Disruption of ultrasonic vocalizations with systemic administration of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 in adult male mice

OBJECTIVE: Social behavior and communication, including ultrasonic vocalizations (USVs), are important for survival and reproductive success across species. N-methyl-D-aspartate (NMDA) receptors contribute to the neural mechanisms underlying social behavior, and pharmacological modulation of these receptors can alter both social behavior and USVs in rodents. However, the effects of NMDA receptor blockade on dyadic USVs and social approach during male-female interactions in mice remain incompletely understood. We therefore investigated the effects of systemic administration of MK-801, a noncompetitive NMDA receptor antagonist, on dyadic vocal activity, social approach, locomotor behavior, and excretory outcomes in adult male mice. METHODS: Sexually experienced male mice were tested in male-female interaction and same-sex social-preference tasks. Using VocalMat, a machine-learning-based tool, we classified the USVs recorded during male-female interactions into 11 call categories and examined their temporal relationship to the proximity of the male subject to the female stimulus. RESULTS: Administration of MK-801 to the male dose-dependently reduced the total number of USVs recorded from the male-female dyad, with a marked reduction at the highest dose, while leaving the treated male's proximity to the female stimulus unchanged. In the same-sex social-preference task, MK-801 reduced the time spent near the social stimulus at the highest dose, although preference for the social stimulus over the non-social object remained significant under all treatment conditions. MK-801 also increased locomotor activity and reduced fecal output and estimated urine output in the open-field task. These findings demonstrate that systemic NMDA receptor blockade differentially affects dyadic vocal communication, social approach, locomotor activity, and excretory outcomes. CONCLUSION: Systemic MK-801 administration to the male reduced the number of USVs recorded during male-female interactions and produced distinct effects on social approach, locomotor activity, and excretory outcomes. These findings indicate that NMDA receptor blockade differentially affects multiple behavioral domains, although the mechanisms underlying the reduction in USVs remain to be determined.