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Principal Investigator: LAURA ELENA ODELL
Organization: UNIVERSITY OF TEXAS EL PASO
Fiscal Year: 2024
Award: $453,040
Funding agency: National Institute on Drug Abuse
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.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><ACTH-Releasing Factor><Adult females><Adult women><Aminalon><Aminalone><Aquadiol><Behavior><Behavioral><CRF-41><Chronic><Clinical><Common Rat Strains><Connector Neuron><Corpus Luteum Hormone><Corticoliberin><Corticotropin-Releasing Factor><Corticotropin-Releasing Factor-41><Corticotropin-Releasing Hormone><Corticotropin-Releasing Hormone-41><Data><Decrease health disparities><Delta4-pregnene-3,20-dione><Development><Differences between sexes><Differs between sexes><Dimenformon><Diogyn><Diogynets><Drugs><Economics><Electronic Nicotine Delivery Product><Electronic Nicotine Delivery Systems><Endocrine Gland Secretion><Epidemic><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Evidence based intervention><Female><Females in adulthood><Future><GABA><Gene Transfer><Goals><Gonadal Hormones><Habenula><Health><Health disparity mitigation><Health disparity reduction><Hormones><Human><Inhalation><Inhaling><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intervention><Intervention Strategies><Knowledge><Learning><Literature><Lower health disparities><Measures><Medial><Mediating><Medication><Methods><Mission><Mitigate health disparities><Modern Man><NIH><National Institutes of Health><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurotransmitters><Nicotine><Nicotine Withdrawal><Outcome><Ovarian hormone><Ovocyclin><Ovocylin><Pathology><Pathway interactions><Peptides><Pharmaceutical Preparations><Play><Population><Precision therapeutics><Predisposition><Pregn-4-ene-3,20-dione><Pregnenedione><Production><Progesterone><Progynon><Public Health><Rat><Rats Mammals><Rattus><Receptor Protein><Reduce health disparities><Reporting><Research><Research Support><Rodent><Rodentia><Rodents Mammals><Severities><Sex Differences><Sexual differences><Stress><Substance Use Disorder><Susceptibility><System><Technology Transfer><Therapeutic Estradiol><Therapeutic Hormone><Therapeutic Progesterone><Tobacco Consumption><Tobacco use><United States National Institutes of Health><Withdrawal><Withdrawal Symptom><Woman><Women in adulthood><Work><addiction><addictive disorder><aerosolized nicotine><anxiety-like behavior><base><bases><biological adaptation to stress><comparing females and males><comparing women and men><corticotropin releasing hormone><design><designing><developmental><drug/agent><e-cig use><e-cigarette use><ecig use><ecigarette use><economic><electronic cigarette use><electronic nicotine delivery device><electronic nicotine distribution system><experience><exposure to nicotine><females compared to males><females compared with males><females versus males><females vs males><gamma-Aminobutyric Acid><immunocytochemistry><improved outcome><innovate><innovation><innovative><insight><interdisciplinary approach><interpeduncular nucleus><interventional strategy><male><men><multidisciplinary approach><negative affect><negative affectivity><neurochemical><neurochemistry><neuronal><nicotine consumption><nicotine exposure><nicotine use><nicotine vapor><novel><pathway><precision therapies><precision treatment><programs><reaction; crisis><receptor><receptor expression><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><stress response><stress; reaction><substance use and disorder><tobacco product use><vapor containing nicotine><vaporized nicotine><women compared to men><women compared with men><women versus men><women vs men><γ-Aminobutyric Acid>