Negative allosteric modulation of α5-GABA A receptors engages dynamic cortical glutamatergic and GABAergic mechanisms underlying adaptive behavior in mice.
bioRxiv : the preprint server for biology January 16, 2026 Fernanda Daher, Caio T Fukushima, Erik A Ingebretsen et al. 1 citation
A negative allosteric modulator of α5-GABA A receptors, Basmisanil (BSM), produces rapid and sustained improvements in motivation, pleasure-seeking, and active coping behaviors in mice, similar to ketamine but without its side effects. BSM activates specific cell types in the medial prefrontal cortex (mPFC) and engages signaling pathways (Erk, Akt-mTOR) that boost synaptic proteins for both glutamatergic and GABAergic function. It also reverses stress-induced impairments in memory and social interaction. Early activation of pyramidal neurons in the mPFC is necessary for BSM's rapid effects, while later GABAergic adaptations sustain long-term benefits, restoring excitation-inhibition balance and highlighting GABAergic targets for stress-related disorders.