Flattening the corticosterone rhythm attenuates 5-HT1A autoreceptor function in the rat: relevance for depression.
Depression is associated with glucocorticoid abnormalities, in particular a flattening of the diurnal cortisol rhythm. Recent data suggest that an important factor in the aetiology of depression may be a deficit in the function and expression of 5-HT(1A) receptors, which has been reported in depressed patients. The present study assessed the possibility that this cortisol abnormality is causal in the 5-HT(1A) receptor deficits. First, a rat model of flattened glucocorticoid rhythm was developed. Controlled release corticosterone pellets implanted for 14 days flattened the corticosterone rhythm and maintained levels constant midway between the nadir and zenith levels observed in sham-operated rats. Secondly, using microdialysis to assess 5-HT release in the hippocampus, the inhibitory response to 8-OHDPAT was measured to determine the sensitivity of somatodendritic 5-HT(1A) autoreceptors. Corticosterone treatment was found to induce a significant attenuation in the response to 8-OHDPAT, indicating functional desensitization of somatodendritic 5-HT(1A) autoreceptors. There was no effect of corticosterone treatment on basal extracellular 5-HT levels. The data suggest that the glucocorticoid abnormalities associated with depression may impact on the functioning of 5-HT(1A) receptors in the brain. These findings suggest that resolution of cortisol abnormalities may be a valuable target for pharmacotherapy in the treatment of depression.
Leitch
Melville M
MM
Psychobiology Research Group, Stanley Research Centre, The Medical School, University of Newcastle upon Tyne, UK. m.m.leitch@ncl.ac.uk
Ingram
Colin D
CD
Young
Allan H
AH
McQuade
Richard
R
Gartside
Sarah E
SE
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000503:physiopathology*; D004343:Drug Implants; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism
D004343:Drug Implants; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D003345:Corticosterone