Chronically dysregulated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms

Major depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing. In a subset of MDD patients, chronic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs, resulting in increased levels o...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2023-08, Vol.48 (9), p.1328-1337
Main Authors: Holloway, Ashley L, Schaid, Michael D, Lerner, Talia N
Format: Article
Language:English
Subjects:
Animals
Corticosterone
Cortisol
Depressive Disorder, Major
Dopamine
Dopamine receptors
Dopamine transporter
Female
Hormones
Hydrocortisone
Hypothalamic-pituitary-adrenal axis
Hypothalamo-Hypophyseal System
Hypothalamus
Male
Mental depression
Mice
Motivation
Neostriatum
Pituitary
Pituitary-Adrenal System
Reinforcement
Sex
Sex differences
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Summary:Major depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing. In a subset of MDD patients, chronic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs, resulting in increased levels of the 'stress hormone' cortisol during the normal rest period (i.e., evening and night). However, the mechanistic relationship between chronically elevated resting cortisol and behavioral deficits in motivation and reward processing remains unclear. Given that women are diagnosed with MDD at twice the rate of men, it is important to understand whether the mechanisms linking cortisol to the symptoms of MDD differ by sex. In this study, we used subcutaneous implants to chronically elevate free plasma corticosterone (the rodent homolog of cortisol; 'CORT') during the rest period in male and female mice and examined changes in behavior and dopamine system function. We found that chronic CORT treatment impaired motivated reward-seeking in both sexes. In female but not male mice, CORT treatment reduced dopamine content in the dorsomedial striatum (DMS). In male but not female mice, CORT treatment impaired the function of the dopamine transporter (DAT) in DMS. From these studies, we conclude that chronic CORT dysregulation impairs motivation by impairing dopaminergic transmission in the DMS, but via different mechanisms in male and female mice. A better understanding of these sex-specific mechanisms could lead to new directions in MDD diagnosis and treatment.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-023-01551-1