Grants and Contracts per year
Grants and Contracts Details
Description
PROJECT SUMMARY/ABSTRACT
Nicotine abuse and addiction represent a significant burden to public health. Nicotine, an active alkaloid in
tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized
liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge
in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the
neurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brain
regions associated with drug reward, especially within the nucleus accumbens core (NAcore). NAcore
glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient potentiation of synaptic
strength (t-SP; measured as increased AMPA to NMDA ratios) and accompanying glutamate receptor changes.
Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse.
We and others recently found that N-acetylcysteine (NAC), an antioxidant and anti-inflammatory currently under
investigation as an addiction therapeutic, appears to inhibit nicotine cue-associated t-SP and restore glial
glutamate transport (GLT-1). As well, preliminary data collected during an R00 award period indicate that NAcore
GLT-1 restoration is necessary for NAC to reduce nicotine seeking, and NAC inhibits expression of the pro-
inflammatory cytokine, tumor necrosis factor alpha (TNFα), within the NAcore. TNFα activates nuclear factor-
kappa B (NF-κB) signaling and regulates learning, memory, and synaptic plasticity. Thus, in Aim 1 we propose
to characterize the role of NF-κB signaling in nicotine self-administration and cued nicotine seeking. As well, this
aim will determine if TNFα signaling impacts t-SP during cued nicotine relapse, and if a monoclonal antibody
against TNFα can inhibit these aberrant processes. Importantly, TNFα monoclonal antibodies are used clinically
for autoimmune disorders and are known to inhibit TNFα from binding to its receptor. Aim 2 will then determine
the role of microglia in t-SP and nicotine seeking using chemogenetics. Interestingly, we have found that GLT-1
expression rapidly increases along with t-SP during cued nicotine seeking. It is unclear, however, if this is
regulated by neuroinflammation and accompanied by astrocyte and microglial migration to the synapse during
nicotine seeking. Therefore, in Aim 3 we propose to bi-directionally control microglia using chemogenetics to
determine their ability to gate NAcore astrocyte-synaptic contact during nicotine seeking. In conclusion, findings
from these investigations will uncover an active, dynamic role of neuroinflammatory signaling in nicotine self-
administration and cue-driven nicotine relapse-associated synaptic plasticity, and broaden the scope of our
current understanding of neurobiological mechanisms underlying nicotine addiction.
Status | Active |
---|---|
Effective start/end date | 9/1/20 → 8/31/24 |
Funding
- National Institute on Drug Abuse: $938,937.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.
Projects
- 1 Active
-
Diversity Supplement for Kendrick: Neuroinflammatory and Glutamatergic Mechanisms of Nicotine Seeking
Gipson-Reichardt, C., Pearson, K. & Stoops, W.
National Institute on Drug Abuse
9/1/20 → 8/31/24
Project: Research project