Targeting α5-GABAA receptors to restore dopamine system function in a translationally relevant model of perimenopausal psychosis

Perimenopause marks a high-risk period for psychiatric instability, often precipitating or exacerbating disorders like schizophrenia. While traditional antipsychotics can be effective, they often worsen vasomotor symptoms and carry side effects that drive high discontinuation rates. We hypothesized that hippocampal hyperactivity, resulting from a decrease in GABAergic transmission, drives mesolimbic dopamine dysregulation in this state. Thus, we proposed that this circuit-level dysfunction can be reversed by targeting α5-containing GABA A receptors (α5-GABA A R). We used the translationally relevant 4-vinylcyclohexene diepoxide (VCD) model of perimenopause, which mimics the progressive loss of ovarian follicles and hormonal instability seen in women. We assessed α5-GABA A R expression in the ventral hippocampus (vHipp) and utilized in vivo extracellular electrophysiology to record ventral tegmental area (VTA) dopamine neuron activity following systemic administration of the selective α5-GABA A R positive allosteric modulator (PAM), MP-III-022. VCD-treated rats exhibited significantly elevated dopamine neuron population activity. This aberrant dopamine activity was completely reversed by systemic administration of MP-III-022. These findings offer a pharmacologically distinct alternative to standard D2 receptor-targeted antipsychotics. Thus, modulating hippocampal-driven dopamine dysregulation via α5-GABA A R represents an efficacious and translatable strategy for treating perimenopausal psychiatric symptoms with the potential for significantly improved patient tolerability.