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We are interested in how novel non-neuronal mechanisms contribute to drug addiction. There is growing recognition that microglial proinflammatory actions play an important role in the brain’s response to drugs of abuse. This work is based on our assumption that drugs of abuse are recognized as “foreign” by the brain’s immune system. Specifically, the toll-like receptor 4 appears to be a site at which drugs of abuse activate microglia. Toll-like receptor 4 activation consequently produces an innate immune response in the brain that initiates the release of glial-derived neuroexcitatory and neurotoxic substances such as proinflammatory cytokines. These glial products may thereby enhance neuronal excitability and potentiate drug-induced changes at the neuronal sites of action (e.g. dopamine transporter, opioid receptors, etc.) throughout the mesocorticolimbic circuitry. Repeated drug-induced microglial activation produces progressive increases in microglial reactivity, further potentiating the neurobiological consequences of chronic drug use. We are currently exploring how self-administration of drugs of abuse, such as cocaine and methamphetamine, alter the reactivity of microglia and how microglial proinflammatory mediators contribute to drug relapse.