The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes
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The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.
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Guanfacine was the most potent α2A-AR-selective agonist with the least side effects.
“Research with visiting Chinese scientist, Jing-Xia Cai, showed that the α2A-AR-selective agonist, guanfacine, was the most potent agent with the least side effects, suggesting that the beneficial effects arose from what is now called the α2A-AR subtype (Arnsten et al., 1988).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 1988
The Summary reports that guanfacine was the most potent of the three agents for improving delayed-response performance in aged monkeys and the least potent at producing sedation or hypotension. The Discussion links its benefit to selectivity for a proposed receptor subtype called Ri, but our copy does not identify Ri as what is now called α2A-AR; that specific identification is not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDose-response studies in monkeys suggest that guanfacine-induced enhancement of PFC function can be completely dissociated from the sedative effects of guanfacine.
“Dose-response studies in monkeys suggest that guanfacine-induced enhancement of PFC function can be completely dissociated from the sedative effects of guanfacine (Arnsten et al., 1988).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten et al., 1988
Guanfacine enhances various PFC functions in animals, including improvements in working memory, behavioral inhibition, and reduced distractibility.
“Guanfacine enhances various PFC functions in animals, including improvements in working memory (Arnsten et al., 1988), behavioral inhibition (Steere and Arnsten, 1997), and reduced distractibility (Arnsten and Contant, 1992).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten et al., 1988
These improvements are observed immediately when guanfacine is infused directly into the PFC and when administered systemically.
“These improvements are observed immediately when guanfacine is infused directly into the PFC (Mao et al., 1999) and when administered systemically (Arnsten et al., 1988; O'Neill et al., 2000; Rama et al., 1996).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten et al., 1988
The beneficial effects of α2-AR agonists for higher cognitive function were first discovered in aged monkeys.
“The beneficial effects of α2-AR agonists for higher cognitive function were first discovered in aged monkeys (Arnsten et al., 1988, Arnsten and Goldman-Rakic, 1985)”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 1988
α2-AR agonists improved working memory performance in aged rhesus monkeys with naturally occurring catecholamine depletion.
“α2-AR agonists also improved working memory performance in aged rhesus monkeys with naturally occurring catecholamine depletion (Arnsten et al., 1988, Arnsten and Goldman-Rakic, 1985, Arnsten and Leslie, 1991, Rama et al., 1996).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 1988
Guanfacine administration to aged monkeys improves working memory.
“Guanfacine administration to aged monkeys improves working memory (Arnsten et al., 1988)”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 1988
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References 38 · Cited by 391
Research works printed but not linked: 6
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- Authors
- Arnsten, A., Cai, J., & Goldman-Rakic, P.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1988-11-01
- Volume
- 8
- Issue
- 11
- Pages
- 4287-4298
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6569464
- OpenAlex
- W2147123664
- Cited by
- 391
- References
- 38
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 10 · 2022: 7 · 2021: 6 · 2020: 12 · 2019: 3 · 2018: 5 · 2017: 10 · 2016: 20 · 2015: 11 · 2014: 13 · 2013: 18 · 2012: 15
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG06036)
- National Institute of Mental Health (MH38546)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- alpha-2 adrenergic agonists, clonidine, working memory, aging, rhesus monkeys, hypotension, sedation, dose-response relationship, delayed response task, cognitive enhancement
- MeSH terms
- Adrenergic alpha-Agonists, Aging, Animals, Azepines, Dioxanes, Dose-Response Relationship, Drug, Female, Guanidines, Hypnotics and Sedatives, Hypotension, Macaca mulatta, Memory, Phenylacetates, Receptors, Adrenergic, alpha, Guanfacine, Idazoxan
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