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

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), ketamine, and psilocybin, are effective for treating depression despite their distinct modes of action. We hypothesized that their underlying mechanisms of action are shared. Mice were administered escitalopram (15 mg/kg daily for 3 weeks, 21 mice), R-/S-/racemic ketamine (10 mg/kg, single injection, 21–22 mice), or psilocin (1 mg/kg, single injection, 22 mice).

Electroconvulsive stimulation (9 times for 3 weeks, 12 mice) and saline were used as controls. After structural magnetic resonance imaging (MRI) of fixed brains, voxel-based morphometry was conducted to assess brain-wide volumetric changes. A single dose of ketamine or psilocin was sufficient to induce MRI-detectable volume changes. All antidepressants increased the volume in the nucleus accumbens, ventral pallidum, and external globus pallidus and decreased the volume in the mediodorsal thalamus, which is distinct from the changes observed with electroconvulsive stimulation. We identified microstructural and molecular changes using super-resolution microscopy and imaging mass spectrometry, respectively. Pallidal volumetric increases were associated with hypertrophy of striatal medium spiny neuron terminals and increased γ-aminobutyric acid (GABA) content. We experimentally addressed whether the overexpression of the vesicular GABA transporter (VGAT) reproduced these changes. The overexpression of striatal VGAT reproduced these structural changes. R-ketamine, SR-ketamine, and psilocin induced more pronounced ventral pallidum hypertrophy, and SSRIs and S-ketamine induced globus pallidus hypertrophy. We discovered shared pallidum-centered structural and molecular changes among various antidepressants, which possibly potentiate the striato-pallidial inhibition associated with antidepressant action. Our data support visualizing antidepressant responses using pallidum-centered GABA MR spectroscopy or structural MRI.