Abstract
Dopamine (DA), through D1/D2 receptor-mediated signaling, plays a major role in the control of epileptic seizures arising in the limbic system. Excitotoxicity leading to neuronal cell death in the affected areas is a major consequence of seizures at the cellular level. In this respect, little is known about the role of DA receptors in the occurrence of epilepsy-induced neuronal cell death. Here we analyze the occurrence of seizures and neurotoxicity in D2R -/- mice treated with the cholinergic agonist pilocarpine. We compared these results with those previously obtained with kainic acid (KA), a potent glutamate agonist. Importantly, D2R -/- mice develop seizures at doses of both drugs that are not epileptogenic for WT littermates and show greater neurotoxicity. However, pilocarpine-induced seizures result in a more widespread neuronal death in both WT and D2R -/- brains in comparison to KA. Thus, the absence of D2R lowers the threshold for seizures induced by both glutamate and acetylcholine. Moreover, the dopaminergic control of epilepsy-induced neurodegeneration seems to be mediated by distinct interactions of D2R signaling with these two neurotransmitters.
(C)2002 Elsevier Science (USA).
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / metabolism
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Cell Death / drug effects
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Cell Death / genetics*
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Dose-Response Relationship, Drug
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Epilepsy / chemically induced
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Epilepsy / genetics
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Epilepsy / metabolism*
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Excitatory Amino Acid Agonists / pharmacology*
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Female
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Genotype
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Glutamic Acid / metabolism
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Kainic Acid / pharmacology
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Limbic System / drug effects
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Limbic System / metabolism*
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Limbic System / physiopathology
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Male
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Muscarinic Agonists / pharmacology*
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Nerve Degeneration / chemically induced
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism*
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Pilocarpine / pharmacology
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RNA, Messenger / metabolism
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Receptors, Dopamine D2 / deficiency*
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Receptors, Dopamine D2 / genetics
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Receptors, Muscarinic / drug effects
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Receptors, Muscarinic / genetics
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Receptors, Muscarinic / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
Substances
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Excitatory Amino Acid Agonists
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Muscarinic Agonists
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RNA, Messenger
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Receptors, Dopamine D2
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Receptors, Muscarinic
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Pilocarpine
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Glutamic Acid
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Acetylcholine
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Kainic Acid
Associated data
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GENBANK/J04192
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GENBANK/X63473