Antiepileptic drugs and muscarinic receptor-dependent excitation in the rat subiculum.
Field and intracellular recordings were made in an in vitro slice preparation to establish whether the antiepileptic drugs topiramate and lamotrigine modulate cholinergic excitation in the rat subiculum. Bath application of carbachol (CCh, 70-100microM) induced: (i) spontaneous and synchronous field oscillations (duration=up to 7s) that were mirrored by intracellular depolarizations with rhythmic action potential bursts; and (ii) depolarizing plateau potentials (DPPs, duration=up to 2.5s) associated with action potential discharge in response to brief (50-100ms) intracellular depolarizing current pulses. Ionotropic glutamatergic receptor antagonists abolished the field oscillations without influencing DPPs, while atropine (1microM) markedly reduced both types of activity. Topiramate (10-100microM, n=8-13 slices) or lamotrigine (50-400microM, n=3-12) decreased in a dose-dependent manner, and eventually abolished, CCh-induced field oscillations. During topiramate application, these effects were accompanied by marked DPP reduction. When these antiepileptic drugs were tested on DPPs recorded in the presence of CCh+ionotropic glutamatergic and GABA receptor antagonists, only topiramate reduced DPPs (n=5-19/dose; IC(50)=18microM, n=48). Similar effects were induced by topiramate during metabotropic glutamate receptor antagonism (n=5), which did not influence DPPs. Thus, topiramate and lamotrigine reduce CCh-induced epileptiform synchronization in the rat subiculum but only topiramate is effective in controlling DPPs. We propose that muscarinic receptor-mediated excitation represents a target for the action of some antiepileptic drugs such as topiramate.
D'Antuono
M
M
Montreal Neurological Institute and Departments of Neurology and Neurosurgery and of Physiology, McGill University, 3801 University Street, Rm. 794, Montréal, H3A 2B4 Québec, Canada.
Kawasaki
H
H
Palmieri
C
C
Curia
G
G
Biagini
G
G
Avoli
M
M
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D000077213:Lamotrigine; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*; D000077236:Topiramate; D014227:Triazines / Q000494:pharmacology
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001285:Atropine; D002217:Carbachol; D000077213:Lamotrigine