Synthesis of glutathione (GSH), an intracellular redox regulator, is compromised in schizophrenia. Patients show a deficit in GSH levels in cerebrospinal fluid and prefrontal cortex, and a decrease in gene expression of both modulatory and catalytic subunits of glutamatecysteine ligase, the rate limiting enzyme of GSH synthesis. A polymorphism of the gene for the modulatory subunit is also associated with the illness. Such GSH deficit might affect neurotransmission via changes in the function of intracellular redox-sensitive proteins. Here, we investigated whether a GSH deficit affects intracellular pathways implicated in dopamine signalling.We studied the effect of GSH deficit on dopamine modulation of NMDA-mediated calcium responses in cultured cortical neurons. GSH deficit was induced by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutamatecysteine ligase.A GSH deficit reversed the direction of the modulation of NMDA responses by dopamine. Moreover, dopamine modulation of NMDA responses was mediated by different cellular mechanisms in control and BSO-treated neurons. In control neurons, dopamine (1M) enhancedNMDAresponses via presynaptic mechanisms. But in BSO-treated neurons, dopamine decreased NMDA responses via activation of D2 receptors and postsynaptic mechanisms. In BSO-treated neurons, the decrease of NMDA responses was abolished when intracellular GSH levels was replenished with GSH-ethylester or when L-type Ca2+ channels were blocked with nifedipine. This suggests that lowintracellular GSH causes a change in modulation of L-type Ca2+ channels by dopamine. Blockade of ryanodine receptors with high ryanodine concentration fully reversed dopamine-induced decrease in BSO-treated neurons. Since caffeine, but also dopamine, evoked stronger calcium release from internal stores in BSO-treated than in control neurons, this indicates that ryanodine receptors, known to be redox-sensitive, are more functional under low GSH conditions.We postulate that an enhancement of the function of ryanodine receptors in GSH-depleted neurons favours D2R/D4R-mediated and calcium-dependent pathways, causing a change in the dopamine modulation of L-type Ca2+ channels in particular. As consequence, dopamine modulation of NMDA-mediated response is strongly altered.We could speculate that antipsychotics through their antagonistic action on D2R might prevent or attenuate the unbalance between signalling pathways induced by a GSH deficit.