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The Journal of Neuroscience, October 1, 2002, 22(19):8771-8777
Mutation of the  2A-Adrenoceptor Impairs Working
Memory Performance and Annuls Cognitive Enhancement by Guanfacine
Jenna S.
Franowicz1,
Lynn E.
Kessler1,
Catherine
M. Dailey
Borja1,
Brian K.
Kobilka2,
Lee E.
Limbird3, and
Amy F. T.
Arnsten1
1 Department of Neurobiology, Yale University School of
Medicine, New Haven, Connecticut 06510, 2 Howard Hughes
Medical Institute and Departments of Medicine and Molecular and
Cellular Physiology, Stanford University, Palo Alto, California
94305, and 3 Department of Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232
Norepinephrine strengthens the working memory, behavioral
inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic  2-adrenoceptors
(2-AR). The 2-AR agonist guanfacine
enhances prefrontal cortical functions in rats, monkeys, and human
beings and ameliorates prefrontal cortical deficits in patients with
attention deficit hyperactivity disorder. The present study examined
the subtype of 2-AR underlying these beneficial effects.
Because there are no selective 2A-AR,
2B-AR, or 2C-AR agonists or antagonists,
genetically altered mice were used to identify the molecular target of
the action of guanfacine. Mice with a point mutation of the
2A-AR, which serves as a functional knock-out, were
compared with wild-type animals and with previously published studies
of 2C-AR knock-out mice (Tanila et al., 1999). Mice were
adapted to handling on a T maze and trained on either a spatial delayed
alternation task that is sensitive to prefrontal cortical damage or a
spatial discrimination control task with similar motor and motivational
demands but no dependence on prefrontal cortex. The effects of
guanfacine on performance of the delayed alternation task were assessed
in additional groups of wild-type versus 2A-AR mutant
mice. We observed that functional loss of the 2A-AR
subtype, unlike knock-out of the 2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning
and resulted in loss of the beneficial response to guanfacine. These
data demonstrate the importance of 2A-AR subtype
stimulation for the cognitive functions of the prefrontal cortex and
identify the molecular substrate for guanfacine and novel therapeutic interventions.
Key words:
prefrontal cortex; norepinephrine; mice; attention
deficit hyperactivity disorder; adrenoceptor subtype; delayed
alternation; neuropsychiatric disorder
Copyright © 2002 Society for Neuroscience 0270-6474/02/22198771-07$05.00/0
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