Guanfacine potentiates the activation of prefrontal cortex evoked by warning signals.
BACKGROUND
Warning signals evoke an alert state of readiness that prepares for a rapid response by priming a thalamo-frontal-striatal network that includes the dorsolateral prefrontal cortex (DLPFC). Animal models indicate that noradrenergic input is essential for this stimulus-driven activation of DLPFC, but the precise mechanisms involved have not been determined. We tested the role that postsynaptic alpha(2A) adrenoceptors play in the activation of DLPFC evoked by warning cues using a placebo-controlled challenge with the alpha(2A) agonist guanfacine.


METHODS
Sixteen healthy young adults were scanned twice with event-related functional magnetic resonance imaging (fMRI), while performing a simple cued reaction time (RT) task following administration of a single dose of oral guanfacine (1 mg) and placebo in counterbalanced order. The RT task temporally segregates the neural effects of warning cues and motor responses and minimizes mnemonic demands.


RESULTS
Warning cues produced a marked reduction in RT accompanied by significant activation in a distributed thalamo-frontal-striatal network, including bilateral DLPFC. Guanfacine selectively increased the cue-evoked activation of the left DLPFC and right anterior cerebellum, although this increase was not accompanied by further reductions in RT. The effects of guanfacine on DLPFC activation were specifically associated with the warning cue and were not seen for visual- or target-related activation.


CONCLUSIONS
Guanfacine produced marked increases in the cue-evoked activation of DLPFC that correspond to the well-described actions of postsynaptic alpha(2) adrenoceptor stimulation. The current procedures provide an opportunity to test postsynaptic alpha(2A) adrenoceptor function in the prefrontal cortex in the pathophysiology of several psychiatric disorders.
Clerkin
Suzanne M
SM
Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA.
Schulz
Kurt P
KP
Halperin
Jeffrey M
JM
Newcorn
Jeffrey H
JH
Ivanov
Iliyan
I
Tang
Cheuk Y
CY
Fan
Jin
J
D058647:Adrenergic alpha-2 Receptor Agonists; D000328:Adult; D001921:Brain / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D003463:Cues; D004311:Double-Blind Method; D005260:Female; D016316:Guanfacine / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*
D058647:Adrenergic alpha-2 Receptor Agonists; D018341:Receptors, Adrenergic, alpha-2; D016316:Guanfacine