Leptin: A potential novel antidepressant
Open accessAbstract
Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: ( i ) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, ( ii ) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and ( iii ) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders.
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Chronic unpredictable/mild/variable stress and chronic social defeat stress are the two most commonly used animal models of depression.
“Chronic unpredictable/mild/variable stress and chronic social defeat stress are the two most commonly used animal models of depression [31, 34–38].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [34]
The chronic unpredictable stress paradigm effectively induces anhedonia along with other depression-related behaviors, including reduced sensitivity to sucrose reward, decreased sex-related reward-seeking behavior, and despair behavior.
“we used a chronic unpredictable stress paradigm, which effectively induces anhedonia along with other depression-related behaviors [34–36], including reduced sensitivity to sucrose reward, decreased sex-related reward-seeking behavior, and despair behavior.”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [34]
The chronic unpredictable stress paradigm models unanticipated stressful experiences that occur in humans and has been widely used as a valid animal model of depression.
“This paradigm models unanticipated stressful experiences that occur in humans, and thus has been widely used as a valid animal model of depression [34, 36, 52].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [34]
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- Authors
- Lu, X.-Y., Kim, C. S., Frazer, A., & Zhang, W.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-01-19
- Volume
- 103
- Issue
- 5
- Pages
- 1593-1598
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1360555
- OpenAlex
- W2001585610
- Cited by
- 446
- References
- 41
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 8 · 2023: 16 · 2022: 23 · 2021: 13 · 2020: 19 · 2019: 22 · 2018: 25 · 2017: 19 · 2016: 21 · 2015: 28 · 2014: 48 · 2013: 31 · 2012: 29
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- leptin, antidepressants, depression, chronic unpredictable mild stress, chronic social defeat, forced swim test, behavioral despair, hippocampus, limbic system, leptin receptor, hypothalamus, body weight, adipose tissue, intracerebroventricular infusion
- MeSH terms
- Adipose Tissue, Animals, Antidepressive Agents, Behavior, Animal, Body Weight, Dose-Response Relationship, Drug, Hippocampus, Hypothalamus, Male, Motor Activity, Neurons, RNA, Messenger, Stress, Psychological, Sucrose, Swimming, Time Factors, Anti-Anxiety Agents, Models, Statistical, Signal Transduction, Rats, Sprague-Dawley, In Situ Hybridization, Leptin, Rats
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