The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.
The effects of MK-801 [( +]-5-methyl-10,11-dihydro-5H-di-benzo[a, d]cyclohepten-5,10-imine) on peripheral and central nicotinic receptors were studied using electrophysiological and biochemical techniques. MK-801 depressed the peak amplitude and accelerated the decay of end-plate currents. The drug (1-10 microM) decreased the frequency of activation of acetylcholine (ACh)-induced single-channel currents in addition to shortening the mean open and burst times of channels activated by either ACh or (+)anatoxin-a (AnTX). MK-801 (10-40 microM) depressed the single potentials and trains of ACh and AnTX-induced potentials in chronically denervated rat soleus muscles. MK-801 blocked the twitch responses (20-100 microM) of both frog sartorius and rat diaphragm muscles evoked by stimulation of their respective nerves. Also this drug (less than 1 microM) decreased the frequency of channels activated by AnTX or ACh in outside-out patch membranes of rat retinal ganglion cells with minimal changes in the channel open time. MK-801 (10-25 microM) depressed (-)nicotine-evoked gamma-amino[2,3-3H]butyric acid release from rat hippocampal synaptosomes; however, it failed to affect the binding of [3H](-)nicotine to brain membranes and also failed to interfere with the binding of [125I]alpha-bungarotoxin to either frog muscle or Torpedo membranes. On the other hand, MK-801 inhibited the binding of [3H]perhydrohistrionicotoxin to Torpedo membranes and such an effect was more pronounced in the presence of carbamylcholine. Neither AnTX nor any other nicotinic agonist increased the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor ion channel complex. The actions of MK-801 were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors. These results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801.
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
A S
AS
Ramoa
M
M
Alkondon
Y
Y
Aracava
J
J
Irons
G G
GG
Lunt
S S
SS
Deshpande
S
S
Wonnacott
R S
RS
Aronstam
E X
EX
Albuquerque
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001427:Bacterial Toxins; D001921:Brain / Q000187:drug effects*; D000087522:Cyanobacteria Toxins; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008387:Marine Toxins / Q000494:pharmacology; D052998:Microcystins; D009132:Muscles / Q000187:drug effects; D011894:Rana pipiens; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects; D014326:Tropanes; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; D003986:Dibenzocycloheptenes; D007473:Ion Channels; D008387:Marine Toxins; D052998:Microcystins; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D011978:Receptors, Nicotinic; D014326:Tropanes; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; C509783:anatoxin a; D000109:Acetylcholine