Glia, including microglia and astrocytes, are the most abundant cell type in the brain and the primary immunocompetent cells of the CNS. Notably, glial cells are activated by drugs of abuse, and their activation and subsequent release of cytokines
and chemokines can impact the physiological and addictive properties of drugs of abuse, including morphine. Morphineinduced proinflammatory glial activation alters neuronal excitability and synaptic connectivity, opposes morphine-induced
analgesia, and increases tolerance, respiratory depression, withdrawal, and reward to morphine (Bland et al., 2010; Hutchinson et al., 2008a, 2009; Narita et al., 2008).
Given these collective findings, the hypotheses that guided the research presented are as follows: (1) drugs of abuse activate glia, thus increasing the likelihood of abuse, and (2) attenuating/preventing morphine-induced glial activation via early-life handling should therefore reduce abuse liability later in life. We present the following evidence in support of these hypotheses: (1) morphine activates glia within the nucleus accumbens (NAcc), inducing a rapid increase in cytokines and chemokines; (2) neonatal handling increases expression of the anti-inflammatory cytokine IL-10, attenuates morphine-induced glial activation within the NAcc, and protects these rats from drug-induced reinstatement of morphine CPP; and (3) treatment of adult rats with a glial modulator, ibudilast, mimics neonatal handling by increasing IL-10 expression, blocking glial activation within the NAcc, and preventing reinstatement of CPP. Neonatal handling increases IL-10 expression postnatally, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia of the NAcc. Thus, these experiments have identified a gene early-life environment interaction on glial function within the NAcc, which predicts risk versus resilience for
relapse liability in a model of addiction.