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Altered glucocorticoid rhythm attenuates the ability of a chronic SSRI to elevate forebrain 5-HT: Implications for the treatment of depression

Lookup NU author(s): Dr Sasha Gartside, Mel LeitchORCiD, Professor Allan Young

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Abstract

Both glucocorticoids and selective serotonin reuptake inhibitors (SSRIs) alter aspects of 5-HT function including somatodendritic 5-HT1A autoreceptor sensitivity. Many depressed patients prescribed SSRIs have pre-existing flattened diumal gluococorticoid rhythm. In these patients, interactions between flattened glucocorticoid rhythm and chronic SSRIs, which impact on the SSRI's ability to elevate forebrain 5-HT, may alter clinical efficacy. To address this issue rats underwent implantation of slow-release corticosterone (75 mg pellet s.c.) (to flatten the glucocorticoid rhythm) or sham surgery, and injection of fluoxetine (10 mg/kg/day i.p., 12 days) or vehicle. Using microdialysis in the frontal cortex we found that (21 h after the last injection) extracellular 5-HT was elevated in fluoxetine- or corticosterone-treated animals, but not in those treated with corticosterone plus fluoxetine. In fluoxetine-treated animals, blockade of terminal reuptake by local perfusion of fluoxetine increased 5-HT to the same level as it did in controls, suggesting normal terminal 5-HT release after chronic fluoxetine. However, 5-HT levels following local reuptake blockade in both the corticosterone and corticosterone plus fluoxetine groups were lower than controls, suggesting a corticosterone-induced decrease in terminal release. Finally in fluoxetine, corticosterone, and corticosterone plus fluoxetine groups, there was marked 5-HT1A receptor desensitization, evidenced by attenuation of the decrease in 5-HT release following systemic fluoxetine injection. The data indicate that, despite desensitization of 5-HT1A autoreceptors, concurrent flattened glucocorticoid rhythm compromises the ability of SSRIs to elevate forebrain 5-HT. These findings suggest a potential mechanism for the reduced antidepressant efficacy of SSRIs in those patients with pre-existing glucocorticoid abnormalities. © 2003 Nature Publishing Group All rights reserved.

Publication metadata

Author(s): Gartside SE, Leitch MM, Young AH

Publication type: Article

Publication status: Published

Journal: Neuropsychopharmacology

Year: 2003

Volume: 28

Issue: 9

Pages: 1572-1578

ISSN (print): 0893-133X

ISSN (electronic): 1470-634X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.npp.1300201

DOI: 10.1038/sj.npp.1300201

PubMed id: 12784107

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