Interleukin (IL)-2 is a brain-derived cytokine that influences mesocorticolimbic dopamine release, and is associated with pathological outcomes that are mediated, at least in part, by aberrations in mesolimbic neurotransmission. The mechanisms by which IL-2 modulates mesolimbic transmission, however, are not known. The NMDA receptor/channel (NMDAR) plays an essential role in neuronal excitability of mesolimbic neurons; we thus examined in neonatal rats the effects of IL-2 on NMDA-activated current (I) in NMDA voltage-clamped neurons freshly isolated from the ventral tegmental area (VTA), the site of origin of the mesolimbic system. IL-2 (0.01-500ng/ml) alone had no effect on membrane conductance. When co-applied with NMDA, IL-2 (50-500ng/ml) significantly potentiated I. In contrast, doses as low as 0.01ng/ml markedly decreased the NMDA response. Dose–response analysis showed that NMDA IL-2 (.50 ng/ml) increased the maximal I, without changing the EC, indicating that IL-2 potentiates I by increasing the NMDA 50 NMDA efficacy of the NMDAR. Moreover, current-voltage analysis revealed that IL-2 potentiation of I was voltage-dependent, being NMDA greater at negative potentials. In contrast, IL-2 inhibition of I was voltage-independent, and IL-2 did not alter the reversal potential. NMDA Additionally, IL-2 (1ng/ml) shifted the NMDA concentration-response curve to the right, significantly increasing the EC for NMDA 50 without changing the maximal I, suggesting that IL-2 inhibits the NMDAR by a competitive mechanism. IL-2 thus acts as a potent NMDA modulator of the NMDAR. IL-2-induced alterations of responses to NMDAR activation may contribute to synaptic plasticity in the mesolimbic system and to pathological outcomes associated with this system.