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

Sheryl S Moy, Brian L. Teng, Viktoriya D. Nikolova, Natallia V. Riddick, Catherine D. Simpson, Amy Van Deusen, William P. Janzen, Maria F. Sassano, Cort Andrew Pedersen, Michael Bruce Jarstfer

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages301-311
Number of pages11
JournalNeuropharmacology
Volume144
DOIs
StatePublished - Jan 1 2019

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Artificial Receptors
Oxytocin Receptors
Oxytocin
Autistic Disorder
Vasopressin Receptors
Penetrance
Social Behavior
Drug Discovery
Vasopressins
Neurotransmitter Agents
Therapeutics
Pharmacology
Drug Therapy
Autism Spectrum Disorder
Brain

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism. / Moy, Sheryl S; Teng, Brian L.; Nikolova, Viktoriya D.; Riddick, Natallia V.; Simpson, Catherine D.; Van Deusen, Amy; Janzen, William P.; Sassano, Maria F.; Pedersen, Cort Andrew; Jarstfer, Michael Bruce.

In: Neuropharmacology, Vol. 144, 01.01.2019, p. 301-311.

Research output: Contribution to journalArticle

Moy, Sheryl S ; Teng, Brian L. ; Nikolova, Viktoriya D. ; Riddick, Natallia V. ; Simpson, Catherine D. ; Van Deusen, Amy ; Janzen, William P. ; Sassano, Maria F. ; Pedersen, Cort Andrew ; Jarstfer, Michael Bruce. / Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism. In: Neuropharmacology. 2019 ; Vol. 144. pp. 301-311.
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