Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

Abstract

The present study compares the effects of two clonidine (0.5, 2, and 5 g/kg, PO) and guanfacine (7 and 29 g/kg, PO) The locus coeruleus (LC) noradrenergic system plays an important role in arousal, vigilance, responses to novel, salient stimuli as well as several aspects of attentional functions (Foote and Morrison 1987;Harley 1987;Robbins and Everitt 1987;McCormick 1989;Aston-Jones et al. 1990;Jäkälä et al. 1992;Robbins and Everitt 1994). For example, in electrophysiological studies, noradrenaline regulates cortical desynchronization/synchronization (Riekkinen Jr. et al. 1990;Berridge and Foote 1991;Riekkinen Jr. et al. 1993), increases the signalto-noise ratio (SNR) in the neocortex (Waterhouse et al. 1981;Morrison and Magistretti 1983), regulates the responsivity of thalamo-cortical relay neurons (Buzsáki et al. 1990;Riekkinen Jr. et al. 1991;Riekkinen Jr. et al. 1993), and facilitates excitatory and inhibitory responses in the limbic system (Segal and Bloom 1976;Sara and Bergis 1991). in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests. In the PAL test, clonidine 2 and guanfacine 29 g/kg improvedThe firing rate of LC noradrenergic neurons is regulated by alpha2-adrenergic autoreceptors (Aghajanian et al. 1977; Aghajanian and VanderMaelen 1982). Activation of these receptors by alpha2-agonists causes autoinhibition of noradrenergic neurons and a reduction in central noradrenergic activity (Cederbaum and Agha- Prichard et al. 1979; Aoki et al. 1994;Scheinin et al 1994;Rosin et al. 1996).Three subtypes of alpha2-adrenoceptors (alpha2A, alpha2B, and alpha2C) have been cloned in humans (Kobilka et al. 1987;Regan et al. 1988;Lomasney et al. 1990). The anatomical distribution of the subtypes is unique MacDonald et al. 1997), suggesting that modulation of these subtypes by subtype selective ligands might be of therapeutic importance. Unfortunately, no such subtype selective ligands are currently available. However, the adverse effects (sedation, hypotension) of unselective alpha2-agonists could be dissociated from their beneficial (cognitionenhancing) effects based on their relative affinities for each receptor subtype. Indeed, in the rat brain, alpha2B messanger (m) RNA is found exclusively in the thalamus , and an action at this receptor subtype could impair thalamocortical arousal mechanisms (Riekkinen, Jr. et al. 1993). The brainstem nucleus tractus solitarius contains alpha2A and alpha2C mRNA, and recently, action at the alpha2A adrenoceptor subtype was shown to mediate the hypotensive effects of alpha2-agonists (MacMillan et al. 1996). In the monkey prefrontal cortex, the alpha2A subtype has the densest distribution of all three alpha2-adrenoceptor subtypes (Aoki et al. 1994). Importantly, in monkeys, the ability of subtype nonselective alpha2-agonists, such as clonidine and guanfacine, to improve prefrontal cortical functions, such as spatial working memory performance, without causin...

Selective effects of clonidine and temazepam on attention and memory

“…This is in contrast to some, but not all, previous studies in humans (Coull et al, 1995a,b;Jäkälä, 1999b). Coull et al (1995a) have suggested that, at higher doses, post-synaptic actions may become prominent, thus increasing noradrenergic tone and leading to performance improvements.…”

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

“…Moderate levels of NE improve PFC function, possibly via α 2A receptors; whereas high levels of NE may engage low affinity α 1 receptors and blunt PFC performance (Arnsten, 2000; Arnsten et al, 2012b; Lapiz and Morilak, 2006). To further support this notion, many studies have focused on elucidating the mechanisms and found that α 2 receptor agonists are able to improve PFC function in mice (Franowicz et al, 2002), rats (Tanila et al, 1996), monkeys (Li et al, 1999; Wang et al, 2007), and even humans (Jakala et al, 1999). …”

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

“…B. Taylor & Russo, 2001). With regard to healthy volunteers, however, findings demonstrating working memory enhancement have been ambiguous, with several studies showing guanfacine-related improvements in selective function, including planning and associative learning (Jakala, Riekkinen, Sirvio, Koivisto, Kejonen, et al, 1999; Jakala, Sirvio, et al, 1999) and other studies failing to document any improvements (Birnbaum, Podell, & Arnsten, 2000; Muller et al, 2005). It has therefore been suggested that the effects of guanfacine on executive and regulatory mechanisms may be more likely observed in conditions characterized by catecholaminergic dysfunction (Arnsten, Steere, Jentsch, & Li, 1998) (Franowicz & Arnsten, 1998; Milstein, Lehmann, Theobald, Dalley, & Robbins, 2007).…”