Exaggeration of epileptic-like patterns by nicotine receptor activation during the GABA withdrawal syndrome.
To understand how nicotinic cholinergic receptors may participate in epileptic seizures, we tested the effects of nicotine and of the competitive nicotinic antagonists dihydro-beta-erythroidine and alpha-bungarotoxin on synaptic paroxysmal depolarization shifts (PDSs) and intrinsic bursts of action potentials recorded in slices from rats presenting a cortical status epilepticus. This model named GABA-withdrawal syndrome (GWS) appears consecutive to the interruption of a prolonged intracortical GABA infusion. Effects of both nicotinic antagonists suggest a distinct involvement of alpha4-beta2 and alpha7 subunits in shaping individual PDSs and patterning repetitive bursts. On one hand, in GWS rats, an increase of PDS latency and prolongation of PDS and bursts were induced by nicotine and reduced by dihydro-beta-erythroidine, but not by alpha-bungarotoxin. The K+ blocker tetraethylammonium also increased duration without changing latency. Thus, dihydro-beta-erythroidine-sensitive receptors exert distinct controls on the presynaptic generation of PDS and on the process which terminates PDSs and bursts. On the other hand, alpha-bungarotoxin depolarized neurons and generated rhythmic discharges of clustered bursts. Clustered bursts were also observed in slices obtained from GWS rats treated with the acetylcholinesterase inhibitor eserine. We suggest that both dihydro-beta-erythroidine and alpha-bungarotoxin-sensitive sites control paroxysmic activities in GWS and could be involved in some human and animal epilepsies presenting mutations of nicotinic cholinergic receptors.
Silva-Barrat
Carmen
C
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR 7091, CNRS, 75634 Paris, France. carmen.silvabarrat@cfx.ap-hop-paris.fr
Velluti
Julio
J
Szente
Magdolna
M
Batini
Cesira
C
Champagnat
Jean
J
D000818:Animals; D004827:Epilepsy / Q000378:metabolism*; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D009538:Nicotine