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 EC(50), 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(NMDA) 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 EC(50) 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.
Ye
J H
JH
Department of Anesthesiology, New Jersey Medical School (UMDNJ), Newark, NJ 07103-2714, USA. ye@umdnj.edu
Tao
L
L
Zalcman
S S
SS
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology*
D018690:Excitatory Amino Acid Agonists; D007376:Interleukin-2; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate