An acute intraperitoneal injection of vehicle or 57 (at 10 or 20 mg/kg) to Oprm1+/+ or Oprm1–/– unfamiliar (non cagemates, same age, same sex, and same treatment) were administered on mice before introducing them by pairs in an open-field for 10 min testing. Behavioral parameters were scored on video recordings to assess the quality of social interactions in these animals, namely the number of nose contacts (NCs), the time spent in NC, the mean duration of NCs, the number of following episodes, and the number of grooming episodes occurring after a social contact, an index of social avoidance. At the dose of 10 mg/kg (Figure 2), 57 restored the number of NCs (genotype effect, F1,42 = 54.2, p < 0.0001; dose effect, F2,42 = 9.6, p < 0.001; genotype × dose interaction, F2,42 = 16.8, p < 0.0001) and time spent in NC (genotype, F1,42 = 45.6, p < 0.0001; dose, F2,42 = 19.9, p < 0.0001; genotype × dose: F2,42 = 17.4, p < 0.0001), the mean duration of NC (genotype, F1,42 = 15.1, p < 0.001; dose, F2,42 = 19.5, p < 0.0001; genotype × dose, F2,42 = 19.8, p < 0.0001) and the number of following episodes (genotype, F1,42 = 38.9, p < 0.001; dose, F2,42 = 24.4, p < 0.0001; genotype × dose, F2,42 = 4.2, p < 0.05) measured in Oprm1–/– mice to similar levels as measured in wild-type controls. Moreover, at this dose, 57 also suppressed grooming episodes occurring after a social contact in mutants (genotype, F1,42 = 8.5, p < 0.01; dose, F2,42 = 11.3, p < 0.001; genotype × dose, F2,42 = 21.4, p < 0.0001). The OT-R agonist had no effect in Oprm1+/+ mice at this dose, except that it increased the number of following episodes. At the dose of 20 mg/kg, compound 57 demonstrated less significant beneficial effects on social parameters measured in mutant animals and started to show some detrimental effects on these parameters in wild-type controls (Figure 2A–E). Such effects may have resulted either from excessive OT-R activation or from recruitment/blockade of V1a or V1b vasopressin receptors at high doses, peripherally or centrally.
Reference: J Med Chem. 2018 Oct 11;61(19):8670-8692. https://doi.org/10.1021/acs.jmedchem.8b00697