Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups.

Introduction: Dysregulation of GABAergic inhibition and glutamatergic excitation has been implicated in exaggerated anxiety. Mouse pups emit distress-like ultrasonic vocalizations (USVs) when they are separated from their dam/siblings, and this behavior is reduced by benzodiazepines (BZs) which modulate GABAergic inhibition. The roles of glutamate receptors on USVs remain to be investigated.

Materials And Methods: We examined the roles of glutamate receptor subtypes on mouse pup USVs using N-methyl-D: -aspartate (NMDA) receptor antagonists with different affinities [dizocilpine (MK-801), memantine, and neramexane] and group II metabotropic glutamate receptor agonist (LY-379268) and antagonist (LY-341495). These effects were compared with classic BZs: flunitrazepam, bromazepam, and chlordiazepoxide. To assess the role of GABA(A) receptor subunits on USVs, drugs that have preferential actions at different GABA(A)-alpha subunits (L-838417 and QH-ii-066) were tested. Seven-day-old CFW mouse pups were separated from their dam and littermates and placed individually on a 19 degrees C test platform for 4 min. Grid crossings and body rolls were measured in addition to USVs.

Results: Dizocilpine dose-dependently reduced USVs, whereas memantine and neramexane showed biphasic effects and enhanced USVs at low to moderate doses. The NMDA receptor antagonists increased locomotion. LY-379268 reduced USVs but also suppressed locomotion. All BZs reduced USVs and increased motor incoordination. Neither L-838417 nor QH-ii-066 changed USVs, but both induced motor incoordination.

Conclusion: Low-affinity NMDA receptor antagonists, but not the high-affinity antagonist, enhanced mouse pup distress calls, which may be reflective of an anxiety-like state. BZs reduced USVs but also induced motor incoordination, possibly mediated by the alpha5 subunit containing GABA(A) receptors.