Chronic morphine treatment alters N-methyl-D-aspartate receptors in freshly isolated neurons from nucleus accumbens.
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 +/- 0.15 microM to 5.1 +/- 1.45 microM. 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-(-)-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.
Martin
Gilles
G
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA, USA. gilles.martin@umassmed.edu
Guadaño-Ferraz
Ana
A
Morte
Beatriz
B
Ahmed
Serge
S
Koob
George F
GF
De Lecea
Luis
L
Siggins
George R
GR
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; D005998:Glycine