We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, these agents depressed in a dose-dependent and reversible manner the current-evoked repetitive firing discharge. These AEDs also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. However, substantial pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostriatal excitatory transmission. Concentrations of LTG and GBP effective in reducing EPSPs, in fact, produced only a slight inhibition of the firing activity of these cells. LTG, but not PHT and GBP, depressed cortically-evoked EPSPs increasing paired-pulse facilitation (PPF) of synaptic transmission, suggesting that a presynaptic site of action was implicated in the effect of this drug. Accordingly, PHT and GBP, but not LTG reduced the membrane depolarizations induced by exogenously-applied glutamate, suggesting that these drugs preferentially reduce postsynaptic sensitivity to glutamate released from corticostriatal terminals. These data indicate that in the striatum PHT, LTG and GBP decrease neuronal excitability by modulating multiple sites of action. The preferential modulation of excitatory synaptic transmission may represent the cellular substrate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia.

Calabresi, P., Centonze, D., Marfia, G.a., Pisani, A., Bernardi, G. (1999). An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons. BRITISH JOURNAL OF PHARMACOLOGY, 126(3), 689-696 [10.1038/sj.bjp.0702361].

An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons

CALABRESI, PAOLO;CENTONZE, DIEGO;MARFIA, GIROLAMA ALESSANDRA;PISANI, ANTONIO;BERNARDI, GIORGIO
1999-02-01

Abstract

We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, these agents depressed in a dose-dependent and reversible manner the current-evoked repetitive firing discharge. These AEDs also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. However, substantial pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostriatal excitatory transmission. Concentrations of LTG and GBP effective in reducing EPSPs, in fact, produced only a slight inhibition of the firing activity of these cells. LTG, but not PHT and GBP, depressed cortically-evoked EPSPs increasing paired-pulse facilitation (PPF) of synaptic transmission, suggesting that a presynaptic site of action was implicated in the effect of this drug. Accordingly, PHT and GBP, but not LTG reduced the membrane depolarizations induced by exogenously-applied glutamate, suggesting that these drugs preferentially reduce postsynaptic sensitivity to glutamate released from corticostriatal terminals. These data indicate that in the striatum PHT, LTG and GBP decrease neuronal excitability by modulating multiple sites of action. The preferential modulation of excitatory synaptic transmission may represent the cellular substrate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia.
feb-1999
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/26 - NEUROLOGIA
English
Con Impact Factor ISI
Electrophysiology; Male; Corpus Striatum; Amines; Rats, Wistar; Rats; Dose-Response Relationship, Drug; Phenytoin; Animals; Triazines; Cerebral Cortex; Electric Stimulation; Glutamic Acid; Membrane Potentials; Anticonvulsants; Action Potentials; Acetic Acids; Excitatory Postsynaptic Potentials; Neurons; gamma-Aminobutyric Acid; Cyclohexanecarboxylic Acids
Calabresi, P., Centonze, D., Marfia, G.a., Pisani, A., Bernardi, G. (1999). An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons. BRITISH JOURNAL OF PHARMACOLOGY, 126(3), 689-696 [10.1038/sj.bjp.0702361].
Calabresi, P; Centonze, D; Marfia, Ga; Pisani, A; Bernardi, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/51481
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