Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior

Z. T. Freeman, K. A. Rice, P. L. Soto, Kelly Pate, M. R. Weed, Nancy A Ator, I. G. DeLeon, Dean Foster Wong, Yun Zhou, Joseph L Mankowski, Mary Christine Zink, Robert John Adams, Eric Hutchinson

Research output: Contribution to journalArticle

Abstract

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs = 0.662, P = 0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs = 0.563, P = 0.045 and rs = 0.692, P = 0.009, respectively). We also tested the efficacy of guanfacine, an a2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P = 0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs = - 0.761, P = 0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Original languageEnglish (US)
Article numbere567
JournalTranslational Psychiatry
Volume5
Issue number5
DOIs
StatePublished - May 26 2015

Fingerprint

Guanfacine
Self-Injurious Behavior
Macaca mulatta
Pharmacology
Macaca
Positron-Emission Tomography
Central Nervous System
Raclopride
Corpus Striatum
Adrenergic Agonists
Aptitude
Impulsive Behavior
Dopamine Receptors
Wounds and Injuries
Cognition
Reaction Time
Psychiatry
Comorbidity
Dopamine
Animal Models

ASJC Scopus subject areas

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

Cite this

@article{2b58b37ea81f408c83007038ab844141,
title = "Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior",
abstract = "Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs = 0.662, P = 0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs = 0.563, P = 0.045 and rs = 0.692, P = 0.009, respectively). We also tested the efficacy of guanfacine, an a2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P = 0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs = - 0.761, P = 0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.",
author = "Freeman, {Z. T.} and Rice, {K. A.} and Soto, {P. L.} and Kelly Pate and Weed, {M. R.} and Ator, {Nancy A} and DeLeon, {I. G.} and Wong, {Dean Foster} and Yun Zhou and Mankowski, {Joseph L} and Zink, {Mary Christine} and Adams, {Robert John} and Eric Hutchinson",
year = "2015",
month = "5",
day = "26",
doi = "10.1038/tp.2015.61",
language = "English (US)",
volume = "5",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior

AU - Freeman, Z. T.

AU - Rice, K. A.

AU - Soto, P. L.

AU - Pate, Kelly

AU - Weed, M. R.

AU - Ator, Nancy A

AU - DeLeon, I. G.

AU - Wong, Dean Foster

AU - Zhou, Yun

AU - Mankowski, Joseph L

AU - Zink, Mary Christine

AU - Adams, Robert John

AU - Hutchinson, Eric

PY - 2015/5/26

Y1 - 2015/5/26

N2 - Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs = 0.662, P = 0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs = 0.563, P = 0.045 and rs = 0.692, P = 0.009, respectively). We also tested the efficacy of guanfacine, an a2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P = 0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs = - 0.761, P = 0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

AB - Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs = 0.662, P = 0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs = 0.563, P = 0.045 and rs = 0.692, P = 0.009, respectively). We also tested the efficacy of guanfacine, an a2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P = 0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs = - 0.761, P = 0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

UR - http://www.scopus.com/inward/record.url?scp=84990923296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990923296&partnerID=8YFLogxK

U2 - 10.1038/tp.2015.61

DO - 10.1038/tp.2015.61

M3 - Article

VL - 5

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 5

M1 - e567

ER -