GLP-1 receptor agonism reduces PTSD-like anxiety and alters amygdala-hippocampal activity patterns in a Chemogenetic...

Dysregulated glutamatergic transmission within amygdala-hippocampal circuits has been implicated in the pathophysiology of post-traumatic stress disorder (PTSD), yet pharmacological approaches targeting stress-related behavioral and molecular alterations remain limited. In the present study, we examined the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide in a single prolonged stress (SPS) mouse model of PTSD combined with chemogenetic activation of basolateral amygdala (BLA) glutamatergic neurons using designer receptors exclusively activated by designer drugs (DREADDs). SPS exposure induced anxiety-like behavior in the open field and elevated plus maze tests and was associated with alterations in hippocampal NMDA receptor subunit expression, CREB signaling, and GLP-1 receptor levels. Liraglutide treatment was associated with improved anxiety-related behavioral measures, with more robust effects observed in the open field test. Chemogenetic activation of BLA glutamatergic neurons produced behavioral effects that differed between control and SPS-exposed animals, suggesting state-dependent modulation of BLA-related circuit output. At the molecular level, SPS increased hippocampal NR2B expression, whereas liraglutide treatment was associated with alterations in NR2B, CREB, and GLP-1 receptor expression. Although differences in c-Fos expression were observed in the BLA and hippocampus, none of the pairwise comparisons remained significant after false discovery rate correction; therefore, these findings are considered exploratory. Collectively, these results suggest that GLP-1 receptor agonism may attenuate PTSD-like behavioral abnormalities and modulate molecular pathways related to glutamatergic signaling and synaptic plasticity. However, these findings do not establish direct circuit-level mechanisms, and further studies incorporating cell-type-specific and real-time circuit analyses are required to clarify the underlying neurobiological substrates.