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Glutamate and Addiction pp 51–61Cite as

Glutamate and Neurotoxicity

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Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

The toxic effects of glutamate exposure on neurons were first recognized nearly half a century ago, when Lucas and Newhouse observed that subcutaneous administration of glutamate caused loss of neurons in the inner nuclear layer of the retina in both adult and neonatal mice (1). Olney extended these findings to other regions of brain, including neurons in the roof of the third ventricle, the hypothalamus, and the dentate gyms (2). Changes evolved rapidly, over minutes in adult mice to several hours in neonates, and were characterized by intracellular edema and pyknotic nuclei, consistent with necrosis. In the next few years the role of glutamate as the major excitatory neurotransmitter in the mammalian central nervous system (CNS) became clear (3–6) and the existence of specific glutamate receptors was demonstrated. Excitotoxicity, the effect of glutamate receptor activation to trigger neuronal cell death, was proposed to play a role in many pathological conditions, in large part based on the observations that injection of glutamate agonists, notably kainate, could result in neuronal death and biochemical abnormalities resembling the pathology seen in disorders such as Huntington’s disease (7,8) and epilepsy (9,10). A role for endogenous glutamate release and subsequent glutamate receptor activation in triggering neuronal death under pathological conditions was further suggested by demonstrations that blockade of presynaptic glutamate release could attenuate neuronal injury in oxygen-deprived cultured hippocampal neurons (11) and that a blockade of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors attenuated neuronal injury in rodent models of global ischemia and hypoglycemic brain damage (12,13). Cell culture models were useful in exploring the ionic changes responsible for glutamate-mediated cell death (see Section 2). More recent observations suggest that receptor-mediated glutamate toxicity may not be limited to neurons, but may also affect oligodendrocytes (14–16). A non-receptor-mediated form of glutamate cytotoxicity due to cystine deprivation and lowering of intracellular glutathione has also been described (17,18),although the levels of sustained exposure required to induce this death are higher than expected in most in vivo situations.

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Authors
  1. B. Joy Snider MD PhD
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  2. Dennis W. Choi MD PhD
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Editors and Affiliations

  1. Clinical Medical Branch, Division of Treatment Research and Development, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Barbara H. Herman PhD

  2. Pharmacology, Integrative & Cellular Neurobiology Research Branch (PICNRB), Division of Neuroscience & Behavioral Research (DNBR), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Jerry Frankenheim PhD

  3. Treatment Research Branch, Division of Clinical and Prevention Research, National Institute on Drug Abuse (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA

    Raye Z. Litten PhD

  4. Division of Neuropharmacological Drug Products Center for Drug Evaluation and Research, Office of Drug Evaluation I, Food and Drug Administration, Rockville, MD, USA

    Philip H. Sheridan MD

  5. Laboratory of Molecular and Cellular Neurobiology, Division of Intramural Clinical and Biological Research, National Institute on Drug Abuse (NIAAA) National Institutes of Health (NIH), Bethesda, MD, USA

    Forrest F. Weight MD

  6. Division of Treatment Research and Development, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Steven R. Zukin MD

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Snider, B.J., Choi, D.W. (2002). Glutamate and Neurotoxicity. In: Herman, B.H., Frankenheim, J., Litten, R.Z., Sheridan, P.H., Weight, F.F., Zukin, S.R. (eds) Glutamate and Addiction. Contemporary Clinical Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-306-4_3

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