Distinct classes of antidepressants commonly act to shape pallidal structure and function in mice

Antidepressants including selective serotonin reuptake inhibitors, ketamine, and psilocybin are all effective for treating depression despite their distinct primary mechanisms. We hypothesized that these drugs may share a common mechanism that underlies their therapeutic actions. We treated mice with one of the following: escitalopram, R- / S -/ RS- ketamine, or psilocin. Additionally, groups exposed to electroconvulsive stimulation and a saline control were included. Following treatment, fixed brains underwent structural magnetic resonance imaging, and voxel-based morphometry was performed to evaluate brain-wide volumetric changes. Compared with control treatment, we observed greater volumes in the nucleus accumbens, ventral pallidum, and external globus pallidus across all antidepressant treatments, and a smaller volume in the mediodorsal thalamus. Specifically, R -ketamine, RS -ketamine, and psilocin induced more pronounced hypertrophy of the ventral pallidum, whereas selective serotonin reuptake inhibitors and S -ketamine predominantly increased the volume of the external globus pallidus. Further analyses using super-resolution microscopy and imaging mass spectrometry revealed corresponding microstructural and molecular changes. Greater pallidal volume was associated with striatal medium spiny neuron terminal hypertrophy and elevated γ-aminobutyric acid (GABA) levels. Interestingly, all antidepressants were also associated with higher striatal dopamine content. Moreover, striatal vesicular GABA transporter overexpression reproduced the medium spiny neuron terminal hypertrophy and increased pallidal GABA content, and was associated with a reduction in innate anxiety. These findings indicate that despite their pharmacological diversity, antidepressant treatments lead to shared pallidum-centered structural and molecular changes. We propose that these shared changes may potentiate the striato-pallidal inhibitory circuit, thereby contributing to the overall antidepressant effect.