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 α2A 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.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Z T
authors.initials: ZT
authors.lastname: Freeman
authors.affiliation: 1] Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Rice
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Soto
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K A M
authors.initials: KA
authors.lastname: Pate
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Weed
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Ator
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: I G
authors.initials: IG
authors.lastname: DeLeon
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA [3] Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Wong
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Mankowski
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Zink
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Adams
authors.affiliation: Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Hutchinson
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001288:Attention / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects*; D002250:Carbon Radioisotopes; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000503:physiopathology*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists; D016316:Guanfacine / Q000494:pharmacology* / Q000627:therapeutic use; D007175:Impulsive Behavior / Q000187:drug effects* / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D020891:Raclopride; D011897:Random Allocation; D011930:Reaction Time; D011954:Receptors, Dopamine / Q000378:metabolism*; D016728:Self-Injurious Behavior / Q000188:drug therapy / Q000503:physiopathology*; D012720:Severity of Illness Index
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D016316:Guanfacine; D020891:Raclopride