Treatment with the Noradrenergic Alpha-2 Agonist Clonidine, But Not Diazepam, Improves Spatial Working Memory in Normal Young Rhesus Monkeys

Franowicz, Jenna S; Arnsten, Amy F.T.

doi:10.1016/s0893-133x(99)00060-3

Cited by 52 publications

(41 citation statements)

References 59 publications

(59 reference statements)

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“…Spatial working memory has been documented to be sensitive to the manipulation of alpha-2 adrenoceptors (Arnsten and Goldman-Rakic 1985;Arnsten et al 1988Arnsten et al , 1996Li and Mei 1994a;Franowicz and Arnsten 1999). Arnsten and coworkers reported that systemi- cally-administered clonidine (or guanfacine) improved the spatial working memory performance of aged monkeys with naturally-occurring NE depletion or young monkeys with experimentally-induced NE depletion and suggested that the beneficial effect of alpha-2 agonists was mediated by postsynaptic alpha-2 adrenoceptors in the PFC (Arnsten and Goldman-Rakic 1985;Arnsten et al 1988).…”

Section: Discussionmentioning

confidence: 99%

Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys

1999

Neuropsychopharmacology

148

103

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Section: Discussionmentioning

confidence: 99%

Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys

1999

Neuropsychopharmacology

148

103

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“…Further evidence of PFC noradrenergic modulation of attentional processing comes from the study of working memory (Arnsten et al 1988;Franowicz and Arnsten 1999, for a review, see Arnsten 2004). In particular, α-2 adrenoceptor stimulation via treatment with guanfacine, a selective α-2A agonist, is reported to enhance performance on both rat delayed-alternation (Carlson et al 1992) and monkey delayed response tasks (Arnsten et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat

et al. 2006

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Rationale-Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DβH)-saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.Objectives-The aim of this work is to examine (1) the effect of cortical noradrenaline depletion on sustained attentional performance in the 5CSRT under a variety of test conditions and (2) the effects of guanfacine, a selective α-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats.Materials and methods-Animals received either intramedial prefrontal anti-DβH-saporin or vehicle and were tested on the baseline task with a variety of additional manipulations including (1) decreasing target duration, (2) increasing rate and (3) temporal unpredictability of target presentation and (4) systemic guanfacine.Results-Anti-DβH-saporin infused into the PFC produced a substantial loss of DβH-positive fibers in that region and in other adjacent cortical areas. There was no significant depletion of DA or 5-HT. NA-depleted animals were not impaired on the baseline task, but were slower to respond correctly under high event rate conditions, and their discriminative accuracy was reduced when stimulus predictability decreased. Guanfacine significantly reduced discriminative accuracy in NA-depleted animals only.Conclusion-Selective cortical NA depletion produced deficits on the 5CSRT test of sustained attention, especially when the attentional load was increased and in response to systemic guanfacine. These results are consistent with a role of coeruleo-cortical NA in the regulation of effortful attentional processes.

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“…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 .…”

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confidence: 99%

“…Low doses of clonidine in healthy individuals likely engage predominantly presynaptic alpha-2 receptors and thus may produce widespread decreases in NE transmission. Low doses of clonidine (0.1-10 ug/kg ) have little effect in normal young adult monkeys, but enhance working memory performance in monkeys with NE depletion (Cai et al 1993;Franowicz and Arnsten 1999). Coull et al (1997) using positron emission tomography (PET) found that low doses of clonidine (1.3 g/kg) did not enhance blood flow in the PFC and indeed reduced regional cerebral blood flow (rCBF) in thalamus during conditions of rest.…”

mentioning

confidence: 99%

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

Avery

Franowicz

Studholme

et al. 2000

Neuropsychopharmacology

132

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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...

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Treatment with the Noradrenergic Alpha-2 Agonist Clonidine, But Not Diazepam, Improves Spatial Working Memory in Normal Young Rhesus Monkeys

Cited by 52 publications

References 59 publications

Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys

Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat

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

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