A critical role for glial cells in addiction is becoming increasingly apparent. For instance, it has recently been demonstrated that opioids directly activate glial cells within the CNS in a nonclassical opioid receptor manner, via the innate immune system’s pattern recognition receptor, toll-like receptor (TLR) 4, and that this opioid-induced glial activation contributes strongly to their rewarding properties. Thus, glial inhibitors such as minocycline, as well as selective TLR4 antagonism, markedly reduce opioid-induced dependence, tolerance, and reward. These combined data are striking because we have shown that opioids such as morphine, stimulants such as cocaine, and inflammatory agents such as LPS all activate glia via the same TLR, which have been referred to as generic “danger” receptors. Therefore, we have hypothesized that early-life exposure to drugs of abuse may have an enduring influence on an organism via its long-term activation of glia.
We have discovered that glia within the Nucleus Accumbens (NAcc) respond to morphine with a rapid increase in cytokine/chemokine expression, which predicts future drug-induced reinstatement of morphine conditioned place preference (CPP). This glial response to morphine is markedly influenced by early-life experience - a neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, profoundly attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling can be mimicked by pharmacological modulation of glia in adulthood with Ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene X early-life environment interaction on morphine-induced glial activation, and a specific role for this glial activation in drug-induced reinstatement of drug-seeking behavior.
Schwarz, JM, Hutchinson, MR, & Bilbo SD. (2011) Early-life experience decreases reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. Journal of Neuroscience, in press.