title: Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.
abstract: Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1agonists, e.g., the first full D1agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1agonists with better pharmacokinetics, functionally selective D1ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.
authors.affiliation: Department of Neurobiology, Yale Medical School, New Haven, Conmnecticut. Electronic address: amy.arnsten@yale.edu.
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Ragy R
authors.initials: RR
authors.lastname: Girgis
authors.affiliation: Neuroscience & Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
authors.forename: David L
authors.initials: DL
authors.lastname: Gray
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D000818:Animals; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D010617:Phenanthridines / Q000008:administration & dosage / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011954:Receptors, Dopamine / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D012565:Schizophrenic Psychology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010617:Phenanthridines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C061532:dihydrexidine; D004298:Dopamine
keywords: D(1) agonist; D(2) receptors; Executive function; Prefrontal cortex; Schizophrenia; Working memory