Enhanced neuronal K+ conductance: a possible common mechanism for sedative-hypnotic drug action.
It is commonly thought that central nervous system depressant drugs exert their actions through enhancement of gamma-aminobutyrate (GABA)-mediated mechanisms. Recently, the cellular electrophysiological evidence from this laboratory and others suggests that both sedative hypnotics and general anaesthetics inhibit central neurons by increasing potassium conductance (GK). We have utilized the mammalian in vitro hippocampal and cerebellar slice preparations at 34-36 degrees C. Intracellular recordings from CA1, CA3, and cerebellar Purkinje cells were obtained. Low dose (sedative) concentrations of ethanol (less than or equal to 20 mM), two different benzodiazepines (midazolam and clonazepam in low nanomolar concentrations), and pentobarbital (10(-6) to 10(-4) M) were applied by pressure ejection or were bath perfused. All drugs caused a hyperpolarization with decreased spontaneous activity, and enhanced post spike afterhyperpolarizations (AHPs). These long-lasting AHPs are presumably due to enhanced calcium-mediated GK. Increased responsiveness to focally applied GABA was only seen at higher doses (ethanol, 100 mM; midazolam, 10(-7) M; pentobarbital, 10(-4) M). These data suggest that the above neurodepressant drugs, when applied at sedative doses to hippocampal pyramidal cells, enhance GK and not the actions of GABA.
Carlen
P L
PL
Gurevich
N
N
Davies
M F
MF
Blaxter
T J
TJ
O'Beirne
M
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002118:Calcium / Q000502:physiology; D002417:Cattle; D000431:Ethanol / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects*; D010424:Pentobarbital / Q000494:pharmacology; D011188:Potassium / Q000502:physiology*; D011689:Purkinje Cells / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D000431:Ethanol; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital; D011188:Potassium; D002118:Calcium