Many factors affect an individual's risk of addiction, including genetic, environmental, and physiological factors. Of these factors, the early-life environment of an individual, including maternal care, may be especially critical. Our research provides strong evidence that maternal care can permanently alter glial cell function within the brain, which has long-term consequences for neural function and behavior. Notably, glial cells (astrocytes and microglia) are activated by drugs of abuse, and their activation and subsequent release of cytokines and chemokines can markedly impact the physiological and addictive properties of drugs of abuse, including morphine. In this proposal, we describe our novel hypothesis that microglial-driven chemokine expression within the nucleus accumbens (NAc) underlies morphine-induced relapse in a model of addiction, and moreover that nurturing maternal care early in life induces resilience of the pups to drug relapse in adulthood by inducing an anti-inflammatory phenotype in microglia. Specifically, we show that: (1) Morphine profoundly activates glia within the adult rat NAc, inducing a rapid (minutes) increase in chemokines; (2) Inhibiting this morphine-induced chemokine response with a glial modulator, Ibudilast, completely prevents morphine- induced reinstatement of CPP assessed months later, without altering initial CPP which remains high; and (3) Neonatal handling mimics the glial modulator by completely preventing morphine-induced chemokine expression within the NAc in adulthood, and prevents the reinstatement of morphine CPP. Moreover, handled rats exhibit increased basal expression of the anti-inflammatory cytokine IL-10 within the brain compared to non-handled control rats, which is established early in life and maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. Our central hypothesis is that this epigenetically induced constitutive increase in microglial IL-10 by enhanced maternal care prevents the morphine-induced chemokine response by glia and thereby prevents the neural plasticity changes underlying drug-induced reinstatement of morphine CPP, independent of changes in reward or stress reactivity. Thus, the overall objective of this application is to fist establish a causal relationship for microglial IL-10 in the resilience to the novel brain chemokine response to morphine and subsequent drug-induced reinstatement. Second, we will determine whether IL-10 impacts chemokine expression by inhibiting canonical proinflammatory gene transcription within microglia.
Substance abuse takes a major toll on our society, and there are few successful treatments. Glial cells direct normal brain development, and increasing evidence suggests these cells profoundly affect the physiological and addictive properties of drugs of abuse. We present evidence that early-life maternal care can permanently alter glial function within the brain, as well as impact drug abuse liability in adulthood. Thus, the overall goal of this proposal is to elucidate the role of glial-derived factors in drug- seeking behavior, which we believe will lead to the identification of novel treatments.
