Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
GABAA (gamma-aminobutyric acidA) receptors are molecular sub strates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-b...
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| Published in | Nature (London) Vol. 401; no. 6755; pp. 796 - 800 |
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| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group
21.10.1999
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| Subjects | |
| Online Access | Get full text |
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| Abstract | GABAA (gamma-aminobutyric acidA) receptors are molecular sub strates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. |
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| AbstractList | GABAA (gamma-aminobutyric acidA) receptors are molecular sub strates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. GABAA (-aminobutyric acidA ) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine 1-subunit gene, that 1-type GABAA receptors, which are mainly expressed in cortical areas and thalamus, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter -aminobutyric acid is preserved. 1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABAA receptors found in the limbic system (2, 5), in monoaminergic neurons (3) and in motoneurons (2, 5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABAA receptor subtypes in distinct neuronal circuits, which is of interest for drug design. |
| Author | Rudolph, Uwe Crestani, Florence Benke, Dietmar Brunig, Ina |
| Author_xml | – sequence: 1 givenname: Uwe surname: Rudolph fullname: Rudolph, Uwe – sequence: 2 givenname: Florence surname: Crestani fullname: Crestani, Florence – sequence: 3 givenname: Dietmar surname: Benke fullname: Benke, Dietmar – sequence: 4 givenname: Ina surname: Brunig fullname: Brunig, Ina |
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| CODEN | NATUAS |
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