Chronic morphine treatment selectively augments metabotropic glutamate receptor-induced inhibition of N-methyl-D-aspartate receptor-mediated neurotransmission in nucleus accumbens.
We compared the effects of different metabotropic glutamate receptor (mGluR) agonists on pharmacologically isolated N-methyl-D-aspartate-excitatory postsynaptic currents (NMDA-EPSCs) in core nucleus accumbens neurons using conventional intracellular recording in untreated and morphine-treated rats. The rats were treated by s.c. implantation of two morphine pellets and studied over a 3- to 6-day period. This model is known to exhibit opiate tolerance and dependence. We elicited NMDA-EPSCs by stimulating locally in the presence of the alpha-amino-3-hydroxy-5-methly-4-isoxazolepropionic acid/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and the gamma-aminobutyric acid receptor antagonist bicuculline (15 microM). We found that trans-1-aminocyclopentane-1,3-decarboxylic acid, an agonist of group 1 and 2 mGluRs, decreased NMDA-EPSC areas (time-integrals) in a dose-dependent manner (1-10 microM) in slices taken from untreated rats. This inhibitory effect was significantly enhanced after chronic morphine treatment. In contrast, although the group 3 mGluR agonist L(+)-2-amino-4-phosphonobutyric acid also markedly reduced NMDA-EPSC areas, there was no apparent change in this effect after chronic morphine. We found that quisqualate, the group 1 mGluR agonist, failed to elicit any effect on NMDA-EPSCs in either untreated or chronically treated rats. Paired-pulse stimulation of core nucleus accumbens NMDA-EPSCs in slices from these groups showed that chronic morphine enhanced paired-pulse facilitation, consistent with a presynaptic reduction in glutamate release. Because of the relevance to opiate tolerance and dependence of the chronic model used, the brain region (accumbens), and the receptors studied, our data provide a cellular substrate that could account for some aspects of these phenomena.
Martin
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The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California, USA.
Przewlocki
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R
Siggins
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GR
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
C114785:2-amino-4-phosphono-propinate; D000701:Analgesics, Opioid; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D011422:Propionates; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D009020:Morphine; D016318:Quisqualic Acid