Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine.
BACKGROUND
Noradrenergic dysfunction has been consistently implicated in depression. Much of the evidence, though, has been indirect, such as an attenuated growth hormone response to the alpha2-adrenoceptor agonist clonidine. To more directly examine central functioning of the noradrenergic system in depression, we have used [15O] H2O positron emission tomography (PET) to measure cerebral blood flow (rCBF) in combination with clonidine as a neuromodulatory probe.


METHODS
Subjects were six depressed and six healthy women, medication free and matched for age and phase of menstrual cycle. Two PET scans were acquired at baseline and two scans at 20 and 35 min following an intravenous clonidine infusion of 1.4 microg/kg while subjects performed a sustained attention task.


RESULTS
The growth hormone response did not show a significant difference between groups. However, PET results revealed a difference in the right superior prefrontal cortex that was resolved as an interaction from decreased rCBF in healthy control subjects but increased rCBF in the depressed group, which was not accounted for by differences in task performance.


CONCLUSIONS
This differential effect of clonidine in the right prefrontal cortex provides in vivo evidence of noradrenergic dysfunction in depression, which we postulate arises from functionally impaired presynaptic alpha2-adrenoceptors as well as regionally "supersensitive" postsynaptic cortical alpha2-adrenoceptors.
Centre for Addiction and Mental Health, Clarke Site, University of Toronto, Toronto, Canada.
C H
CH
Fu
L J
LJ
Reed
J H
JH
Meyer
S
S
Kennedy
S
S
Houle
B S
BS
Eisfeld
G M
GM
Brown
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D001288:Attention / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology*; D005260:Female; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D017397:Prefrontal Cortex / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D014055:Tomography, Emission-Computed
D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha; D019382:Human Growth Hormone; D003000:Clonidine