Glucocorticoid receptor antagonists hasten and augment neurochemical responses to a selective serotonin reuptake inhibitor antidepressant.
BACKGROUND
Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs have a delayed onset and commonly produce an incomplete therapeutic response. The therapeutic actions of SSRIs are thought to depend on increased forebrain extracellular serotonin (5-HT), after desensitization of somatodendritic 5-HT(1A) 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 IP) or vehicle once daily, in combination with either a GR antagonist (Org 34850 15 mg/kg SC or Org 34517 25 mg/kg SC) or vehicle twice daily. After 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 after acute systemic administration of fluoxetine (10 mg/kg IP), indicating desensitization of 5-HT(1A) autoreceptors. Concurrent chronic administration (14 days) of Org 34850 or Org 34517 enhanced the fluoxetine-induced increase in basal 5-HT. Org 34850 also hastened the 5-HT(1A) autoreceptor desensitization induced by chronic fluoxetine treatment. Org 34850 alone (14 days) failed to alter basal 5-HT or 5-HT(1A) autoreceptor desensitization.


CONCLUSIONS
Antidepressant response is proposed to depend on 5-HT(1A) autoreceptor desensitization and elevation of forebrain 5-HT. These data suggest adjunctive GR antagonists might both hasten and enhance antidepressant responses to SSRIs.
Johnson
Daniel A
DA
Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, Newcastle University, Newcastle upon Tyne, United Kingdom.
Grant
Emma J
EJ
Ingram
Colin D
CD
Gartside
Sarah E
SE
D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D001923:Brain Chemistry / Q000187:drug effects*; D004357:Drug Synergism; D005473:Fluoxetine / Q000627:therapeutic use*; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013256:Steroids / Q000627:therapeutic use*; D013450:Sulfones / Q000627:therapeutic use*
D052117:Benzodioxoles; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D011965:Receptors, Glucocorticoid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013256:Steroids; D013450:Sulfones; C526064:Org 34517; C526063:Org 34850