Mutation of the α2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine

Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic α 2 -adrenoceptors (α 2 -AR). The α 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 α 2 -AR underlying these beneficial effects. Because there are no selective α 2A -AR, α 2B -AR, or α 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 α 2A -AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of α 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 α 2A -AR mutant mice. We observed that functional loss of the α 2A -AR subtype, unlike knock-out of the α 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 α 2A -AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions.