsWe showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα.ConclusionsTaken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.
Highlights
The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction
These results suggest that genetic blockade of TLR3 impairs cocaine-conditioned place preference (CPP)
When compared to LV-green fluorescence protein (GFP) control mice, Lentivirus-mediated re-expression of Tlr3 (LV-TLR3)-treated mice showed significantly increased locomotor activity after repeated cocaine administration (20 mg/kg/day; Fig. 4d; F(3,42) = 42.882, ***p < 0.001). These results indicate that cocaine-induced CPP and locomotor activity revert deficits after restoring TLR3 expression in the nucleus accumbens (NAc), and support the notion that TLR3 may play a stimulative role in cocaine-induced behavior
Summary
The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are involved in drug dependence; the detailed mechanism is largely unknown. Repeated use of cocaine causes long-lasting changes in the brain’s reward circuitry, a crucial component of which is the nucleus accumbens (NAc) [2]. Animal behavioral studies have demonstrated that proinflammatory cytokines of the central immune system are. Toll-like receptors (TLRs) are evolutionarily conserved pattern-recognition receptors (PRRs) that are critically involved in host defense mechanisms in many species, including plants and humans [11]. Animal studies have demonstrated the participation of the innate immune system, especially the TLR family, in the behavioral response to multiple drugs of abuse [12,13,14]. Blockade of TLR4 suppresses opioid-induced conditioned place preference (CPP) and reduces opioid self-administration in
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