Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior.
The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory.
Adult experimental rats were tested for their recognition of a juvenile conspecific rat that they had briefly met 30 or 120 min previously. The modulatory effects of vasopressin (AVP), the selective V1AR antagonist SR49059, and WAY 267,464 were examined together with those of the selective OTR antagonist Compound 25 (C25). Drugs were administered immediately after the first meeting.
Control rats showed recognition of juveniles at a 30 min, but not a 120 min retention interval. AVP (0.005, but not 0.001 mg/kg intraperitoneal (i.p.)) improved memory such that recognition was evident after 120 min. This was prevented by pretreatment with SR49059 (1 mg/kg) and WAY 267,464 (10, 30, and 100 mg/kg). Given alone, SR49059 (1 mg/kg) and WAY 267,464 (30 and 100 mg/kg) impaired memory at a 30 min retention interval. The impairment with WAY 267,464 was not prevented by C25 (5 mg/kg), suggesting V1AR rather than OTR mediation of the effect. Given alone, C25 also impaired memory.
These results highlight a tonic role for endogenous AVP (and oxytocin) in social recognition memory and indicate that WAY 267,464 functions in vivo as a V1AR antagonist to prevent the memory-enhancing effects of AVP.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Benelli A, Bertolini A, Poggioli R, Menozzi B, Basaglia R, Arletti R (1995) Polymodal dose-response curve for oxytocin in the social recognition test. Neuropeptides 28:251–255
Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ (2004) Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 29:483–493
Bluthe RM, Schoenen J, Dantzer R (1990) Androgen-dependent vasopressinergic neurons are involved in social recognition in rats. Brain Res 519:150–157
Brown A, Brown TB, Calabrese A, Ellis D, Puhalo N, Ralph M, Watson L (2010) Triazole oxytocin antagonists: identification of an aryloxyazetidine replacement for a biaryl substituent. Bioorg Med Chem Lett 20:516–520
Cho MM, DeVries AC, Williams JR, Carter CS (1999) The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster). Behav Neurosci 113:1071–1079
Choleris E, Little SR, Mong JA, Puram SV, Langer R, Pfaff DW (2007) Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice. Proc Natl Acad Sci U S A 104:4670–4675
Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368
Dluzen DE, Muraoka S, Engelmann M, Landgraf R (1998) The effects of infusion of arginine vasopressin, oxytocin, or their antagonists into the olfactory bulb upon social recognition responses in male rats. Peptides 19:999–1005
Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y, Tsujimoto G, Mishima K, Iwasaki K, Fujiwara M (2007) Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav Brain Res 178:123–127
Engelmann M, Landgraf R (1994) Microdialysis administration of vasopressin into the septum improves social recognition in Brattleboro rats. Physiol Behav 55:145–149
Engelmann M, Ludwig M, Landgraf R (1994) Simultaneous monitoring of intracerebral release and behavior: endogenous vasopressin improves social recognition. J Neuroendocrinol 6:391–395
Engelmann M, Wotjak CT, Landgraf R (1995) Social discrimination procedure: an alternative method to investigate juvenile recognition abilities in rats. Physiol Behav 58:315–321
Engelmann M, Ebner K, Wotjak CT, Landgraf R (1998) Endogenous oxytocin is involved in short-term olfactory memory in female rats. Behav Brain Res 90:89–94
Engelmann M, Hädicke J, Noack J (2011) Testing declarative memory in laboratory rats and mice using the nonconditioned social discrimination procedure. Nat Protoc 6:1152–1162
Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278–8285
Fjellestad-Paulsen A, Söderberg-Ahlm C, Lundin S (1995) Metabolism of vasopressin, oxytocin, and their analogues in the human gastrointestinal tract. Peptides 16:1141–1147
Frank E, Landgraf R (2008) The vasopressin system—from antidiuresis to psychopathology. Eur J Pharmacol 583:226–242
Gabor CS, Phan A, Clipperton-Allen AE, Kavaliers M, Choleris E (2012) Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition. Behav Neurosci 126:97–109
Gannon RL (2014) Non-peptide oxytocin receptor ligands and hamster circadian wheel running rhythms. Brain Res 1585:184–190
Grundschober C, Risterucci C, Mueggler T, Biemans B, Bissantz C, Belli S, Schmitt M, Schnider P (2012) The oxytocin agonist WAY267464 is also a potent vasopressin V1a antagonist and V2 agonist. In: International Society for Autism Research. Sheraton Hall (Sheraton Centre Toronto)
Hicks C, Jorgensen W, Brown C, Fardell J, Koehbach J, Gruber CW, Kassiou M, Hunt GE, McGregor IS (2012) The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats. J Neuroendocrinol 24:1012–1029
Hicks C, Ramos L, Reekie T, Misagh G, Narlawar R, Kassiou M, McGregor IS (2014) Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non‐peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats. Br J Pharmacol 171:2868–2887
Hudson P, Pitt G, Batt R, Roe M (2005) Piperazines as oxytocin agonists. In: Patent fetcher (PCT, ed). International Application: Ferring B.V.
Lahoud N, Maroun M (2013) Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction. Psychoneuroendocrinology 38:2184–2195
Larrazolo-Lopez A, Kendrick KM, Aburto-Arciniega M, Arriaga-Avila V, Morimoto S, Frias M, Guevara-Guzman R (2008) Vaginocervical stimulation enhances social recognition memory in rats via oxytocin release in the olfactory bulb. Neuroscience 152:585–593
Le Moal M, Dantzer R, Michaud B, Koob G (1987) Centrally injected arginine vasopressin (AVP) facilitates social memory in rats. Neurosci Lett 77:353–359
Lee HJ, Caldwell HK, Macbeth AH, Tolu SG, Young WS 3rd (2008) A conditional knockout mouse line of the oxytocin receptor. Endocrinology 149:3256–3263
Lim MM, Young LJ (2004) Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience 125:35–45
Lukas M, Bredewold R, Landgraf R, Neumann ID, Veenema AH (2011a) Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats. Psychoneuroendocrinology 36:843–853
Lukas M, Toth I, Reber SO, Slattery DA, Veenema AH, Neumann ID (2011b) The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology 36:2159–2168
Lukas M, Toth I, Veenema AH, Neumann ID (2013) Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics. Psychoneuroendocrinology 38:916–926
Macdonald K, Feifel D (2013) Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Front Neurosci 7:35
Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, Durroux T, Mouillac B, Corbani M, Guillon G (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 24:609–628
Mens WBJ, Witter A, Van Wimersma Greidanus TB (1983) Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 262:143–149
Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M (2011) Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 12:524–538
Olszewski PK, Ulrich C, Ling N, Allen K, Levine AS (2014) A non-peptide oxytocin receptor agonist, WAY-267,464, alleviates novelty-induced hypophagia in mice: insights into changes in c-Fos immunoreactivity. Pharmacol Biochem Behav 124:367–372
Popik P, Van Ree JM (1991) Oxytocin but not vasopressin facilities social recognition following injection into the medial preoptic area of the rat brain. Eur Neuropsychopharmacol 1:555–560
Popik P, Vetulani J (1991) Opposite action of oxytocin and its peptide antagonists on social memory in rats. Neuropeptides 18:23–27
Popik P, Vetulani J, Van Ree JM (1992) Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology 106:71–74
Ramos L, Hicks C, Kevin R, Caminer A, Narlawar R, Kassiou M, McGregor IS (2013) Acute prosocial effects of oxytocin and vasopressin when given alone or in combination with 3,4-methylenedioxymethamphetamine in rats: involvement of the V1A receptor. Neuropsychopharmacology 38:2249–2259
Ramos L, Hicks C, Caminer A, McGregor IS (2014) Inhaled vasopressin increases sociability and reduces body temperature and heart rate in rats. Psychoneuroendocrinology 46:46–51
Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S (2010) Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58:69–77
Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V, Finardi A, Donzelli A, Pattini L, Rubino T, Parolaro D, Nishimori K, Parenti M, Chini B (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69:875–882
Sala M, Braida D, Donzelli A, Martucci R, Busnelli M, Bulgheroni E, Rubino T, Parolaro D, Nishimori K, Chini B (2013) Mice heterozygous for the oxytocin receptor gene (Oxtr+/-) show impaired social behaviour but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect. J Neuroendocrinol 25:107–118
Sekiguchi R, Wolterink G, Van Ree JM (1991) Analysis of the influence of vasopressin neuropeptides on social recognition of rats. Eur Neuropsychopharmacol 1:123–126
Serradeil-Le Gal C, Wagnon J, Garcia C, Lacour C, Guiraudou P, Christophe B, Villanova G, Nisato D, Maffrand J, Le Fur G (1993) Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. J Clin Invest 92:224–231
Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, Yanagisawa T, Kimura T, Matzuk MM, Young LJ (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 102:16096–16101
Tobin VA, Hashimoto H, Wacker DW, Takayanagi Y, Langnaese K, Caquineau C, Noack J, Landgraf R, Onaka T, Leng G, Meddle SL, Engelmann M, Ludwig M (2010) An intrinsic vasopressin system in the olfactory bulb is involved in social recognition. Nature 464:413–417
Veenema AH, Bredewold R, De Vries GJ (2012) Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways. Horm Behav 61:50–56
Research was funded by two National Health and Medical Research Council (NHMRC) grants (1033444 and 1011518) to ISM. ISM has been supported by an Australian Professorial Fellowship from the Australian Research Council and is currently an NHMRC Principal Research Fellow. Animal experiments conducted in this study comply with the Australian code for the care and use of animals for scientific purposes.
Conflict of interest
The authors declare no conflict of interest.
About this article
Cite this article
Hicks, C., Ramos, L., Reekie, T.A. et al. WAY 267,464, a non-peptide oxytocin receptor agonist, impairs social recognition memory in rats through a vasopressin 1A receptor antagonist action. Psychopharmacology 232, 2659–2667 (2015). https://doi.org/10.1007/s00213-015-3902-5
- WAY 267,464
- Vasopressin 1A receptor
- Compound 25
- Social discrimination
- Social recognition