Saturday, April 27, 2024
4/27/2024
Project Summary/Abstract Tobacco abuse is a significant health concern and remains the leading cause of preventable death in the United States, accounting for nearly one in five deaths in US adults. Smoking cessation treatment strategies, such as nicotine replacement therapy or varenicline (Chantix®), have shown some clinical efficacy in helping individuals quit smoking. However, high rates of relapse persist even for individuals receiving replacement therapy, which highlights the need for a more holistic understanding of the neurobiological underpinnings of nicotine addiction and relapse to better promote long-term abstinence from tobacco use. Maladaptive glutamatergic plasticity has been implicated across several major drugs of abuse and these synaptic alterations mediate the associative learning processes that occur between environmental stimuli and drugs of abuse. Specifically, cue-induced reinstatement of nicotine seeking in rats is associated with rapid, transient synaptic potentiation (t-SP) of medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore), as measured by an increase in dendritic spine head diameter (dh) as well as activation of extracellular matrix metalloproteinases (MMPs). The underlying molecular and cellular mechanisms that modulate this structural and functional plasticity remains poorly understood. Particularly, it is not known if neuroinflammatory mechanisms modulate the expression of these synaptic alterations. Thus, I propose to examine the role of proinflammatory tumor necrosis factor alpha (TNFa) and NF-¿B signaling on t-SP in the NAcore using a rodent model of cue-induced nicotine reinstatement. Specifically, I hypothesize that viral-vector mediated inhibition of I¿B kinase (IKK, which activates NF-¿B) signaling will attenuate t-SP in the NAcore and cue-induced nicotine reinstatement, whereas activation of IKK will potentiate these measures. Additionally, I propose that TNFa signaling underlies postsynaptic t-SP, MMP activation, and cue-induced reinstatement of nicotine seeking. This research has the potential to identify a novel mechanism through which postsynaptic t-SP is produced in response to drug-associated stimuli. As well, this research may reveal a novel and dynamic role for neuroinflammatory mechanisms in drug relapse and may guide the future development of new and effective pharmacotherapeutics. Throughout the duration of the proposed studies, I will be trained in confocal microscopy, three-dimensional analysis of dendritic spine morphology, immunohistochemistry, and viral-vector mediated genetic manipulation.
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