Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Amy F.T. Arnsten, Ragy R. Girgis, David L. Gray, Richard B. Mailman

Research output: Contribution to journalReview article

40 Citations (Scopus)

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 D1 receptors (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 D1 agonists, e.g., the first full D1 agonist, 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 D1 agonists with better pharmacokinetics, functionally selective D1 ligands, 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.

Original languageEnglish (US)
Pages (from-to)67-77
Number of pages11
JournalBiological Psychiatry
Volume81
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Prefrontal Cortex
Dopamine
Schizophrenia
Short-Term Memory
Therapeutics
Pharmacokinetics
Dopamine D1 Receptors
Dendritic Spines
Pyramidal Cells
Drug Industry
Primates
Atrophy
Haplorhini
Ligands
Brain
Research
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Arnsten, Amy F.T. ; Girgis, Ragy R. ; Gray, David L. ; Mailman, Richard B. / Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. In: Biological Psychiatry. 2017 ; Vol. 81, No. 1. pp. 67-77.
@article{9ab02d5c08d14e6ca147d690f23e7c93,
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 D1 receptors (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 D1 agonists, e.g., the first full D1 agonist, 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 D1 agonists with better pharmacokinetics, functionally selective D1 ligands, 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.",
author = "Arnsten, {Amy F.T.} and Girgis, {Ragy R.} and Gray, {David L.} and Mailman, {Richard B.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.biopsych.2015.12.028",
language = "English (US)",
volume = "81",
pages = "67--77",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "1",

}

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. / Arnsten, Amy F.T.; Girgis, Ragy R.; Gray, David L.; Mailman, Richard B.

In: Biological Psychiatry, Vol. 81, No. 1, 01.01.2017, p. 67-77.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

AU - Arnsten, Amy F.T.

AU - Girgis, Ragy R.

AU - Gray, David L.

AU - Mailman, Richard B.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 D1 receptors (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 D1 agonists, e.g., the first full D1 agonist, 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 D1 agonists with better pharmacokinetics, functionally selective D1 ligands, 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.

AB - 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 D1 receptors (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 D1 agonists, e.g., the first full D1 agonist, 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 D1 agonists with better pharmacokinetics, functionally selective D1 ligands, 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.

UR - http://www.scopus.com/inward/record.url?scp=84959432687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959432687&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2015.12.028

DO - 10.1016/j.biopsych.2015.12.028

M3 - Review article

C2 - 26946382

AN - SCOPUS:84959432687

VL - 81

SP - 67

EP - 77

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 1

ER -