Sex-Dependent Effects of Stress on Immobility Behavior and VTA Dopamine Neuron Activity: Modulation by Ketamine
Open accessAbstract
Background: Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine system underactivation is implicated in the pathophysiology of depression, little is known about the female dopamine system at baseline and post-stress. Methods: The effects of chronic mild stress were examined on ventral tegmental area dopamine neuron activity and forced swim test immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10 mg/kg, i.p.) on forced swim test immobility and ventral tegmental area function was then tested. Results: Baseline ventral tegmental area dopamine activity was comparable in both sexes. At baseline, females exhibited roughly double the forced swim test immobility duration than males, which corresponded to ~50% decrease in ventral tegmental area dopamine population activity compared with similarly treated (i.e., post-forced swim test) males. Following chronic mild stress, there was greater immobility duration in both sexes and reduced ventral tegmental area dopamine neuron activity by approximately 50% in males and nearly 75% in females. Ketamine restored behavior and post-forced swim test ventral tegmental area dopamine activity for up to 7 days in females as well as in both male and female chronic mild stress-exposed rats. Conclusions: These data suggest increased female susceptibility to depression-like phenotypes (i.e., greater immobility, ventral tegmental area hypofunction) is associated with higher dopamine system sensitivity to both acute and repeated stress relative to males. Understanding the neural underpinnings of sex differences in stress vulnerability will provide insight into mechanisms of disease and optimizing therapeutic approaches in both sexes.
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Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons, an effect more pronounced in females.
“Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons [52, 53], an effect more pronounced in females [53].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [53]
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Self-citation
- Authors
- Rincón-Cortés, M., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- ORCID
- Grace, Anthony A.
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-06-07
- Volume
- 20
- Issue
- 10
- Pages
- 823-832
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC5632304
- OpenAlex
- W2624113673
- Cited by
- 98
- References
- 72
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 21 · 2020: 11 · 2019: 18 · 2018: 5 · 2017: 4 · 2013: 1
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- sex differences, chronic mild stress, depression, ventral tegmental area, dopaminergic neurons, ketamine, antidepressant effects, stress vulnerability
- MeSH terms
- Action Potentials, Acute Disease, Animals, Antidepressive Agents, Chronic Disease, Disease Models, Animal, Female, Ketamine, Male, Motor Activity, Sex Characteristics, Stress, Psychological, Rats, Sprague-Dawley, Ventral Tegmental Area, Dopaminergic Neurons
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