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  4. Glutamatergic and neuroimmune mechanisms of N-acetylcysteine-mediated inhibition of cue-induced nicotine seeking
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Glutamatergic and neuroimmune mechanisms of N-acetylcysteine-mediated inhibition of cue-induced nicotine seeking

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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.

Date Created
2019
Contributors
  • Namba, Mark Douglas (Author)
  • Gipson-Reichardt, Cassandra D (Thesis advisor)
  • Conrad, Cheryl D. (Committee member)
  • Neisewander, Janet L (Committee member)
  • Arizona State University (Publisher)
Topical Subject
  • Neurosciences
  • Behavioral Sciences
  • pharmacology
  • CD40
  • GLT-1
  • neuroinflammation
  • Nucleus Accumbens
  • Reinstatement
  • TNF
  • Neuropharmacology
  • Psychopharmacology
  • Nicotine addiction--Treatment.
Resource Type
Text
Genre
Masters Thesis
Academic theses
Extent
vii, 50 pages : color illustrations
Language
eng
Copyright Statement
In Copyright
Primary Member of
ASU Electronic Theses and Dissertations
Peer-reviewed
No
Open Access
No
Handle
https://hdl.handle.net/2286/R.I.53465
Statement of Responsibility
by Mark Douglas Namba
Description Source
Viewed on March 24, 2020
Level of coding
full
Note
Partial requirement for: M.A., Arizona State University, 2019
Note type
thesis
Includes bibliographical references (pages 31-43)
Note type
bibliography
Field of study: Psychology
System Created
  • 2019-05-15 12:24:02
System Modified
  • 2021-08-26 09:47:01
  •     
  • 1 year 6 months ago
Additional Formats
  • OAI Dublin Core
  • MODS XML

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