Dishary Sharmin, Daniela Rüedi-Bettschen, Laís F Berro, Jemma E Cook, Jaren A Reeves-Darby, Tanya Pareek, Md Yeunus Mian, Farjana Rashid, Lalit Golani, Eliseu da Cruz Moreira-Junior, Donna M Platt, James M Cook, James K Rowlett
{"title":"利用定量观察技术评估新型 GABAkine 咪唑二氮卓对恒河猴的镇静-运动效应。","authors":"Dishary Sharmin, Daniela Rüedi-Bettschen, Laís F Berro, Jemma E Cook, Jaren A Reeves-Darby, Tanya Pareek, Md Yeunus Mian, Farjana Rashid, Lalit Golani, Eliseu da Cruz Moreira-Junior, Donna M Platt, James M Cook, James K Rowlett","doi":"10.1177/02698811241286760","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Benzodiazepines bind to γ-aminobutyric acid type A (GABA<sub>A</sub>) receptor subtypes identified by different α subunits (i.e., α1GABA<sub>A</sub>, α2GABA<sub>A</sub>, α3GABA<sub>A</sub>, and α5GABA<sub>A</sub>). Sedative-motor effects of benzodiazepines are thought to involve α1GABA<sub>A</sub> and α3GABA<sub>A</sub> subtypes.</p><p><strong>Aims: </strong>We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABA<sub>A</sub> receptors), with varying degrees of selective efficacy at different GABA<sub>A</sub> receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABA<sub>A</sub> and α3GABA<sub>A</sub> efficacy.</p><p><strong>Methods: </strong>Adult female rhesus monkeys (<i>N</i> = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABA<sub>A</sub> subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABA<sub>A</sub> subtypes), and MP-III-22 (preferential potency and efficacy for α5GABA<sub>A</sub> subtypes).</p><p><strong>Results: </strong>As with alprazolam, all GABAkines induced significant levels of mild sedation (\"rest/sleep posture\"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABA<sub>A</sub> subtypes.</p><p><strong>Conclusions: </strong>GABAkines with preferential efficacy at α2/α3GABA<sub>A</sub> and/or α5GABA<sub>A</sub> subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABA<sub>A</sub> activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABA<sub>A</sub> subtype in this milder form of sedation.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1157-1169"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys.\",\"authors\":\"Dishary Sharmin, Daniela Rüedi-Bettschen, Laís F Berro, Jemma E Cook, Jaren A Reeves-Darby, Tanya Pareek, Md Yeunus Mian, Farjana Rashid, Lalit Golani, Eliseu da Cruz Moreira-Junior, Donna M Platt, James M Cook, James K Rowlett\",\"doi\":\"10.1177/02698811241286760\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Benzodiazepines bind to γ-aminobutyric acid type A (GABA<sub>A</sub>) receptor subtypes identified by different α subunits (i.e., α1GABA<sub>A</sub>, α2GABA<sub>A</sub>, α3GABA<sub>A</sub>, and α5GABA<sub>A</sub>). Sedative-motor effects of benzodiazepines are thought to involve α1GABA<sub>A</sub> and α3GABA<sub>A</sub> subtypes.</p><p><strong>Aims: </strong>We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABA<sub>A</sub> receptors), with varying degrees of selective efficacy at different GABA<sub>A</sub> receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABA<sub>A</sub> and α3GABA<sub>A</sub> efficacy.</p><p><strong>Methods: </strong>Adult female rhesus monkeys (<i>N</i> = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABA<sub>A</sub> subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABA<sub>A</sub> subtypes), and MP-III-22 (preferential potency and efficacy for α5GABA<sub>A</sub> subtypes).</p><p><strong>Results: </strong>As with alprazolam, all GABAkines induced significant levels of mild sedation (\\\"rest/sleep posture\\\"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABA<sub>A</sub> subtypes.</p><p><strong>Conclusions: </strong>GABAkines with preferential efficacy at α2/α3GABA<sub>A</sub> and/or α5GABA<sub>A</sub> subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABA<sub>A</sub> activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABA<sub>A</sub> subtype in this milder form of sedation.</p>\",\"PeriodicalId\":16892,\"journal\":{\"name\":\"Journal of Psychopharmacology\",\"volume\":\" \",\"pages\":\"1157-1169\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/02698811241286760\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/02698811241286760","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys.
Background: Benzodiazepines bind to γ-aminobutyric acid type A (GABAA) receptor subtypes identified by different α subunits (i.e., α1GABAA, α2GABAA, α3GABAA, and α5GABAA). Sedative-motor effects of benzodiazepines are thought to involve α1GABAA and α3GABAA subtypes.
Aims: We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABAA receptors), with varying degrees of selective efficacy at different GABAA receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABAA and α3GABAA efficacy.
Methods: Adult female rhesus monkeys (N = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABAA subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABAA subtypes), and MP-III-22 (preferential potency and efficacy for α5GABAA subtypes).
Results: As with alprazolam, all GABAkines induced significant levels of mild sedation ("rest/sleep posture"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABAA subtypes.
Conclusions: GABAkines with preferential efficacy at α2/α3GABAA and/or α5GABAA subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABAA activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABAA subtype in this milder form of sedation.
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The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.
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