Neuroimmune and Developmental Mechanisms Regulating Motivational Behaviors for Opioids

<p>Opioid drug abuse represents a serious public health concern with few effective therapeutic strategies. A primary goal for researchers modeling substance abuse disorders has been the delineation of the biological and environmental factors that shape an individual’s susceptibility or resistance to the reinforcing properties of abused substances. Early-life environmental conditions are frequently implicated as critical mediators for later-life health outcomes, although the cellular and molecular mechanisms that underlie these effects have historically been challenging to identify. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation in the nucleus accumbens (NAc), and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). The experiments described in this dissertation were thus designed to address if inflammatory signaling in the NAc may underlie the effects of early-life experience on later-life opioid drug-taking. The results demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug concentration-dependent manner. Transcriptional profiling of the NAc reveals a suppression of pro-inflammatory cytokine and chemokine signaling molecules and an increase in anti-inflammatory IL-10 in handled rats following repeated exposure to remifentanil. To directly test the hypothesis that anti-inflammatory signaling can alter drug-taking behavior, bilateral intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) or control pDNA were delivered into the NAc of naïve rats. pDNA-IL-10 treatment reduces remifentanil self-administration in a drug concentration-dependent manner, similar to the previous observations in handled rats. Additional experiments confirmed that neither handling nor pDNA-IL-10 treatment alters operant responding for food or sucrose rewards. These results help define the conditions under which ventral striatal neuroimmune signaling may influence motivated behaviors for highly reinforcing opioid drugs.</p>Dissertatio