Novel positive allosteric modulators of alpha 5 subunit-containing GABAA receptors (α5-GABAARs) reverse the hyperdopaminergic state in a neurodevelopmental model of schizophrenia

Dysfunction in the GABAergic system has been described in schizophrenia, including decreased expression of α5 subunit-containing GABA_A receptors (α5-GABA_ARs) in patients with schizophrenia. This study explores the therapeutic potential of positive allosteric modulators (PAMs) of the α5-GABA_AR to reduce the hyperdopaminergic state produced by the neurodevelopmental methylazoxymethanol acetate (MAM) model of schizophrenia. Male offspring rats generated from pregnant females injected with saline or MAM at gestational day 17 were used for the electrophysiological recordings as adults. In vivo electrophysiological recordings were performed to assess the effects of 10 mg/kg of the novel α5-GABA_AR-preferring PAM alogabat on dopamine (DA) neuron activity in the ventral tegmental area (VTA); a dose shown to produce sustained, ≥80% α5-GABA_AR occupancy over a time period of 0.5-3.5 h post-dose. A less extensive confirmatory study was also performed with a second α5-GABA_AR PAM, Compound 100. The primary outcome was that at a dose of 10 mg/kg, which corresponded to an α5-GABA_AR occupancy of ≥80% for alogabat and 70% for Compound 100, reversed the increased number of spontaneously active DA neurons in MAM rats. Alogabat data showed that these effects were driven by a reduction in the central and lateral (but not medial) portions of the VTA; regions that project to the associative striatum. These findings suggest that selective targeting of α5-GABA_ARs may help normalize aberrant DA activity. The study highlights α5-GABA_ARs as a promising therapeutic target, potentially addressing positive symptoms by restoring excitatory-inhibitory balance in a key region of the brain implicated in the pathophysiology of schizophrenia.