A preclinical comparison of oxytocin and the non-peptide oxytocin receptor agonist WAY 267,464 as potential therapeutics for psychiatric disorders

Abstract

Introduction: Many researchers have proposed that the neuropeptide oxytocin (OT) might be used as a therapeutic to enhance social functioning in psychiatric disorders that feature impaired social behaviour. Despite an increasing number of clinical studies, current evidence in favour of meaningful clinical outcomes with OT is marginal at best. Such results might simply reflect the poor oral bioavailability and blood-brain barrier permeability of OT, as well as its poor selectivity for the oxytocin receptor (OTR) over the vasopressin 1A receptor (V1AR). These problems have encouraged the development of ‘small-molecule’ non-peptide OT ligands that aim to provide improved bioavailability and receptor selectivity relative to OT. One promising candidate is the non-peptide OTR agonist WAY 267,464. Surprisingly, there has been limited preclinical testing of WAY 267,464 to date. The present thesis thus provides a comprehensive in vitro, in vivo and ex vivo comparison of WAY 267,464 and OT in rats. Methods: Chapter 2 compared WAY 267,464 and OT on in vitro receptor pharmacology, social preference and regional brain activation. In Chapter 3, the effects of WAY 267,464 on social recognition memory were examined. Chapter 4 characterised the effects of WAY 267,464, OT and vasopressin (AVP) on body temperature and heart rate using biotelemetry. Chapter 5 examined the long-term effects of adolescent OT pretreatment on methamphetamine (METH) self-administration in adulthood. Results: WAY 267,464 increased social preference and caused similar brain activation to OT. WAY 267,464 prevented the facilitatory effects of AVP on social memory, and blocked OT-induced hypothermia and bradycardia. WAY 267,464 showed a dual agonist/antagonist action at the OTR and V1AR, respectively, while OT and AVP exhibited strong agonist activity at both receptors. Lastly, adolescent OT pretreatment reduced METH responding in adulthood. Conclusions: WAY 267,464 is not a simple OTR agonist, and has potent V1AR antagonist properties that have important implications for its therapeutic potential. Exogenous OT may be a promising pharmacotherapy for drug addiction. However, a better mechanistic understanding of its effects is necessary for the development of targeted medications.