Neural-Glial Interactions in Addiction

Increasing evidence suggests the activation of glia, including microglia and astrocytes, by drugs of abuse can markedly impact their physiological and addictive properties. 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.  We have extended this literature by demonstrating that microglial-driven cytokine & 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. More recently we demonstrated that neonatal handling attenuates intravenous self-administration of the opioid remifentanil, and intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats reduces remifentanil self-administration, similar to the effect of handling. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs.

            Our ongoing work is focused on the role of microglia in shaping the normal development of the NAc. We made the striking discovery that microglia specifically prune dopamine D1 receptors during adolescence, and that this glial activity is necessary for the development of normal social behavior in male rats. We believe these data may have profound implications for the impact of early-life events that persistently impact glial development and function, and thus their response to drugs of abuse (e.g., during adolescence). 

Representative Publications:

  1. Schwarz, JM, Hutchinson, MR, Bilbo, SD.  (2011) Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.  Journal of Neuroscience, 31(49):  17835-47. PMCID: PMC3259856
  2. Schwarz, JM, & Bilbo SD.  (2013) Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction.  Journal of Neuroscience, 33(3):961-71. PMCID: PMC3713715
  3. Lacagnina, ML, Kopec, AM, Cox SS, Hanamsagar, R, Wells C, Slade S, Grace, PM, Watkins LR, Levin, ED, Bilbo, SD. (2017) Opioid self-administration is attenuated by early-life experience and gene therapy for anti-inflammatory IL-10 in the nucleus accumbens.  Neuropsychopharmacology, 42(11): 2128-2140. PMCID:PMC5603817
  4. Kopec, AM, Smith, CJ, Ayre, NR, Sweat, SC, Bilbo, SD. Microglial elimination of dopamine D1 receptors defines sex-specific changes in nucleus accumbens development and social play behavior during adolescence. Nature Communications, 9(1):3769.