The action of glutamate and N -Methyl-D-asparate (NDMA) on melanin-concentrating hormone (MCH) release was examined in primary cultures of rat hypothalamic neurons. Increasing concentrations of both glutamate and NMDA stimulated MCH release in a dose-dependent manner. We report here a specific toxic effect of 10−4 M glutamate not observed after NMDA-induced MCH release. The involvement of the NMDA receptor in the MCH-evoked secretion was confirmed using MK-801 a specific NMDA non-competitive inhibitor. MK-801 inhibited NMDA-induced MCH release in a dose dependent manner. At 10−6 M, this drug significantly inhibited MCH release suggesting an endogenous glutamatergic stimulation of MCH secretion. This study established that MCH neurons are sensitive to glutamate stimulation and that the evoked MCH secretion is mediated via NMDA receptor activation.