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 po stsynaptic currents (NMDA-EPSCs) in core nucleus accumbens neurons using co nventional intracellular recording in untreated and morphine-treated rats. The rats were treated by s.c. implantation of two morphine pellets and stud ied over a 3- to 6-day period. This model is known to exhibit opiate tolera nce and dependence. We elicited NMDA-EPSCs by stimulating locally in the pr esence of the alpha-amino-3-hydroxy-5-methly-4-isoxazolepropionic acid/kain ate receptor antagonist 6-cyano-7-nitroquinoxaiine-2,3-dione (10 mu M) and the gamma-aminobutyric acid receptor antagonist bicuculline (15 mu M). We f ound that trans-1-aminocyclopentane-1,3-decarboxylic acid, an agonist of gr oup 1 and 2 mGluRs, decreased NMDA-EPSC areas (time-integrals) in a dose-de pendent manner (1-10 mu M) in slices taken from untreated rats. This inhibi tory effect was significantly enhanced after chronic morphine treatment. In contrast, although the group 3 mGluR agonist L(+)-2-amino-4-phosphonobutyr ic acid also markedly reduced NMDA-EPSC areas, there was no apparent change in this effect after chronic morphine. We found that quisqualate, the grou p 1 mGluR agonist, failed to elicit any effect on NMDA-EPSCs in either untr eated or chronically treated rats. Paired-pulse stimulation of core nucleus accumbens NMDA-EPSCs in slices from these groups showed that chronic morph ine enhanced paired-pulse facilitation, consistent with a presynaptic reduc tion in glutamate release. Because of the relevance to opiate tolerance and dependence of the chronic model used, the brain region (accumbens), and th e receptors studied, our data provide a cellular substrate that could accou nt for some aspects of these phenomena.