Abstract
We compared the effects of different metabotropic glutamate receptor (mGluR) agonists on pharmacologically isolatedN-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 α-amino-3-hydroxy-5-methly-4-isoxazolepropionic acid/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM) and the γ-aminobutyric acid receptor antagonist bicuculline (15 μM). We found thattrans-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 μM) 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.
Footnotes
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Send reprint requests to: Dr. G.R. Siggins, CVN-12, Department of Neuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Road., La Jolla, CA 92037.
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↵1 This work was supported by National Institutes of Health/National Institute on Drug Abuse Grant DA03665
- Abbreviations:
- PKC
- protein kinase C
- CNQX
- 6-cyano-7-nitroquinoxaline-2,3-dione
- NAcc
- nucleus accumbens
- mGluRs
- metabotropic glutamate receptors
- NMDA
- N-methyl-d-aspartate
- trans-ACPD
- trans-1-aminocyclopentane-1,3-decarboxylic acid
- EPSC
- excitatory postsynaptic currents
- l-AP4
- l(+)-2-amino-4-phosphonobutyric acid
- ACSF
- artificial cerebrospinal fluid
- Received April 3, 1998.
- Accepted July 20, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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