Chronic semaglutide treatment enhances the incentive motivational value of a small food reward and associated cue in male and female rats

Stephen E. Chang, Christopher A. Turner, Natalia Morales Pagán, Daniela Pereira, Sophia Kleer, Shelly B. Flagel
2025 · doi:10.64898/2025.12.06.692775
preprint OA: closed
🔓 Open OA copy Full text JSON View at publisher

Abstract

Rationale Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are increasingly utilized in clinical practice due to their efficacy in promoting sustained weight loss following chronic administration. While acute treatment with GLP-1 receptor agonists has been shown to suppress food intake and reward-seeking behaviors in rodent models, the impact of prolonged exposure on preclinical measures of motivated behavior remains insufficiently characterized. Objectives This study aimed to systematically evaluate the effects of chronic administration of semaglutide on both the acquisition and expression phases of Pavlovian conditioned approach (PavCA)—a behavioral paradigm used to assess the attribution of incentive salience to a food-paired cue. The influence of chronic semaglutide on the conditioned reinforcing properties of the food-associated cue, performance on a progressive ratio (PR) schedule for food reward, and ad libitum consumption of the food reward were also assessed. Results Chronic semaglutide administration did not significantly alter either the acquisition or the expression of PavCA behavior. However, relative to vehicle-treated controls, semaglutide markedly enhanced responding for the food-associated cue during a conditioned reinforcement test and increased PR responding for the food reward. In contrast, semaglutide reduced both free consumption of the food reward and homecage chow intake. Conclusions These findings demonstrate that chronic semaglutide administration potentiates the incentive value of food-paired cues and increases motivation for food reward under restricted access conditions, yet attenuates overall food consumption when food is freely available. This dissociation highlights the nuanced effects of semaglutide on motivated behavior and suggests an amplification of the reinforcing properties of discrete, limited food rewards and associated cues.
Full text 2,108 characters · extracted from oa-html · 4 sections · click to expand

Abstract

Rationale Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are increasingly utilized in clinical practice due to their efficacy in promoting sustained weight loss following chronic administration. While acute treatment with GLP-1 receptor agonists has been shown to suppress food intake and reward-seeking behaviors in rodent models, the impact of prolonged exposure on preclinical measures of motivated behavior remains insufficiently characterized.

Objectives

This study aimed to systematically evaluate the effects of chronic administration of semaglutide on both the acquisition and expression phases of Pavlovian conditioned approach (PavCA)—a behavioral paradigm used to assess the attribution of incentive salience to a food-paired cue. The influence of chronic semaglutide on the conditioned reinforcing properties of the food-associated cue, performance on a progressive ratio (PR) schedule for food reward, and ad libitum consumption of the food reward were also assessed.

Results

Chronic semaglutide administration did not significantly alter either the acquisition or the expression of PavCA behavior. However, relative to vehicle-treated controls, semaglutide markedly enhanced responding for the food-associated cue during a conditioned reinforcement test and increased PR responding for the food reward. In contrast, semaglutide reduced both free consumption of the food reward and homecage chow intake.

Conclusions

These findings demonstrate that chronic semaglutide administration potentiates the incentive value of food-paired cues and increases motivation for food reward under restricted access conditions, yet attenuates overall food consumption when food is freely available. This dissociation highlights the nuanced effects of semaglutide on motivated behavior and suggests an amplification of the reinforcing properties of discrete, limited food rewards and associated cues. Full Text Availability The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-html ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Funding

funders
[{'doi': None, 'name': 'University of Michigan Research Scouts Program', 'awards': ['OORRS033123']}, {'doi': '10.13039/100000026', 'name': 'National Institute on Drug Abuse', 'awards': ['T32DA060142']}, {'doi': '10.13039/100000026', 'name': 'National Institute on Drug Abuse', 'awards': ['T32DA007281']}, {'doi': '10.13039/100000057', 'name': 'National Institute of General Medical Sciences', 'awards': ['R25GM086262']}]

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2025) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

References (56)

Source provenance

crossref
last seen: 2026-06-14T06:15:22.423487+00:00
europepmc
last seen: 2026-05-20T01:45:00.602351+00:00
unpaywall
last seen: 2026-07-10T06:41:27.906138+00:00