reduces innate immune signaling, and pioglitazone suppresses alcohol drinking and relapse to alcohol seeking in rats [59]. Additional subtypes of PPAR agonists may prove effective in the treatment of addictions given that clofibrate, a PPAR alpha agonist, blocks the rewarding effects of nicotine in monkeys and rats [60], and another PPAR alpha agonist prevents fatty liver in ethanol-fed animals [61]. Naltrexone is an opioid inhibitor approved for the treatment of alcoholism and is also known to inhibit ethanol-induced microglial activation and neurodegeneration in mice [62]. The commercially available (−) isomers of naltrexone and naloxone interact with both opioid and TLR4 receptors, whereas the synthetic (+) isomers interact specifically with TLR4 [63]. (+) Naloxone reduces alcohol-induced sedation and motor impairment in mice, indicating a specific role of TLR4 signaling in mediating the behavioral action of acute alcohol [28*]. It should be noted that while there is evidence that the anti-inflammatory properties of these drugs are responsible for modifying the ethanol-related behaviors above, other mechanisms cannot be ruled out without further investigation. These examples indicate there are FDA-approved drugs currently available that inhibit innate immune signaling and, therefore, may offer promise in treating the neuroimmune component of alcohol abuse.
