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The Journal of Neuroscience, October 15, 1999, 19(20):9081-9089

Chronic Morphine Treatment Alters NMDA Receptor-Mediated Synaptic Transmission in the Nucleus Accumbens

Gilles Martin¹, Serge H. Ahmed¹, Thomas Blank², Joachim Spiess², George F. Koob¹, and George R. Siggins¹

¹ Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and ² Department of Molecular Neuroendocrinology, The Max-Planck Institute for Experimental Medicine, Goettingen, Germany

In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice preparation of rat. We evoked pharmacologically isolated NMDA EPSCs by local stimulation and elicited inward currents by NMDA superfusion. In control slices, Mg²⁺ and phorbol 12,13-diacetate (PDAc), a protein kinase C activator, strongly inhibited and increased, respectively, NMDA EPSC amplitudes. The PDAc effects were likely postsynaptic because PDAc enhanced the currents evoked by superfused NMDA to the same extent that it did the NMDA EPSCs. Chronic morphine treatment significantly decreased NMDA EPSC amplitudes and the sensitivity of NMDA EPSCs to Mg²⁺ and PDAc, as well as the kinetics of the decay (inactivation rate) of the EPSCs (from 97 ± 2.5 msec in untreated rats to 78.7 ± 1.8 msec in slices from treated rats). One week after withdrawal, the Mg²⁺ and PDAc effects were still significantly less than those in control slices. Interestingly, 1 week of withdrawal led to an increased NMDA EPSC inactivation rate compared with controls. These data demonstrate that chronic morphine treatment significantly alters NMDA receptor-mediated synaptic transmission in the accumbens, and these effects persist 1 week after withdrawal. These long-term effects may represent an important neuroadaptation in opiate dependence.

Key words: NMDA glutamate receptors; electrophysiology; phorbol ester; protein kinase C; chronic morphine treatment; kinetics

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19209081-09$05.00/0

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