The α -2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys

Abstract

In aged monkeys with naturally occurring catecholamine depletion, alpha-2 adrenergic agonists such as guanfacine have repeatedly been shown to improve dorsolateral prefrontal cortical function, as assessed by the spatial delayed response task. Both low (0.0001-0.001 mg/kg) and high (0.5 mg/kg) but not intermediate (0.01-0.05 mg/kg) doses of guanfacine improve spatial working memory performance in aged animals. However, it is not known whether guanfacine would similarly improve performance in young animals. In the present study, the effects of guanfacine on delayed response performance were characterized in seven young adult rhesus monkeys. Low doses of guanfacine (0.0001-0.01 mg/kg) had no effect on task performance, while high doses of guanfacine (0.1-0.7 mg/kg) significantly improved task performance. The highest doses produced mild sedation that was independent of drug effects on delayed response. The most effective dose of guanfacine was challenged with the alpha-2 antagonist idazoxan (0.1 mg/kg). This dose of idazoxan had no effect on task performance when given alone. Consistent with an alpha-2 mechanism, idazoxan significantly decreased delayed response performance in guanfacine-treated animals. These results support the hypothesis that delayed response performance in young intact animals can be improved through actions at alpha-2 adrenergic receptors.

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).…”

Activation of β2-adrenoceptor enhances synaptic potentiation and behavioral memory via cAMP-PKA signaling in the medial prefrontal cortex of rats

“…The release of low to moderate levels of NE activates a-2A adrenoceptors and improves PFC functions, such as working memory performance and attention (Arnsten and Goldman-Rakic 1985;Arnsten et al 1988;Franowicz and Arnsten 1998;Li et al 1999;Franowicz et al 2002;Wang et al 2007). By contrast, higher levels of NE, as well as stress, activate a-1 adrenoceptors and impair PFC functions (Arnsten and Jentsch 1997;Birnbaum et al 1999;Mao et al 1999;Marzo et al 2010).…”

Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD

“…The a-2A agonist clonidine has been used widely in the treatment of ADHD children, 27 suggesting a potential role for the receptor in symptom expression. More definitive evidence emerges from recent work showing that the selective a-2A agonist guanfacine improves function on tasks reliant on prefrontal cortical functions in monkeys 11,28 and in humans, 26 but does not affect behavior when the prefrontal cortex is not challenged. 11 Thus, pharmacologic investigations point to an important role for the NE system, especially the a-2A receptor, in the cognitive operations of the prefrontal cortex that are suspected of involvement in ADHD.…”