Liraglutide reduces PTSD-like anxiety and alters amygdala-hippocampal activity in chemogenetic mouse model

Pharmacological interventions for Post-Traumatic Stress Disorder (PTSD) remain limited, despite clear evidence of dysregulated glutamatergic transmission within amygdala-hippocampal circuits contributing to its pathophysiology. Current treatments often fall short in addressing the complex behavioral and molecular alterations associated with chronic stress. The glucagon-like peptide-1 (GLP-1) receptor, primarily known for its metabolic roles, is also expressed in the brain and has been implicated in neuroprotection and mood regulation, suggesting a potential novel therapeutic avenue for neurological and psychiatric conditions like PTSD.

Researchers investigated the effects of the GLP-1 receptor agonist liraglutide in a single prolonged stress (SPS) mouse model of PTSD. This model was combined with chemogenetic activation of basolateral amygdala (BLA) glutamatergic neurons using DREADDs (designer receptors exclusively activated by designer drugs) to probe circuit-level interactions. Mice underwent SPS exposure, followed by liraglutide treatment (specific dose and duration not detailed in abstract). Behavioral endpoints included anxiety-like measures in the open field and elevated plus maze tests. Molecular analyses focused on hippocampal NMDA receptor subunit expression, CREB signaling, GLP-1 receptor levels, and c-Fos expression in the BLA and hippocampus.

The SPS exposure successfully induced anxiety-like behavior in both the open field and elevated plus maze tests. This was accompanied by significant alterations in hippocampal NMDA receptor subunit expression, CREB signaling, and GLP-1 receptor levels. Treatment with liraglutide was associated with improved anxiety-related behavioral measures, with effects being notably more robust in the open field test. At the molecular level, SPS increased hippocampal NR2B expression. Liraglutide treatment was found to alter the expression of NR2B, CREB, and GLP-1 receptor in the hippocampus. 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. Although differences in c-Fos expression were observed in the BLA and hippocampus, these findings were considered exploratory as none of the pairwise comparisons remained significant after false discovery rate correction. No specific numerical data (e.g., percentages, p-values) were provided in the abstract for these findings.

Liraglutide treatment improved anxiety-related behavioral measures in SPS mice, with more robust effects observed in the open field test.