Altered glucocorticoid rhythm attenuates the ability of a chronic SSRI to elevate forebrain 5-HT: implications for the treatment of depression.
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 diurnal 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.
Gartside
S E
SE
Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, The Medical School, Newcastle, UK. sasha.gartside@ncl.ac.uk
Leitch
M M
MM
Young
A H
AH
D000704:Analysis of Variance; D000818:Animals; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D004333:Drug Administration Routes / Q000662:veterinary; D005473:Fluoxetine / Q000008:administration & dosage; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017551:Microdialysis / Q000379:methods; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D005473:Fluoxetine; D005938:Glucocorticoids; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors