Jingwei Gao, Cong Lin, Lehua Deng, H.Y. Wang, Xiaohui Wang
Abstract Neuroimmune activation via Toll-like receptor 4 (TLR4) contributes to the pathophysiology of substance use disorders. Although (+)-naltrexone can antagonize TLR4 without engaging classical opioid receptors, its modest potency limits translational potential. The dual-site optimization at C3 and N17 was performed and identified CIAC101, an isobutyl-substituted (+)-naltrexone derivative with nanomolar TLR4 antagonism, representing ∼6200-fold higher potency than (+)-naltrexone. CIAC101 dose-dependently blocked lipopolysaccharides-induced NF-κB activation and reduced the expression of pro-inflammatory mediators in microglia BV-2 cells. In vivo, low-dose CIAC101 (0.2 mg/kg) attenuated methamphetamine (METH)–induced behavioral sensitization and conditioned place preference without intrinsic rewarding effects. Mechanistically, CIAC101 reduced microglial activation and inflammatory gene expression within addiction-relevant circuits, notably medial prefrontal cortex and ventral tegmental area. Together, these data nominate CIAC101 as a potent, central nervous system (CNS)-penetrant TLR4 antagonist that couples robust antineuroinflammatory activity with efficacy against METH-evoked neurobehavioral adaptations, advancing a neuroimmune strategy for treating stimulant addiction.