PT  - JOURNAL ARTICLE
AU  - Meera E. Modi
AU  - Mark J. Majchrzak
AU  - Kari R. Fonseca
AU  - Angela Doran
AU  - Sarah Osgood
AU  - Michelle Vanase-Frawley
AU  - Eric Feyfant
AU  - Heather McInnes
AU  - Ramin Darvari
AU  - Derek L. Buhl
AU  - Natasha M. Kablaoui
TI  - Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing
AID  - 10.1124/jpet.116.232702
DP  - 2016 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 164--172
VI  - 358
IP  - 2
4099  - http://jpet.aspetjournals.org/content/358/2/164.short
4100  - http://jpet.aspetjournals.org/content/358/2/164.full
SO  - J Pharmacol Exp Ther2016 Aug 01; 358
AB  - 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.