Interleukin-2 modulates N-methyl-D-aspartate receptors of native mesolimbic neurons

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-NMDA) in voltage-clamped neurons freshly isolated from the ventral tegmental area (VTA), the site of origin of the mesolimbic system. IL-2 (0.01-500 ng/ml) alone had no effect on membrane conductance. When co-applied with NMDA, IL-2 (50-500 ng/ml) significantly potentiated I-NMDA. In contrast, doses as low as 0.01 ng/ml markedly decreased the NMDA response. Dose-response analysis showed that IL-2 (> 50 ng/ml) increased the maximal I-NMDA without changing the EC50, indicating that IL-2 potentiates I-NMDA by increasing the efficacy of the NMDAR. Moreover, current-voltage analysis revealed that IL-2 potentiation of I,,,, was voltage-dependent, being greater at negative potentials. In contrast, IL-2 inhibition of I-NMDA was voltage-independent, and IL-2 did not alter the reversal potential. Additionally, IL-2 (1 ng/ml) shifted the NMDA concentration-response curve to the right, significantly increasing the EC50 for NMDA without changing the maximal I-NMDA, suggesting that IL-2 inhibits the NMDAR by a competitive mechanism. IL-2 thus acts as a potent 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. (C) 2001 Elsevier Science B.V. All rights reserved.