Chronic Morphine Treatment AltersN-Methyl-d-aspartate Receptors in Freshly Isolated Neurons from Nucleus Accumbens

Abstract

Although there is now evidence of a role for N-methyl-D-aspartate (NMDA) receptors in nucleus accumbens (NAcc) neurons in the effects of chronic opiate treatment, the cellular and molecular mechanisms underlying this phenomenon are still unclear. Therefore, we studied the effects of chronic morphine on the pharmacological and biophysical properties of NMDA receptors in freshly isolated medium spiny neurons from NAcc. We found that chronic morphine treatment did not alter the affinity for NMDA receptor agonists such as glutamate, homoquinolinic acid, and NMDA, but decreased the affinity of glycine, the allosteric NMDA receptor coagonist, from 2.24 Ϯ 0.15 M to 5.1 Ϯ 1.45 M. Chronic morphine treatment also altered the affinity of two noncompetitive NMDA receptor antagonists, 7-chloro-kynurenic acid and ifenprodil. However, morphine had no effect on a third antagonist, D-(Ϫ)-2-amino-5-phosphonopentanoic acid. Single-exponential fits of desensitized NMDA current tails gave tau values ranging from 0.5 to 4 s in neurons from both control and morphine-treated rats. However, a shift to the left of the distribution of tau values after morphine treatment revealed that NMDA current desensitization rate was accelerated in a majority of NAcc neurons. Taken together with our recent molecular studies, our data are consistent with a shift away from NMDA receptor subunit (NR) NR2B and 2C function toward increased NR2A subunit expression or function after chronic morphine, a process that could alter excitability and integrative properties and may represent a neuroadaptation of NAcc medium spiny neurons underlying morphine dependence.During the past decade the nucleus accumbens, an interface between limbic regions and the extrapyramidal motor system, has emerged as a key structure mediating the acute and chronic behavioral effects of drugs of abuse (Koob et al., 1992). Although behavioral studies conclusively demonstrated a key role for NAcc in opiate self-administration, relatively little is known about the cellular and molecular mechanisms responsible for acute opiate effects, and even more remains to be understood about chronic effects. Recently, NMDA receptors have been recognized as a critical factor underlying tolerance to various drugs of abuse. Trujillo and Akil (1991) and Marek et al. (1991) were the first to report that intraventricular infusion of MK-801 (dizocilpine maleate), a selective noncompetitive NMDA receptor antagonist, could strongly attenuate the morphine withdrawal syndrome, a finding subsequently confirmed by others (Tiseo et al., 1994;Elliott et al., 1995).Numerous studies established that NMDA receptors, formed by the association of two or more subunits, have multiple binding sites for various agents such as endogenous agonists, competitive antagonists, and Mg 2ϩ , Zn 2ϩ , or polyamines. To date, five NMDA receptors subunits (NR1, NR2A-D) have been identified. It is believed that, in native NMDA receptors, these subunits are assembled in various combinations to create heteromultimeric receptors. In...

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