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- All Subjects: neuroinflammation
- Creators: Conrad, Cheryl D.
Description
Nicotine self-administration is associated with decreased expression of the glial glutamate transporter 1 (GLT-1) and the cystine-glutamate exchange protein xCT in the nucleus accumbens core (NAcore). N-acetylcysteine (NAC), which is an antioxidant, anti-inflammatory, and glutamatergic agent, restores these proteins associated with increased relapse vulnerability. However, the specific molecular mechanisms driving NAC inhibitory effects on cue-induced nicotine reinstatement are unknown. Thus, the present study assessed NAC’s effects on cue-induced nicotine reinstatement are dependent on NAcore GLT-1 expression. Here, rats were treated with NAC in combination with intra-NAcore vivo-morpholinos to examine the role of GLT-1 in NAC-mediated inhibition of cue-induced nicotine seeking. Subchronic NAC treatment attenuated cue-induced nicotine seeking in male rats and an antisense vivo-morpholino (AS) designed to selectively suppress GLT-1 expression in the NAcore blocked this effect. NAC treatment was also associated with an inhibition of pro-inflammatory tumor necrosis factor alpha (TNFα) expression in the NAcore. As well, GLT-1 AS markedly increased expression of CD40, a known marker of pro-inflammatory M1 activation of microglia and macrophages. To further examine whether NAC-induced decreases in nicotine seeking involve suppression of TNFα, we manipulated a downstream mediator of this pathway, nuclear factor kappa B (NF-kB). Considering the putative role of NF-κB in learning, memory, and synaptic plasticity, separate experiments were performed where rats were treated with herpes simplex virus (HSV) vectors designed to increase (HSV-IKKca) or decrease (HSV-IKKdn) NF-κB signaling through interactions with IκB Kinase (IKK). The goal was to examine the role of NF-κB signaling in mediating nicotine seeking behavior and if NF-κB signaling regulates GLT-1 expression. HSV-IKKdn alone and in combination with NAC inhibited cue-induced nicotine reinstatement, while HSV-IKKca blocked the attenuating effect of NAC on reinstatement. Interestingly, both HSV-IKKdn and HSV-IKKca, regardless of NAC treatment, inhibited GLT-1 expression. Taken together, these results suggest that while GLT-1 may be a conserved neurobiological substrate underlying relapse vulnerability across drugs of abuse, immunomodulatory mechanisms may regulate drug-induced alterations in glutamatergic plasticity that mediate cue-induced drug-seeking behavior through GLT-1-independent mechanisms.
ContributorsNamba, Mark Douglas (Author) / Gipson-Reichardt, Cassandra D (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / Arizona State University (Publisher)
Created2019
Description
A prominent aspect of Alzheimer’s disease (AD) is the presence of neuroinflammation is mediated by the activation of microglial cells, which are the immune cells in the central nervous system (CNS) that express an array of cytokines that may promote an inflammatory response. The main cytokines produced are: tumor necrosis factor-alpha (TNF-), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The presence of these cytokines in the CNS may lead to neuronal death, to the production of toxic chemicals (such as nitric oxide), and to the generation of amyloid beta (a major pathological feature of AD). Previous studies have shown that modulation of the inflammatory response in the nervous system can potentially prevent and/or delay the onset of neurodegenerative diseases such as AD. Therefore, it is important to identify the process that induces CNS inflammation. For example, mitochondrial lysates have been found to produce an inflammatory response due to their ability to stimulate TNF-, Aβ, and APP mRNA [10]. Interestingly, extracellular mitochondria have been detected in the brain due to neurons degrading old mitochondria extracellularly. Therefore, we set out to study the effect of whole mitochondria isolated by differential centrifugation from human neuroblastoma cells (BE(2)-M17 cells) on the neuroinflammatory response in a human microglia model (THP-1 cells). Despite our best efforts, in the end it was unclear whether the mitochondrial fraction or other cellular components induced the inflammatory response we observed. Thus, further work with an improved mitochondrial isolation method should be carried out to address this issue.
ContributorsStokes, Laura Jean (Author) / DeCourt, Boris (Thesis director) / Sweazea, Karen (Committee member) / Gonzales, Rayna (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05