Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing

Abstract

Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non–brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response.

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice

“…Recently, similar substitutions of OT, in which Leu 8 is changed to Lys appended with a polyethylene glycol spacer and a palmitoyl group, have been reported (Modi et al. ).…”

Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism

“…OXT treatment began at PND90 when rats reached an average weight of 150 g. OXT (Sigma-Aldrich Co., LLC., Darmstadt, Germany) was intraperitoneally injected in the IP OXT-VPA group in a dose of 10 mg/kg/bodyweight for 8 days consecutively. This dosage was established based on previous published work of our group [ 54 , 55 ] and others [ 56 ]. Behavioral tests were initiated on the 6th day of OXT treatment and lasted three days during which the OXT administration continued.…”

Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala

“…Oxytocin receptors are found in the brain and in various peripheral tissues, where binding mediates oxytocin’s classic role in lactation, parturition, and sexual reflexes in males and females [25]. There are several other oxytocin binding sites in the periphery, including the gut, heart, vascular system, and vagus nerve, which all may contribute to behavioral effects of oxytocin, including inhibition of appetite and fear [25,26]. The central versus peripheral contributions to oxytocin’s putative effects on alcohol drinking also remain to be determined.…”