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 (BP _ND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding ( r _s=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 ( r _s=0.563, P=0.045 and r _s=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α ₂A 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 ( r _s=−0.761, P=0.009). The elevated PET BP _ND 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.