Article abstract
Nature Neuroscience 10, 376 - 384 (2007)
Published online: 4 February 2007 | doi:10.1038/nn1846
Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Susheel Vijayraghavan1, Min Wang1, Shari G Birnbaum1,3, Graham V Williams2 & Amy F T Arnsten1
Abstract
Dopamine (DA) D1 receptor (D1R) stimulation in prefrontal cortex (PFC) produces an 'inverted-U' dose-response, whereby either too little or too much D1R stimulation impairs spatial working memory. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. The cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms. The current study demonstrates that the D1R agonist inverted-U response can be observed in PFC neurons of behaving monkeys: low levels of D1R stimulation enhance spatial tuning by suppressing responses to nonpreferred directions, whereas high levels reduce delay-related firing for all directions, eroding tuning. These sculpting actions of D1R stimulation are mediated in monkeys and rats by cyclic AMP intracellular signaling. The evidence for an inverted U at the cellular level in behaving animals promises to bridge in vitro molecular analyses with human cognitive experience.
- Department of Neurobiology, Yale Medical School, 333 Cedar Street, New Haven, Connecticut 06520-8001, USA.
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, Connecticut 06511, USA.
- Present address: University of Texas Southwestern Medical Center, Department of Psychiatry, NC6.102, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Correspondence to: e-mail: amy.arnsten@yale.edu
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