Agmatine mitigates hyperexcitability of ventral tegmental area dopaminergic neurons in prenatally stressed male offspring

Abstract

Prenatal stress (PS) alters development of the brain, resulting in heightening the risk in offspring of cognitive deficits and addiction behaviors. The ventral tegmental area (VTA) plays a crucial role in processing stressful events, and promoting cognitively based motivational behavior. Previous research, including our own, has shown that PS affects the development of VTA dopaminergic (DA) neurons, leading to functional differences. In this study PS was induced in pregnant mice using both psychological and physical methods. Psychological stress involved placing the mice in a communication stress box to observe others under physical stress, while physical stress was applied by immersion in water for 5 min daily for 7 days. Agmatine, a neuromodulator with neuroprotective properties, was examined for its effects on the electrophysiological functioning of VTA DA neurons in the male offspring of stressed mice. Patch-clamp recordings of VTA DA cells from offspring maternally exposed to psychological or physical stress revealed enhanced cellular excitability, evidenced by increased firing frequency and greater firing following inhibition. Additionally, a decrease in action potential half-width and latency to the first spike were observed, indicating altered firing properties. Prenatal administration of agmatine mitigated these effects, preventing the PS-induced hyperexcitability of the VTA DA cells. Our findings extend previous work by demonstrating that both physical and psychological PS can significantly alter the electrophysiological functionality of VTA DA neurons, resulting in increased excitability. Agmatine effectively reduced these electrophysiological changes, highlighting its potential as a neuroprotective agent against neural alterations caused by negative maternal events during gestation.