15 research outputs found

    Opioid activation of toll-like receptor 4 contributes to drug reinforcement

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    Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.M. R. Hutchinson... J. Thomas, K. van Steeg... A. A. Somogyi... et al

    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

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    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.Xiaohui Wang, Alexis L. Northcutt, Thomas A. Cochran, Xiaozheng Zhang, Timothy J. Fabisiak, Mackenzie E. Haas, Jose Amat, Hongyuan Li, Kenner C. Rice, Steven F. Maier, Ryan K. Bachtell, Mark R. Hutchinson, and Linda R. Watkin

    DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling

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    Advance online publication 3 February 2015The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.A L Northcutt, M R Hutchinson, X Wang, M V Baratta, T Hiranita, T A Cochran, M B Pomrenze, E L Galer, T A Kopajtic, C M Li, J Amat, G Larson, D C Cooper, Y Huang, C E O'Neill, H Yin, N R Zahniser, J L Katz, K C Rice, S F Maier, R K Bachtell, and L R Watkin

    The behaviour of sharks

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    Australopithecines: Ancestors of the African Apes?

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