Altered Glucocorticoid Rhythm Attenuates the Ability of a Chronic SSRI to Elevate Forebrain 5-HT: Implications for the Treatment of Depression

Abstract

Both glucocorticoids and selective serotonin reuptake inhibitors (SSRIs) alter aspects of 5-HT function including somatodendritic 5-HT 1A 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-HT 1A receptor desensitization, evidenced by attenuation of the decrease in 5-HT release following systemic fluoxetine injection. The data indicate that, despite desensitization of 5-HT 1A 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.

Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term Treatment with Fluoxetine in a Mouse Model of Anxiety/Depression Based on Repeated Corticosterone Administration

“…1), but this response was less pronounced in the latter group, suggesting a functional desensitization of 5-HT 1A autoreceptor. These findings are consistent with initial studies showing that maternal separation or UCMS in rodents (Lanfumey et al, 1999;Gartside et al, 2003;Froger et al, 2004;Bambico et al, 2009) reduced 5-HT 1A autoreceptor sensitivity. When fluoxetine was given for 28 days, the hypothermic response to 8-OH-DPAT was also significantly attenuated in both vehicle-and corticosterone-pretreated mice (Fig.…”

The evidence for a neurobiological model of childhood antisocial behavior.

“…Recent evidence has suggested that 5-HT 1A receptor sensitivity in the dorsal raphe nucleus and the hippocampus may be altered by prolonged glucocorticoid administration (Fairchild, Leitch, & Ingram, 2003;Karten, Nair, van Essen, Sibug, & Joëls, 1999), and this may have consequences for 5-HT neurotransmission in key projection regions such as the frontal cortex (Gartside, Leitch, & Young, 2003;see Porter, Gallagher, Watson, & Young, 2004, for a review of the evidence for effects of glucocorticoids on 5-HT function in humans).…”

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

“…Implantation of corticosteroid-releasing pellets in rodents to induce an HPA axis dysregulation has been shown to attenuate the ability of antidepressants to elevate forebrain 5-HT levels. 16 Interestingly, there is also increasing evidence that antiglucocorticoid treatments have the opposite effect by enhancing the forebrain 5-HT response to antidepressants. 17 This suggests that reducing normal physiological levels of glucocorticoid receptor activation can increase the elevation of 5-HT in response to SSRIs.…”