title: Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory.
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.
authors.affiliation: Department of Neurobiology, Yale Medical School, 333 Cedar Street, New Haven, Connecticut 06520-8001, USA.
authors.forename: Susheel
authors.initials: S
authors.lastname: Vijayraghavan
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: Graham V
authors.initials: GV
authors.lastname: Williams
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007478:Iontophoresis / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D012680:Sensitivity and Specificity; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP