Supranormal Stimulation of D1Dopamine Receptors in the Rodent Prefrontal Cortex Impairs Spatial Working Memory Performance
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Although previous research has emphasized the beneficial effects of dopamine (DA) on functions of the prefrontal cortex (PFC), recent studies of animals exposed to mild stress indicate that excessive DA receptor stimulation may be detrimental to the spatial working memory functions of the PFC (Arnsten and Goldman-Rakic, 1990; Murphy et al., 1994, 1996a,b, 1997). In particular, these studies have suggested that supranormal stimulation of D 1 receptors may contribute to the detrimental actions of DA in the PFC (Murphy et al., 1994, 1996a). The current study directly tested this hypothesis by examining the effects of infusing a full D 1 receptor agonist, SKF 81297, into the PFC of rats performing a spatial working memory task, delayed alternation. SKF 81297 produced a dose-related impairment in delayed-alternation performance. The impairment was reversed by pretreatment with a D 1 receptor antagonist, SCH 23390, consistent with drug actions at D 1 receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., 1994, 1996a). There was a significant relationship between infusion location and drug efficacy; animals with cannulae anterior to the PFC were not impaired by SKF 81297 infusions. Taken together, these results demonstrate that supranormal D 1 receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D 1 receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996). Increased D 1 receptor stimulation during stress may serve to take the PFC “off-line” to allow posterior cortical and subcortical structures to regulate behavior, but may contribute to the vulnerability of the PFC in many neuropsychiatric disorders.
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Either blockade of D1/5 receptors or excessive stimulation of D1/5 receptors in the PFC impairs spatial working memory.
“Cognitive studies in animals have shown that either blockade of D1/5 receptors or excessive stimulation of D1/5 receptors in the PFC impairs spatial working memory (106–108).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [108]
The paper reports that excessive D1 receptor stimulation in rat PFC impaired delayed-alternation performance, a spatial working-memory task. Its introduction also describes evidence that insufficient D1 stimulation impairs PFC cognition, but this study’s antagonist dose alone did not impair performance (Experiment 2, page unavailable). The passages identify D1 receptors, not D1/5 receptors, so the D5 part of the claim is not established by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBoth blockade and excessive stimulation of D1 receptors impair spatial working memory.
“Both blockade and excessive stimulation of D1 receptors impair spatial working memory65–67.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [67]
In both rats and monkeys, stress-induced PFC dysfunction can be blocked by dopamine D1 receptor or norepinephrine α1-adrenoceptor antagonists, and conversely, it can be mimicked by high levels of D1R or α1-AR stimulation in PFC.
“In both rats and monkeys, stress-induced PFC dysfunction can be blocked by dopamine D1 receptor (D1R) or norepinephrine α1-adrenoceptor (AR) antagonists19,54, and conversely, it can be mimicked by high levels of D1R55 or α1-AR56,57 stimulation in PFC.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [55]
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Arnsten, A. F. T., & Goldman-Rakic, P. S. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.4.362 · Cited by 6 · see citing works
Self-citationThe Neurochemical Modulation of Prefrontal Control Processes
Robbins, T. W., & Kehagia, A. A. (2017) · The Wiley Handbook of Cognitive Control · doi:10.1002/9781118920497.ch19 · Cited by 4 · see citing works
- Authors
- Zahrt, J., Taylor, J. R., Mathew, R. G., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1997-11-01
- Volume
- 17
- Issue
- 21
- Pages
- 8528-8535
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6573725
- OpenAlex
- W2119410682
- Cited by
- 796
- References
- 4
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 24 · 2021: 19 · 2020: 20 · 2019: 27 · 2018: 27 · 2017: 18 · 2016: 30 · 2015: 29 · 2014: 31 · 2013: 38 · 2012: 34
- FWCI
- 8.53
- 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)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D1 receptor, prefrontal cortex, spatial working memory, delayed alternation, SKF 81297, SCH 23390, dopamine D1 receptor antagonist, stress, cognitive impairment
- MeSH terms
- Animals, Benzazepines, Dopamine, Infusions, Parenteral, Male, Memory, Models, Neurological, Models, Psychological, Psychomotor Performance, Spatial Behavior, Stress, Psychological, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Dopamine D1, Dopamine Agonists, Dopamine Antagonists, Maze Learning, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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