Dose-Dependent Effects of the Dopamine D1 Receptor Agonists A77636 or SKF81297 On Spatial Working Memory in Aged Monkeys
Abstract
With advancing age, monkeys develop deficits in spatial working memory resembling those induced by lesions of the prefrontal cortex (PFC). Aged monkeys also exhibit marked loss of dopamine from the PFC, a transmitter known to be important for proper PFC cognitive function. Previous results suggest that D1 agonist treatment can improve spatial working memory abilities in aged monkeys. However, this research was limited by the use of drugs with either partial agonist actions or significant D2 receptor actions. In our study, the selective dopamine D1 receptor full agonists A77636 and SKF81297 were examined in aged monkeys for effects on the working memory functions of the PFC. Both compounds produced a significant, dose-related effect on delayed response performance without evidence of side effects: low doses improved performance although higher doses impaired or had no effect on performance. Both the improvement and impairment in performance were reversed by pretreatment with the D1 receptor antagonist, SCH23390. These findings are consistent with previous results demonstrating that there is a narrow range of D1 receptor stimulation for optimal PFC cognitive function, and suggest that very low doses of D1 receptor agonists may have cognitive-enhancing actions in the elderly.
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An intermediate (optimal) level of dopaminergic D1 receptor activation is important for working memory tasks to be accomplished.
“The common finding among these studies is the importance of an intermediate, that is, optimal, level of dopaminergic (D1) receptor activation to enable working memory tasks to be accomplished.”
From The Temporal Dynamics Model of Emotional Memory Processing: A Synthesis on the Neurobiological Basis of Stress-Induced Amnesia, Flashbulb and Traumatic Memories, and the Yerkes-Dodson Law (2007) · cites this paper as Cai and Arnsten [416]
There is an inverted-U-shaped relationship between dopamine receptor signaling in the prefrontal cortex and working memory performance.
“A number of researchers have commented on the inverted-U-shaped relationship between dopamine receptor signaling in the prefrontal cortex and working memory performance (Arnsten et al. [414]; Murphy et al. [415]; Cai and Arnsten [416]; Arnsten [363]; Arnsten [417]; Brunel and Wang [418]; Dreher et al. [419]; Yamashita and Tanaka [420]; Williams and Castner [421]; Tanaka et al. [422]).”
From The Temporal Dynamics Model of Emotional Memory Processing: A Synthesis on the Neurobiological Basis of Stress-Induced Amnesia, Flashbulb and Traumatic Memories, and the Yerkes-Dodson Law (2007) · cites this paper as Cai and Arnsten [416]
The WM effect of dopaminergic agents depends on the baseline dopamine level.
“Animal studies reported that the WM effect of dopaminergic agents (e.g., dihydrexidine or other D1 agonists) depends on the baseline dopamine level”
From Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits (2023) · cites this paper as Cai & Arnsten, 1997
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- Authors
- Cai, J. X., & Arnsten, A. F. T.
- Affiliations
- Kunming Institute of Zoology (CN)
- Corresponding author
- Arnsten, A.F.T.
- ORCID
- Arnsten, A.F.T.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1997-10
- Volume
- 283
- Issue
- 1
- Pages
- 183-189
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2135550220
- Cited by
- 285
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 18 · 2014: 14 · 2013: 14 · 2012: 15
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute on Aging (AG06036)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- dopamine D1 receptor agonist, SKF 81297, spatial working memory, aged monkeys, prefrontal cortex, cognitive aging, dose-dependent effects, SCH 23390, dopamine depletion
- MeSH terms
- Adamantane, Aging, Animals, Benzazepines, Benzopyrans, Female, Macaca mulatta, Male, Memory, Prefrontal Cortex, Receptors, Dopamine D1, Dopamine Agonists
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