Mutation of the α_2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine

Abstract

Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors (alpha2-AR). The alpha2-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 alpha2-AR underlying these beneficial effects. Because there are no selective alpha2A-AR, alpha2B-AR, or alpha2C-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 alpha2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of alpha2C-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 alpha2A-AR mutant mice. We observed that functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-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 alpha2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions.

Alpha-2 Adrenoceptor Activation Inhibits Phencyclidine-Induced Deficits of Spatial Working Memory in Rats

“…In addition, alpha-2B receptors are expressed in thalamic nuclei (Tavares et al, 1996;Winzer-Serhan and Leslie, 1997), and dorsomedial and anterior nuclei of the thalamus also contribute substantially to performance (Bailey and Mair, 2004;Floresco et al, 1999). So far, both the alpha-2A and alpha-2C subtypes have been implicated in cognition, as reflected by deficiencies in working memory performance in 2A or 2C knockout mice (Franowicz et al, 2002;Tanila et al, 1999). Therefore, all three subtypes are positioned to modulate potentially working memory function.…”

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

“…It is well documented that a 2 -, especially a 2A -adrenoceptors (ARs) in the PFC are involved in regulating working memory function (Arnsten et al, 1988;Arnsten and Goldman-Rakic, 1985;Arnsten and Li, 2005;Franowicz and Arnsten, 1998;Franowicz et al, 2002;Li and Mei, 1994;Mao et al, 1999). a 2 -AR agonists such as clonidine and guanfacine administered systemically or locally into the PFC improve working memory performance in rats and monkeys (Arnsten et al, 1988;Arnsten and Goldman-Rakic, 1985;Franowicz and Arnsten, 1998;Mao et al, 1999;Tanila et al, 1996).…”

“…a 2 -AR agonists such as clonidine and guanfacine administered systemically or locally into the PFC improve working memory performance in rats and monkeys (Arnsten et al, 1988;Arnsten and Goldman-Rakic, 1985;Franowicz and Arnsten, 1998;Mao et al, 1999;Tanila et al, 1996). It has been shown that the beneficial effect of clonidine or guanfacine on working memory performance is mediated by a 2A -ARs (Arnsten et al, 1988;Arnsten and Li, 2005;Franowicz et al, 2002). In addition to working memory performance, a 2A -AR stimulation in the PFC also enhances visuomotor association learning in monkeys (Wang et al, 2004a, b).…”

Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

“…Thus, it seems that the NE turnover in the frontal cortex is under stronger inhibitory a 2 -autoreceptor control than that in the hypothalamus. Interestingly, the a 2A -ARs in mouse frontal cortex were also reported to mediate the beneficial effects of cognitiveenhancing effects of guanfacine, an a 2 -AR agonist clinically employed in the treatment of ADHD (Franowicz et al, 2002). Still, the extent to which a 2 -ARs contribute to modulating the neurochemical and behavioral response to D-Amph-like psychostimulants is not thoroughly understood.…”