Abstract
Pharmacological agents that mediate a persistent GABAergic conductance are of considerable interest for treatment of epilepsy. (R)-roscovitine is a membrane permeable cyclin-dependent kinase inhibitor, designed to block cell division. It is currently undergoing a phase II clinical trial as an anticancer drug. We show that (R)-roscovitine increases a tonic GABA-mediated current in rat hippocampal neurons. This enhanced tonic current appears independent of synaptic GABA release and requires functional transmembrane GABA transport. The effect of (R)-roscovitine is associated with neither modification of GABAA receptors nor protein kinase activity, but is associated with a significant increase in intracellular GABA concentration in hippocampal GABAergic neurons. (R)-roscovitine-induced tonic inhibition significantly suppresses spontaneous spiking activity of hippocampal pyramidal cells. Therefore, (R)-roscovitine is a potent modulator of neuronal activity in rat hippocampus and may provide a tool for preventing paroxysmal activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Animals
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Animals, Newborn
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Calcium / pharmacology
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Dose-Response Relationship, Drug
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Dose-Response Relationship, Radiation
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Electric Stimulation
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Excitatory Amino Acid Antagonists / pharmacology
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GABA Agents / pharmacology
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Glutamate Decarboxylase / metabolism
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Hippocampus / cytology*
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In Vitro Techniques
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Inhibitory Postsynaptic Potentials / drug effects
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Inhibitory Postsynaptic Potentials / radiation effects
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Neurons / drug effects*
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Patch-Clamp Techniques / methods
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Protein Kinase Inhibitors / pharmacology*
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Purines / pharmacology*
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Rats
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Roscovitine
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gamma-Aminobutyric Acid / metabolism*
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gamma-Aminobutyric Acid / pharmacology
Substances
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Excitatory Amino Acid Antagonists
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GABA Agents
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Protein Kinase Inhibitors
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Purines
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Roscovitine
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gamma-Aminobutyric Acid
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6-Cyano-7-nitroquinoxaline-2,3-dione
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Glutamate Decarboxylase
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glutamate decarboxylase 1
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Calcium