D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Arrestin
Prefrontal Cortex
Short-Term Memory
Dopamine
Adenylyl Cyclases
Cognition
Dopamine Agonists
Pharmaceutical Preparations
Ligands
Neurons

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

@article{86dc82eeacf14d0e84133adbe61b7d20,
title = "D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex",
abstract = "Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.",
author = "Yang Yang and Lee, {Sang Min} and Fumiaki Imamura and Krishne Gowda and Shantu Amin and Mailman, {Richard B.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41380-018-0312-1",
language = "English (US)",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex

AU - Yang, Yang

AU - Lee, Sang Min

AU - Imamura, Fumiaki

AU - Gowda, Krishne

AU - Amin, Shantu

AU - Mailman, Richard B.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.

AB - Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.

UR - http://www.scopus.com/inward/record.url?scp=85058137684&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058137684&partnerID=8YFLogxK

U2 - 10.1038/s41380-018-0312-1

DO - 10.1038/s41380-018-0312-1

M3 - Article

C2 - 30532019

AN - SCOPUS:85058137684

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -