Insertion of alpha7 nicotinic receptors at neocortical layer V GABAergic synapses is induced by a benzodiazepine, midazolam.
Benzodiazepines act mainly at postsynaptic gamma-aminobutyric acid type A (GABA(A)) receptors. In rat neocortical layer V pyramidal neurons, we found that midazolam (MDZ), a benzodiazepine, increases the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) via insertion of alpha7 nicotinic acetylcholine receptors (nAChRs) at presynaptic GABAergic boutons. Although nicotine alone had no effect, MDZ plus nicotine dramatically increased mIPSC frequency. Neostigmine, an acetylcholinesterase inhibitor, mimicked the actions of nicotine. MDZ increased the number of alpha-bungarotoxin-bound boutons that were blocked by protein kinase C (PKC) inhibitors, as revealed by confocal imaging of a neuron-synaptic bouton preparation. Thus, MDZ may induce membrane translocation of alpha7 nAChRs on GABAergic boutons via activation of PKC, enabling endogenous acetylcholine to increase GABA release. The above actions seem unique to MDZ because neither other benzodiazepines (diazepam and flunitrazepam) nor zolpidem had this effect. The findings reveal both a novel cholinergic modulatory mechanism affecting GABAergic transmission and a novel action of some general anesthetics.
Yamamoto
Sumii
S
Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
Yamada
Junko
J
Ueno
Shinya
S
Kubota
Hisahiko
H
Furukawa
Tomonori
T
Yamamoto
Seiji
S
Fukuda
Atsuo
A
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D008874:Midazolam / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism*; D009388:Neostigmine / Q000494:pharmacology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D018757:GABA Modulators; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D001569:Benzodiazepines; D009388:Neostigmine; D005680:gamma-Aminobutyric Acid; D011493:Protein Kinase C; D008874:Midazolam