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Semaglutide Activates the Orexin/Hypocretin and Basal Forebrain Cholinergic Systems and Increases Acetylcholine Levels in the Hippocampus of Young and Aged Rats
Wohlfeld C, Blas A, Woodruff J, Frick M, Maciejewska N, Patel A, Grillo C, Reagan L et al.. bioRxiv, 2026-08-06
Topic: Gut, metabolism and diet
GLP-1 agonist drug repurposing efforts may establish new clinical niches in managing psychiatric and neurological disorders. However, a comprehensive understanding of GLP-1 neurobiology and an appreciation of specific neural mechanisms by which GLP-1 agonists might provide therapeutic effects is limited and stands as a barrier to these efforts. When considering current preclinical research evaluating GLP-1 agonist central mechanisms, a considerable knowledge gap remains regarding which specific cellular populations and systems define potential therapeutic effects in the brain. In this research, we used cFos immunohistochemistry to identify specific neuronal populations that exhibited altered cellular activity following acute administration of semaglutide to rats. We found that the orexin/hypocretin and basal forebrain cholinergic systems are activated following acute semaglutide administration in male and female young adult rats (3-5 months). Informed by the results of our histological analysis, we next employed in vivo microdialysis to test our hypothesis that semaglutide would acutely increase acetylcholine release in the rodent hippocampus. Here, we report that semaglutide acutely increases acetylcholine efflux in the ventral hippocampus of conscious and freely moving rats regardless of biological sex in both young adult and aged rats (23-26 months). Given the relevance of hippocampal cholinergic neurotransmission in learning and memory, our research mechanistically connects GLP-1 agonists with established targets in cognitive decline and dementia.
Key findings
- We found that the orexin/hypocretin and basal forebrain cholinergic systems are activated following acute semaglutide administration in male and female young adult rats (3-5 months).
- Informed by the results of our histological analysis, we next employed in vivo microdialysis to test our hypothesis that semaglutide would acutely increase acetylcholine release in the rodent hippocampus.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “rats”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Wohlfeld, C., Blas, A., Woodruff, J., Frick, M., Maciejewska, N., Patel, A., et al. (2026). Semaglutide Activates the Orexin/Hypocretin and Basal Forebrain Cholinergic Systems and Increases Acetylcholine Levels in the Hippocampus of Young and Aged Rats. bioRxiv. https://doi.org/10.64898/2026.08.03.742612
Vancouver
Wohlfeld C, Blas A, Woodruff J, Frick M, Maciejewska N, Patel A, et al. Semaglutide Activates the Orexin/Hypocretin and Basal Forebrain Cholinergic Systems and Increases Acetylcholine Levels in the Hippocampus of Young and Aged Rats. bioRxiv. 2026. doi:10.64898/2026.08.03.742612.
BibTeX
@article{wohlfeld2026-d54ff148,
author = {Wohlfeld, C. and Blas, A. and Woodruff, J. and Frick, M. and Maciejewska, N. and Patel, A. and Grillo, C. and Reagan, L. and others},
title = {{Semaglutide Activates the Orexin/Hypocretin and Basal Forebrain Cholinergic Systems and Increases Acetylcholine Levels in the Hippocampus of Young and Aged Rats}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.08.03.742612},
url = {https://doi.org/10.64898/2026.08.03.742612}
}
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