Administration of a non-NMDA antagonist, gyki 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine
| Autor: | E. O'Hearn, Mark E. Molliver |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Cerebellum Neurotoxins Purkinje cell Excitotoxicity Glutamic Acid Olivary Nucleus Pharmacology Biology medicine.disease_cause Synaptic Transmission Neuroprotection Rats Sprague-Dawley Benzodiazepines Purkinje Cells medicine Animals Receptors AMPA Dose-Response Relationship Drug General Neuroscience Ibogaine Glutamate receptor Drug Synergism Climbing fiber Rats Up-Regulation medicine.anatomical_structure Nerve Degeneration Synapses NMDA receptor Excitatory Amino Acid Antagonists Neuroscience medicine.drug |
| Zdroj: | Neuroscience. 127:373-383 |
| ISSN: | 0306-4522 |
| Popis: | Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-D-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p. x 3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis. |
| Databáze: | OpenAIRE |
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