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Effects of benzodiazepines and non‐benzodiazepine compounds on the GABA‐induced response in frog isolated sensory neurones
Author(s) -
Yakushiji Takashi,
Fukuda Takemi,
Oyama Yasuo,
Akaike Norio
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb14600.x
Subject(s) - flumazenil , benzodiazepine , gabaa receptor , zolpidem , chemistry , inverse agonist , clonazepam , gamma aminobutyric acid , diazepam , pharmacology , antagonist , partial agonist , endocrinology , medicine , nitrazepam , receptor , biology , biochemistry , insomnia
1 The effects of benzodiazepines and non‐benzodiazepine compounds on the γ‐aminobutyric acid (GABA)‐induced chloride current (I Cl ) were studied in frog isolated sensory neurones by use of a concentration‐jump (termed ‘concentration‐clamp’) technique, under single‐electrode voltage‐clamp conditions. The drugs used were classified into four categories as follows: full benzodiazepine receptor agonists (diazepam, clonazepam, nitrazepam, midazolam, clotiazepam and etizolam), partial agonists (CL 218,872, Ro 16–6028, Ro 17–1812 and Ro 23–0364), inverse agonists (Ro 15–3505, FG 7142 and β‐CCE) and a benzodiazepine receptor antagonist, Ro 15–1788 (flumazenil). 2 All full agonists at concentrations of 3 × 10 −6 m . or less increased dose‐dependently the peak amplitude of I Cl elicited by 3 × 10 −6 m . GABA to twice to three times larger than the control. However, no further augmentation of the GABA response was observed at concentrations of 1 × 10 −5 m . or higher. Partial agonists also showed a dose‐dependent augmentation of the GABA response at concentrations ranging from 3 × 10 −8 m . to 3 × 10 −5 m ., but their efficacies of augmentation of the GABA response were only about half or less of those of full agonists. Of the inverse agonists, β‐CCE had a unique dose‐dependent effect on the GABA response. β‐CCE reduced dose‐dependently the GABA response at concentrations of less than 3 × 10 −6 m ., but augmented it at concentrations of 3 × 10 −5 m . and 6 × 10 −5 m . The inverse agonists reduced dose‐dependently the GABA response. The benzodiazepine antagonist, flumazenil, slightly augmented the GABA response at concentrations between 3 × 10 −7 m . and 3 × 10 −5 m . 3 These results show clear differences in the effects on the GABA response between these four categories of compounds known to affect the benzodiazepine recognition site of the GABA/benzodiazepine receptor‐chloride channel complex. Our experimental system of frog isolated sensory neurones and a ‘concentration‐clamp’ technique appears to be useful for evaluating efficacy of compounds on responses mediated by the GABA/benzodiazepine receptor‐chloride channel complex.