A stressor can trigger adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that produces lasting adaptations. TMT exposure may activate metabotropic glutamate receptor 3 (mGlu3), triggering excitatory corticolimbic adaptations that underlie behavioral changes. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after stressor, rats underwent behavioral testing (context re-exposure, zero maze and acoustic startle response) followed by RT-PCR gene expression in the insular cortex and BNST. During the TMT exposure, rats displayed stress-reactive behaviors that were not affected by the VU6010572. During the context re-exposure, prior TMT exposure and VU6010572 pretreatment both produced a hyperactive response. TMT exposure did not affect zero maze or ASR measures, but VU6010572 increased time spent in the open arms and habituation to ASR, indicating anxiolytic-like effects. In the insular cortex, TMT exposure resulted in excitatory adaptations as shown by increased expression of mGlu (Grm3, Grm5), NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) and AMPA (GriA3) receptor transcripts. Interestingly, mGlu3 signaling during stressor mediated GriN3B upregulation. Stress reactivity during TMT exposure was associated with Grm5, GriN2A, GriN2C, and GriA3 upregulation in the insular cortex and context re-exposure reactivity in the TMT/vehicle, but not the TMT/mGlu3 NAM group. In the BNST, GriN2A, GriN2B and GriN3B were increased by VU6010572, but TMT prevented these effects. These data demonstrate that mGlu3 signaling contributes to the lasting behavioral and molecular adaptations of predator odor stressor.
Interoceptive Insular Cortex Mediates Both Innate Fear and Contextual Threat Conditioning to Predator Odor
