Glucocorticoid receptor antagonists hasten and augment neurochemical responses to a selective serotonin reuptake inhibitor antidepressant

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  2. Dr Daniel Johnson
  3. Professor Colin Ingram
  4. Dr Sasha Gartside
Author(s)Johnson DA, Grant EJ, Ingram CD, Gartside SE
Publication type Article
JournalBiological Psychiatry
ISSN (print)0006-3223
ISSN (electronic)1873-2402
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Background: Selective serotonin reuptake inhibitor (SSRI) antidepressants have a delayed onset and commonly produce an incomplete therapeutic response. The therapeutic actions of SSRIs are thought to depend on increased forebrain extracellular 5 HT, following desensitization of somatodendritic 5-HT1A autoreceptors. Here we determined whether concurrent glucocorticoid receptor (GR) blockade enhances these neurochemical responses to the SSRI, fluoxetine. Methods: Male rats were treated (3, 7, or 14 days) with either fluoxetine (10 mg/kg i.p.) or vehicle once daily, in combination with either a GR antagonist (Org 34850 15 mg/kg s.c. or Org 34517 25 mg/kg s.c.) or vehicle twice daily. Following treatment, 5-HT in the medial prefrontal cortex was measured by microdialysis. Results: Chronic fluoxetine treatment (14 days) raised basal 5-HT and also attenuated the fall in 5 HT following acute systemic administration of fluoxetine (10 mg/kg i.p.) indicating desensitization of 5 HT1A autoreceptors. Concurrent chronic dministration (14 days) of Org 34850, or Org 34517, enhanced the fluoxetine-induced increase in basal 5 HT. Org 34850 also hastened the 5-HT1A autoreceptor desensitization induced by chronic fluoxetine treatment. Org 34850 alone (14 days) failed to alter basal 5 HT or 5 HT1A autoreceptor desensitization. Conclusion: Antidepressant response is proposed to depend on 5 HT1A autoreceptor desensitization and elevation of forebrain 5-HT. These data suggest adjunctive GR antagonists may both hasten and enhance antidepressant responses to SSRIs.
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