Development of tolerance to amnesic effects of chlordiazepoxide in relation to GABAergic and cholinergic neuronal systems

Sei ichi Ishihara, Masayuki Hiramatsu, Tsutomu Kameyama, Toshitaka Nabeshima

研究成果: Article

6 引用 (Scopus)

抄録

Chronic administration of benzodiazepines has been reported to produce tolerance in animals and humans. We investigated whether benzodiazepines produce tolerance to the amnesic effects and effects on benzodiazepine receptors, GABAergic and/or cholinergic neuronal systems of repeated administration of chlordiazepoxide, using a passive avoidance task and autoradiographic techniques. Tolerance developed to the amnesic effect of chlordiazepoxide when the drug was administered at a dose of 30 mg/kg (i.p.) once a day for 14 days. Bicuculline (1.0 and 1.5 mg/kg), a GABAA receptor antagonist, did not induce amnesia in normal mice, but did so in chlordiazepoxide-tolerant mice. Muscimol (0.25 mg/kg), a GABAA receptor agonist, in combination with a low dose of chlordiazepoxide, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. Scopolamine, an acetylcholine receptor antagonist, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. In the autoradiographical study, although repeated treatment with chlordiazepoxide had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, it decreased [3H]muscimol binding to GABAA receptors, with a decrease in affinity in the cortex and hippocampus. Furthermore, repeated administration of chlordiazepoxide increased [3H]quinuclidinyl benzilate binding to muscarinic acetylcholine receptors in the hippocampus. These results suggest that tolerance develops to the amnesic effects of chlordiazepoxide, and that tolerance may be due to down-regulation of GABAA receptors and/or up-regulation of acetylcholine receptors.

元の言語English
ページ(範囲)313-319
ページ数7
ジャーナルEuropean Journal of Pharmacology
230
発行部数3
DOI
出版物ステータスPublished - 19-01-1993
外部発表Yes

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Chlordiazepoxide
Cholinergic Agents
GABA-A Receptors
Amnesia
Muscimol
Cholinergic Receptors
Benzodiazepines
Hippocampus
Quinuclidinyl Benzilate
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Flunitrazepam
Scopolamine Hydrobromide
Bicuculline
Cholinergic Antagonists
Muscarinic Receptors
Up-Regulation
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Pharmacology

これを引用

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abstract = "Chronic administration of benzodiazepines has been reported to produce tolerance in animals and humans. We investigated whether benzodiazepines produce tolerance to the amnesic effects and effects on benzodiazepine receptors, GABAergic and/or cholinergic neuronal systems of repeated administration of chlordiazepoxide, using a passive avoidance task and autoradiographic techniques. Tolerance developed to the amnesic effect of chlordiazepoxide when the drug was administered at a dose of 30 mg/kg (i.p.) once a day for 14 days. Bicuculline (1.0 and 1.5 mg/kg), a GABAA receptor antagonist, did not induce amnesia in normal mice, but did so in chlordiazepoxide-tolerant mice. Muscimol (0.25 mg/kg), a GABAA receptor agonist, in combination with a low dose of chlordiazepoxide, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. Scopolamine, an acetylcholine receptor antagonist, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. In the autoradiographical study, although repeated treatment with chlordiazepoxide had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, it decreased [3H]muscimol binding to GABAA receptors, with a decrease in affinity in the cortex and hippocampus. Furthermore, repeated administration of chlordiazepoxide increased [3H]quinuclidinyl benzilate binding to muscarinic acetylcholine receptors in the hippocampus. These results suggest that tolerance develops to the amnesic effects of chlordiazepoxide, and that tolerance may be due to down-regulation of GABAA receptors and/or up-regulation of acetylcholine receptors.",
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Development of tolerance to amnesic effects of chlordiazepoxide in relation to GABAergic and cholinergic neuronal systems. / Ishihara, Sei ichi; Hiramatsu, Masayuki; Kameyama, Tsutomu; Nabeshima, Toshitaka.

:: European Journal of Pharmacology, 巻 230, 番号 3, 19.01.1993, p. 313-319.

研究成果: Article

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