α₅-GABA_A allosteric modulation triggers and prolongs dopamine neuronal activity via AMPA receptors

Negative allosteric modulators (NAMs) of gamma-aminobutyric acid (GABA_A) receptors targeting the α₅-subunit, primarily expressed on glutamate pyramidal neurons in the hippocampus and cortex, reduce inhibitory tone and enhance α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor throughput. The α₅-GABA_A-NAM, L-655,708, has shown rapid and sustained antidepressant-like effects in rodents.

This study aimed to investigate the effects of L-655,708 on the monoamine and glutamate systems in rats in relation to the antidepressant-like response.

Male Sprague-Dawley rats received a single dose of L-655,708 (3 mg/kg, i.p.) or vehicle. In vivo extracellular recordings were conducted in the dorsal raphe nucleus (DRN), locus coeruleus (LC), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC) acutely, 1 day, 1 week, and 2 weeks post-injection. AMPA and N-methyl-D-aspartate (NMDA) responsiveness in the hippocampal CA1 region was assessed using microiontophoresis.

The NMDA-induced response in the CA1 hippocampus was significantly reduced 1 day post-injection of L655,708, while the AMPA response remained unchanged. Although mPFC pyramidal neurons' firing was not changed, there was a two-fold increase in population activity of VTA dopamine (DA) neurons 1 day post-injection, lasting up to 1 week. Flumazenil, the benzodiazepine site antagonist, and 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), an AMPA receptor antagonist, blocked this effect. L-655,708 had no acute effect on firing activity of serotonin or norepinephrine neurons.

L-655,708 enhanced VTA DA neuron population activity for up to 1 week after a single injection. This effect was dependent on AMPA and took place through action on the benzodiazepine site.