Wednesday, February 5, 2025
2/5/2025
ABSTRACT Tobacco use remains a major public health and economic concern, particularly in women who are more susceptible to the long-term consequences of nicotine exposure. Clinical evidence has revealed that stress produced by nicotine withdrawal can be intensified by fluctuations in gonadal hormones in women, although the underlying mechanisms remain obscure. Thus, there is a critical need to determine the mechanisms by which stress systems enhance withdrawal severity in females versus males, and the influence of ovarian hormones on these measures in adult females. If this knowledge gap is not filled, then the challenges of reducing nicotine use and developing specialized medications for females will remain largely insurmountable. The long-term goal of our research program is to identify the mechanisms that mediate nicotine use among different clinical populations that are uniquely susceptible to this problem. The objective of this application is to determine the mechanisms that promote withdrawal from chronic nicotine vapor inhalation. Recent work in male rodents has revealed that nicotine withdrawal is modulated in the medial habenula-interpeduncular nucleus (MHb-IPN) pathway. Our central hypothesis is that sex differences in withdrawal are modulated in the local circuits of the IPN, where stress and ovarian hormones modulate withdrawal severity in females. Specifically, our mechanistic hypothesis is that females experience greater inhibitory tone in the IPN via local interneurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). These GABA interneurons express type 1 receptors for the stress peptide, corticotropin-releasing factor (CRFR1). We posit that chronic nicotine produces a greater enhancement of CRF production and CRFR1 receptor expression which further promotes GABAergic inhibitory tone in the IPN of females. The rationale for the proposed research is that its successful completion is likely to contribute to a mechanistic framework for the development of new cessation strategies, particularly for women. Guided by strong preliminary data, the following specific aims were designed to: 1) identify the mechanisms by which the IPN controls nicotine withdrawal in females and males and 2) determine the effects of ovarian hormones on IPN-modulated nicotine withdrawal in females. The proposed studies constitute a multi- disciplinary approach involving tract tracing, behavior, immunocytochemistry, neurochemistry, and gene-transfer technology to compare sex differences (Aim 1) and the influence of ovarian hormones (Aim 2) on withdrawal severity and inhibitory tone in the IPN. The proposed work is innovative because it combines state-of-the-art methods to unveil the mechanisms by which inhibitory tone in the IPN modulates withdrawal in a sex- and hormone-dependent manner. The proposed research is significant because the results are expected to inform the development of future interventions that will selectively target the underlying mechanisms of withdrawal. Ultimately, the results of our research continuum are expected to contribute meaningfully to the design of precision therapeutics that will reduce health disparities produced by chronic nicotine use, particularly in women.
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