Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

Abstract

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat Nucleus Accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is 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, 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 is 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 glial activation in drug-induced reinstatement of drug-seeking behavior.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…In a similar manner, an acute injection of morphine rapidly increases mRNA expression of both microglial CD11b and astrocytic GFAP in the NAc, but not the hippocampus (Schwarz et al, 2011). Concomitant systemic treatment with a pharmacological modulator of glial activation such as ibudilast, which functions as a nonselective phosphodiesterase inhibitor but has broad effects on glial function (Gibson et al, 2006), is effective at preventing CD11b and GFAP induction by morphine ), a result replicated by targeted intra-NAc infusions of ibudilast (Schwarz et al, 2011). Minocycline, a highly lipidsoluble tetracycline antibiotic that can also modulate glial activity, is capable of preventing LPS-induced upregulation of microglial Iba1 but has no effect on astrocytic GFAP upregulation following LPS (Yoon et al, 2012).…”

“…Importantly, these measures of glial activation are not found across the entire brain, but are rather restricted within certain brain regions, including the VTA, dentate gyrus, periaqueductal gray, dorsal caudate, and other regions that have previously been associated with opioid dependence . In a similar manner, an acute injection of morphine rapidly increases mRNA expression of both microglial CD11b and astrocytic GFAP in the NAc, but not the hippocampus (Schwarz et al, 2011). Concomitant systemic treatment with a pharmacological modulator of glial activation such as ibudilast, which functions as a nonselective phosphodiesterase inhibitor but has broad effects on glial function (Gibson et al, 2006), is effective at preventing CD11b and GFAP induction by morphine ), a result replicated by targeted intra-NAc infusions of ibudilast (Schwarz et al, 2011).…”

“…Consequently, opioid-induced neuroimmune signaling appears to be largely pro-inflammatory, although transcription of the anti-inflammatory cytokine IL-10 is also induced by acute morphine (Schwarz et al, 2011), an effect that parallels LPS injection (de Waal Malefyt et al, 1991). For instance, acute treatment of morphine rapidly increases gene expression of interferon-γ (IFN-γ) and several classes of chemokines within the NAc, an effect which is suppressed by pre-treatment with ibudilast (Schwarz et al, 2011). This effect was mediated in part through significant induction of antiinflammatory IL-10 gene expression in response to ibudilast treatment (Schwarz et al, 2011).…”

“…In addition, variations in early-life environmental conditions represent an important area for future research. For instance, rats that receive enriched maternal care show decreased preference for morphine as well as increased expression of anti-inflammatory IL-10 in the NAc, which may be persistently altered due to decreased Il-10 gene methylation in microglia (Schwarz et al, 2011). Given the unique developmental ontogeny of microglia (see Box 2) and their critical role in early brain development, it could be hypothesized that microglial-specific epigenetic modifications of inflammatory signaling could cause longlasting changes in risk or resilience to opioid reinforcement.…”

Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy

“…Finally, an epigenetic neuroimmune link to abuse liability following maladaptive early life experiences has been established. Schwarz et al (2011) demonstrated that early life events in rodents caused specific adaptions in the methylation of the IL-10 gene within nucleus accumbens microglia, which in turn, was associated with an increase in morphine's rewarding properties. 23…”