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Volume 17, Number 1, Issue of January 1, 1997 pp. 11-22
Copyright ©1997 Society for Neuroscienceµ-Opioid Receptors Modulate NMDA Receptor-Mediated Responses in Nucleus Accumbens Neurons
Received May 28, 1996; revised Oct. 1, 1996; accepted Oct. 4, 1996.
Gilles Martin, Zhiguo Nie, and George Robert Siggins Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037
The nucleus accumbens (NAcc) may play a major role in opiate dependence, and central NMDA receptors are reported to influence opiate tolerance and dependence. Therefore, we investigated the effects of the selective µ-opioid receptor agonist [D-Ala2-N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) on membrane properties of rat NAcc neurons and on events mediated by NMDA and non-NMDA glutamate receptors, using intracellular recording in a brain slice preparation. Most NAcc neurons showed a marked inward rectification (correlated with Cs+- and Ba2+-sensitive inward relaxations) when hyperpolarized, as well as a slowly depolarizing ramp with positive current pulses. Superfusion of DAMGO did not alter membrane potential, input resistance, or the inward relaxations. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) used to block non-NMDA glutamate receptors and bicuculline to block GABAA receptors, 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-phosphonovaleric acid (D-APV). DAMGO (0.1-1 µM) significantly decreased both NMDA- and non-NMDA-EPSP amplitudes with reversal of this effect by naloxone and the µ-selective antagonist [Cys2-Tyr3-Orn5-Pen7]-somatostatinamide (CTOP). To assess a postsynaptic action of DAMGO, we superfused slices with tetrodotoxin and evoked inward currents by local application of glutamate agonists. Surprisingly, 0.1-1 µM DAMGO markedly enhanced the NMDA currents (with reversal by CTOP) but reduced the non-NMDA currents. At higher concentrations (5 µM), DAMGO reduced NMDA currents, but this effect was enhanced, not blocked, by CTOP. These results indicate a complex DAMGO modulation of the NMDA component of glutamatergic synaptic transmission in NAcc: µ receptor activation decreases 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.
Key words: glutamate; naloxone; NMDA-EPSP; opiate; DAMGO; AMPA; kainate; intracellular recording; electrophysiology; CTOP; slice preparation
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