Enantiomer-specific modulation of GABA_A receptors differentially regulates stress-induced dopamine dysregulation

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that can emerge following exposure to severe trauma and is frequently accompanied by comorbid psychiatric symptoms, including psychosis. Hallucinations and delusions associated with PTSD are thought to arise from dysregulated mesolimbic dopamine signaling; however, converging evidence indicates dopamine dysfunction is secondary to hippocampal hyperactivity driven by impaired GABAergic transmission. An emerging pharmacological strategy is the use of positive allosteric modulators (PAMs) of GABA_A receptors. Given their dense expression within the hippocampus, receptors containing the α5 subunit (α5-GABA_ARs) have demonstrated antipsychotic-like efficacy across multiple preclinical models.

Whether this therapeutic potential reflects α-subunit specificity or broader properties of structurally related PAMs remains unclear. We compared three structurally related GABA_A receptor PAMs with distinct α-subunit selectivity.

Using an acute inescapable footshock stress model, which reliably produces increased mesolimbic dopamine activity, we performed in vivo extracellular electrophysiology to record dopamine neuron activity in the ventral tegmental area (VTA) after intra-hippocampal administration of GABA_AR PAMs.

MP-III-022, a selective α5-GABA_AR PAM, normalized stress-induced elevations in VTA dopamine neuron population activity, consistent with prior reports. GL-I-54, which preferentially modulates α2/α3-GABA_ARs, failed to restore dopamine system function following stress, while modulation with the α5-preferring enantiomer GL-II-73 was associated with normalization of mesolimbic dopamine activity.

These findings indicate that stereochemical and subunit-selective modulation of GABA_A receptors critically determines circuit-level outcomes following stress and reinforce α5-GABA_A receptors as a key target for normalizing hippocampal-driven dopamine system dysfunction associated with psychosis-relevant states.