# Novel neuroendocrine mechanisms underlying nicotine seeking and withdrawal-induced hyperphagia

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $245,005

## Abstract

Project Summary
Smoking cessation is associated with significant increases in consumption of palatable food and body weight,
which negate many of the health benefits conferred by smoking abstinence. Indeed, individuals who successfully
quit smoking gain 7-22 pounds of body weight, which, in turn, contributes to increased risk of obesity, diabetes
type II, hypertension and other comorbidities. Moreover, post-cessation weight gain is often cited as the primary
reason for continued smoking and smoking relapse in both men and women. Unfortunately, existing treatments
for post-cessation weight gain are ineffective. Despite the public health significance of post-cessation weight
gain, the neurobiological mechanisms underlying the relationships between smoking, food intake, and body
weight regulation are poorly defined. Therefore, optimizing the health benefits of smoking cessation requires
greater understanding of the neural mechanisms mediating nicotine withdrawal-induced hyperphagia in order to
prevent weight gain and relapse during smoking abstinence. With this in mind, we have developed a rodent
model of withdrawal-induced hyperphagia and body weight gain following voluntary nicotine taking. Our exciting
preliminary data indicate that systemic administration of a glucagon-like peptide-1 (GLP-1) receptor agonist is
sufficient to attenuate nicotine-seeking behavior during abstinence following nicotine self-administration. These
results highlight, for the first time, a novel role for GLP-1 receptors in an animal model of smoking relapse and
suggest that increased GLP-1 signaling may reduce other withdrawal-induced phenotypes including
hyperphagia. We will extend our preliminary findings to female rats and expand upon them in both sexes to
screen the efficacy of two different GLP-1 receptor agonists in attenuating nicotine seeking, hyperphagia and
weight gain during nicotine abstinence (Aim 1). Our previous studies have shown that GLP-1 receptor agonists
reduce intake of palatable food in drug-naïve rodents by activating GLP-1 receptors expressed in brain regions
known to regulate food reward and drug-seeking behavior, including the ventral tegmental area (VTA) and lateral
dorsal tegmental area (LDTg). Since the neural circuits and mechanisms regulating hedonic feeding and drug
seeking overlap, to a degree, these results support the hypothesis that activation of central GLP-1 receptors
attenuates nicotine withdrawal-induced behavioral responses. Therefore, we will infuse GLP-1 receptor agonists
directly into the VTA and LDTg during nicotine abstinence to determine if activation of discrete populations of
central GLP-1 receptors is sufficient to attenuate nicotine seeking and hyperphagia during withdrawal (Aim 2).
These experiments will provide the first insights into the neuroendocrine mechanisms underlying nicotine
seeking, hyperphagia and weight gain during nicotine abstinence. Findings from these studies will have an
immediate translational impact, ...

## Key facts

- **NIH application ID:** 10017038
- **Project number:** 5R21DA045792-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HEATH D SCHMIDT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,005
- **Award type:** 5
- **Project period:** 2019-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017038

## Citation

> US National Institutes of Health, RePORTER application 10017038, Novel neuroendocrine mechanisms underlying nicotine seeking and withdrawal-induced hyperphagia (5R21DA045792-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10017038. Licensed CC0.

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