2. Academic Validation
  3. Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism

Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism

  • Neuropharmacology. 2019 Jan;144:301-311. doi: 10.1016/j.neuropharm.2018.10.036.
Sheryl S Moy 1,  Brian L Teng 2,  Viktoriya D Nikolova 3,  Natallia V Riddick 3,  Catherine D Simpson 4,  Amy Van Deusen 5,  William P Janzen 5,  Maria F Sassano 6,  Cort A Pedersen 3,  Michael B Jarstfer 7
Affiliations

Affiliations

  • 1 Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].
  • 2 Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 3 Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
  • 4 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 5 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 6 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
  • 7 Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].
PMID: 30399367 DOI: 10.1016/j.neuropharm.2018.10.036
Abstract

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate Oxytocin Receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

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