MU-OPIOID RECEPTORS MODULATE NMDA RECEPTOR-MEDIATED RESPONSES IN NUCLEUS-ACCUMBENS NEURONS

The nucleus accumbens (NAcc) may play a major role in opiate dependenc e, and central NMDA receptors are reported to influence opiate toleran ce and dependence. Therefore, we investigated the effects of the selec tive mu-opioid receptor agonist [D-Ala(2)-N-Me-Phe(4),Gly-ol(5)]-enkep halin (DAMGO) on membrane properties of rat NAcc neurons and on events mediated by NMDA and non-NMDA glutamate receptors, using intracellula r recording in a brain slice preparation. Most NAcc neurons showed a m arked inward rectification (correlated with Cs+- and Ba2+-sensitive in ward relaxations) when hyperpolarized, as well as a slowly depolarizin g ramp with positive current pulses. Superfusion of DAMGO did not alte r membrane potential, input resistance, or the inward relaxations. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) used to bl ock non-NMDA glutamate receptors and bicuculline to block GABA(A) rece ptors, EPSPs evoked by local stimulation displayed characteristics of an NMDA component: (1) long duration, (2) voltage sensitivity, and (3) blockade by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleri c acid (D-APV). DAMGO (0.1-1 mu M) significantly decreased both NMDA- and non-NMDA-EPSP amplitudes with reversal of this effect by naloxone and the mu-selective antagonist [Cys(2)-Tyr(3)-Orn(5)-Pen(7)]-somatost atinamide (CTOP). To assess a postsynaptic action of DAMGO, we superfu sed slices with tetrodotoxin and evoked inward currents by local appli cation of glutamate agonists. Surprisingly, 0.1-1 mu M DAMGO markedly enhanced the NMDA currents (with reversal by CTOP) but reduced the non -NMDA currents. At higher concentrations (5 mu M), DAMGO reduced NMDA currents, but this effect was enhanced, not blocked, by CTOP. These re sults indicate a complex DAMGO modulation of the NMDA component of glu tamatergic synaptic transmission in NAcc: mu receptor activation decre ases NMDA-EPSP amplitudes presynaptically yet increases NMDA currents postsynaptically, These new data may provide a cellular mechanism for the previously reported role of NMDA receptors in opiate tolerance and dependence.