Glutamate-induced increase of extracellular glutamate through N-methyl-D-aspartate receptors in ethanol withdrawal.
Ethanol withdrawal is a physiopathological state associated with increased number and function of N-methyl-D-aspartate glutamate receptors. We assessed the effect of N-methyl-D-aspartate receptor stimulation on the extracellular levels of glutamate in vivo by the focal application of N-methyl-D-aspartate in the striatum of dependent rats following withdrawal from chronic treatment with ethanol. In control, chronic sucrose-treated rats, 800 microM N-methyl-D-aspartate increased glutamate levels to 268% of baseline values. In ethanol-withdrawn animals, 12 h after interruption of the chronic treatment, the application of N-methyl-D-aspartate increased glutamate levels to 598% of baseline values. In ethanol-intoxicated rats N-methyl-D-aspartate was ineffective. Concentration-response curves showed that in ethanol withdrawn animals N-methyl-D-aspartate was five-fold more potent than in controls. In withdrawn animals, the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (1.0 mg/kg i.p.) or ethanol (5 g/kg i.g.) markedly reduced the N-methyl-D-aspartate-induced increase in glutamate levels. These results are consistent with the up-regulation of N-methyl-D-aspartate receptors by chronic ethanol and add biochemical evidence for the presence of N-methyl-D-aspartate receptors facilitating glutamate release through a positive feedback mechanism. The glutamate-induced, N-methyl-D-aspartate receptor-mediated elevations of extracellular glutamate may constitute a neurochemical substrate for the neuropathological alterations associated with alcoholism.
Rossetti
Z L
ZL
B.B. Brodie Department of Neuroscience and CNR Centre for Neuropharmacology, University of Cagliari, Italy.
Carboni
S
S
Fadda
F
F
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005246:Feedback; D018698:Glutamic Acid / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate