TY - JOUR T1 - Mutation of the α<sub>2A</sub>-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine JF - The Journal of Neuroscience JO - J. Neurosci. SP - 8771 LP - 8777 DO - 10.1523/JNEUROSCI.22-19-08771.2002 VL - 22 IS - 19 AU - Jenna S. Franowicz AU - Lynn E. Kessler AU - Catherine M. Dailey Borja AU - Brian K. Kobilka AU - Lee E. Limbird AU - Amy F. T. Arnsten Y1 - 2002/10/01 UR - http://www.jneurosci.org/content/22/19/8771.abstract N2 - Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic α2-adrenoceptors (α2-AR). The α2-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 α2-AR underlying these beneficial effects. Because there are no selective α2A-AR, α2B-AR, or α2C-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 α2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of α2C-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 α2A-AR mutant mice. We observed that functional loss of the α2A-AR subtype, unlike knock-out of the α2C-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 α2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions. ER -