DUAL EFFECT OF OXYTOCIN RECEPTOR ACTIVATION ON ASTROCYTE GLUTAMATE RELEASE

The neuropeptide oxytocin (OT) is known to serve as a neuromodulator within the central nervous system, interplaying with other neurotransmission pathways. Within the context of synapse modulation different studies have demonstrated that OT and its receptor (the oxytocin receptor, OTR) may play an active role in the regulation of astrocyte function. Here, we investigate the ability of OTR to couple both inhibitory and stimulatory pathways in astrocytes, as already reported in neurons. We examined OT actions over a nanomolar concentration range, by assessing functional studies on glutamate release and intracellular Ca²⁺ dynamics in astrocyte processes freshly prepared from the striatum of adult male rats. The results obtained show that OT can induce dual responses in astrocyte processes: facilitatory responses, mediated by G_q-dependent PLC activation, were observed both at rest and during depolarization, while inhibitory responses, mediated by PTX-sensitive G_i/o coupling, appeared only under depolarized conditions. These effects occur within the same OT concentration range and are paralleled by Ca²⁺- dependent glutamate release, confirming a tight link between calcium signaling and gliotransmission. Pharmacological dissection with PTX and a PLC inhibitor confirmed the respective engagement of G_i/o and G_q pathways. Moreover, the biased agonists atosiban and carbetocin selectively reproduced these responses. Together, these findings highlight the ability of OT to dually modulate astrocytic glutamate release through context-dependent engagement of distinct G proteins, supporting a key role for OT in bidirectional neuron–astrocyte communication and identifying astrocytic OTR as potential pharmacological targets for modulating striatal glutamatergic transmission in neuropsychiatric and neurodegenerative disorders.