Effects of the Negative Allosteric Modulation of GABAA Receptors on the Monoamine and Glutamate Systems in the Rat: Relevance to the Antidepressant Response

Abstract

Background: Negative allosteric modulators (NAMs) of gamma-aminobutyric acid A (GABA_A receptors bind with high affinity to the α5 subunit located primarily on glutamate pyramidal neurons, thereby directly increasing AMPA throughput - their specificity limits off-target effects, reducing the possibility of adverse side effects. The α5-preferring GABA_A-NAM L-655,708 has been shown to exert rapid and sustained antidepressant-like action in rats.

Aim: This study aims to examine the effects of L-655,708 on the activity of monoamine and glutamate systems in rats in relation to the antidepressant response.

Methods: Experiments were performed in male Sprague-Dawley rats anesthetized using chloral hydrate. In vivo electrophysiological recordings of neuronal activity were carried out, in the dorsal raphe nucleus (DRN), locus coeruleus (LC) and ventral tegmental area (VTA) and prefrontal cortex (PFC) respectively, within two hours, one day, one week and two weeks after a single administration of vehicle solution or L-655,708 (3 mg/kg; i.p.). The responsiveness of AMPA and NMDA receptors in pyramidal neurons in the CA1 region of the hippocampus was also assessed using extracellular recording techniques with microiontophoresis.

Results: One day post-injection, L655,708 elicited a threefold enhancement in the population activity of DA neurons in the VTA compared to controls. This increase was attenuated after administration of flumazenil, a competitive GABAA receptor antagonist, and NBQX, an AMPA receptor antagonist. The effect was sustained for up to one week following injection of L-655,708, but was back at baseline after two weeks. Additionally, NMDA receptor responsiveness in hippocampal CA1 neurons was significantly reduced, while AMPA responsiveness remained unchanged.

Conclusion: L-655,708 caused a robust increase in the population activity of DA neurons in the VTA one day and one week after injection, surpassing the duration of the effects of ketamine. These findings support the potential of α5 GABA-NAMs as a fast-acting, targeted antidepressant agent.