The Alpha-2A-Adrenoceptor Agonist, Guanfacine, Increases Regional Cerebral Blood Flow in Dorsolateral Prefrontal Cortex of Monkeys Performing a Spatial Working Memory Task

Abstract

Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors.The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) Evidence from a variety of disciplines indicates that norepinephrine (NE) has a critical beneficial influence on the working memory functions of the prefrontal cortex (PFC) through its actions at post-synaptic, alpha-2A adrenergic receptors (reviewed in Arnsten et al. 1996). In monkeys, the ability to perform spatial working memory tasks has been closely linked to the dorsolateral PFC (dlPFC) surrounding the principal sulcus, especially the caudal two thirds of the principal sulcal region (Goldman and Rosvold 1970;Goldman-Rakic 1987).Alpha-2 adrenergic agonists such as clonidine, guanfacine, and medetomidine can improve spatial working memory performance in monkeys (Arnsten et al. 1988), rats (Carlson et al. 1992), and humans (Coull et al. 1995;Jakala et al. 1999), but have little effect or impair tasks dependent on posterior cortices or hippocampus (reviewed in Arnsten 1998). Dose response curves are con- N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 3 Guanfacine Increases PFC Blood Flow in Monkeys 241 sistent with beneficial actions at post-synaptic alpha-2 receptors, as the drugs become more potent and more efficacious in animals and patients with NE depletion (Arnsten and Goldman-Rakic 1985;Cai et al. 1993;Franowicz and Arnsten 1999;McEntee and Mair 1990). However, very high doses of guanfacine have recently been found to significantly improve spatial working memory performance in normal adult monkeys as well . It is likely that the alpha-2A receptor subtype underlies guanfacine's beneficial effects on working memory function (Arnsten et al. 1988;Tanila et al. 1999), and guanfacine is currently the most selective alpha-2A agonist available (Uhlen and Wikberg 1991).Several findings suggest that alpha-2 agonists improve, while alpha-2 antagonists impair, working memory function through direct actions in the PFC. For example, infusion of the alpha-2 antagonist, yohimbine, into the monkey PFC produces a delay-related impairment in working memory, whereas alpha-1 and beta adrenergic antagonists are without effect (Li and Mei 1994). Similarly, electrophysiological studies show that iontophoretic application of yohimbine onto PFC neurons suppresses delay-related activity, the cellular measure of working memory Sawaguchi 1998). Conversely, iontophoretic or systemic administration of clonidine increases delay-related firing, and this enhancement is reversed by iontophoretic application of yohimbine . Similarly, infusion of the alpha-2 agonist medetomidine, into aged rat PFC improves spatial working memory performance (Tanila et al. 1996).Very few studies have taken advantage of imaging technologies to examine NE alpha-2 mechanisms in the cortex. Most human studies ha...

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

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Stimulants: Therapeutic Actions in ADHD

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