Neuropeptide Y and glutamatergic mechanisms in the amygdala and ventral hippocampus differentially mediate impaired social behavior in diabetic mice

•In diabetic mice AMPA and NPY Y2 receptor function in social behavior was studied.•NBQX injected into hippocampus or amygdala ameliorated diabetic social impairment.•NPY levels were increased in amygdala, but not in hippocampus, of diabetic mice.•BIIE 0246 injected into amygdala ameliorated diabetic social impairment.•NPY Y2 and AMPA receptors play important roles in diabetic social impairment. Though patients with diabetes mellitus are reported to show deficits in social interaction, the mechanisms of these impairments are unclear. The present study investigated the role of AMPA and neuropeptide Y (NPY) receptors in the ventral hippocampus (vHC) and basolateral amygdala (BLA) in the social behavior of diabetic mice. In the three-chamber test, streptozotocin (STZ)-induced diabetic mice showed impairment in social novelty preference, but not in sociability. Injection of the AMPA receptor antagonist NBQX into vHC or BLA each restored social novelty preference in STZ-induced diabetic mice. NPY content in amygdala, but not in vHC, of STZ-induced diabetic mice was increased relative to non-diabetic mice. In STZ-induced diabetic mice, injection of the NPY Y2 receptor antagonist BIIE 0246 into BLA restored social novelty preference, whereas injection of BIIE 0246 into vHC was without effect. Finally, in non-diabetic mice social novelty preference was impaired by the NPY Y2 receptor agonist NPY 13–36 injected into BLA and restored by co-injection of NBQX. These results indicate that in diabetic mice glutamatergic function is enhanced in both vHC and BLA, which impairs social novelty preference through AMPA receptors. In addition, they indicate that NPYergic function in BLA, but not vHC, is enhanced in diabetic mice, which impairs social novelty preference through NPY Y2 receptors.