Mutation of the α2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine
Open accessAbstract
Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors (alpha2-AR). The alpha2-AR agonist guanfacine enhances prefrontal cortical functions in rats, monkeys, and human beings and ameliorates prefrontal cortical deficits in patients with attention deficit hyperactivity disorder. The present study examined the subtype of alpha2-AR underlying these beneficial effects. Because there are no selective alpha2A-AR, alpha2B-AR, or alpha2C-AR agonists or antagonists, genetically altered mice were used to identify the molecular target of the action of guanfacine. Mice with a point mutation of the alpha2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of alpha2C-AR knock-out mice (Tanila et al., 1999). Mice were adapted to handling on a T maze and trained on either a spatial delayed alternation task that is sensitive to prefrontal cortical damage or a spatial discrimination control task with similar motor and motivational demands but no dependence on prefrontal cortex. The effects of guanfacine on performance of the delayed alternation task were assessed in additional groups of wild-type versus alpha2A-AR mutant mice. We observed that functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning and resulted in loss of the beneficial response to guanfacine. These data demonstrate the importance of alpha2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions.
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Guanfacine does not improve mice with a genetic mutation of α2A-AR where receptor no longer binds agonists.
“guanfacine does not improve mice with a genetic mutation of the α2A-AR where the receptor is no longer able to bind agonists”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Franowicz et al., 2002
The ‘Response to the α2-AR agonist guanfacine’ section reports that guanfacine improved delayed-alternation performance in wild-type mice but had no effect in the α2A-AR mutants. The ‘Subjects’ section describes the mutation as a functional knockout with reduced receptor density and impaired signaling; it does not establish that the receptor can no longer bind agonists. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBeneficial effects of α2-AR agonists on cognition arise from postsynaptic α2A-AR in PFC.
“early research determined that the beneficial effects of α2-AR agonists on cognition arose from postsynaptic receptor actions in the PFC (Arnsten and Goldman-Rakic, 1985, Cai et al., 1993), with a pharmacological profile consistent with the α2A-AR subtype (Arnsten et al., 1988, Arnsten and Leslie, 1991), a finding later confirmed in genetically altered mice (Franowicz et al., 2002).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Franowicz et al., 2002
Systemic administration of guanfacine significantly improves working memory performance in wild-type mice performing delayed alternation task.
“Systemic administration of guanfacine significantly improves working memory performance in wild-type mice performing the delayed alternation task”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Franowicz et al., 2002
Guanfacine's actions in mice are at the α2A-AR subtype.
“confirming actions at the α2A-AR subtype”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Franowicz et al., 2002
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- Authors
- Franowicz, J. S., Kessler, L. E., Borja, C. M. D., Kobilka, B. K., Limbird, L. E., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Vanderbilt University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-10-01
- Volume
- 22
- Issue
- 19
- Pages
- 8771-8777
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757781
- OpenAlex
- W2154917565
- Cited by
- 185
- References
- 7
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 7 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 12 · 2015: 11 · 2014: 12 · 2013: 7 · 2012: 8
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Institute on Aging (R37AG006036, R37 AG06036)
- National Heart, Lung, and Blood Institute (R01HL043671, R37HL043671, HL43671)
- 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
- alpha2A-adrenoceptor, guanfacine, working memory, prefrontal cortex, alpha2C-adrenoceptor, norepinephrine, attention deficit hyperactivity disorder, cognitive enhancement, receptor subtype specificity
- MeSH terms
- Adrenergic alpha-Agonists, Animals, Behavior, Animal, Cognition, Male, Memory, Short-Term, Mice, Inbred C57BL, Mice, Mutant Strains, Guanfacine, Point Mutation, Prefrontal Cortex, Receptors, Adrenergic, alpha-2, Maze Learning, Mice, Adrenergic alpha-2 Receptor Agonists
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