Woolverton W L, Nader M A
Department of Psychiatry, University of Chicago, IL, USA.
Psychopharmacology (Berl). 1995 Dec;122(3):230-6. doi: 10.1007/BF02246544.
The purpose of the present study was to further investigate the relationship between the DS effects of PB and those of benzodiazepines (BZs) and to begin to collect pharmacological information concerning receptor mechanisms involved in this behavioral effect of BZs. Rhesus monkeys (n = 3), trained to discriminate pentobarbital (PB; 10 mg/kg, IG) from saline under a discrete-trials shock avoidance procedure, were given IG diazepam (0.3-10 mg/kg), chlordiazepoxide (1.0-30 mg/kg), or etizolam (0.3-10 mg/kg) alone and in combination with flumazenil (0.01-1.7 mg/kg, IM). Flumazenil was administered 10 min prior to the administration of saline, PB or the BZs. All three BZs fully substituted for PB in all monkeys. Diazepam was the most potent with a mean ED50 of 0.81 mg/kg (SEM = 0.04) while chlordiazepoxide was the least potent (mean ED50 = 5.78 mg/kg, SEM = 1.22 mg/kg). The ED50 for etizolam was 1.22 mg/kg (SEM = 0.37 mg/kg). Pretreatment with flumazenil (0.01-1.0 mg/kg) resulted in a dose-related parallel shift to the right in the dose-response function for PB-appropriate responding in all monkeys for all three BZs. The mean (n = 3) pKB value with 0.1 mg/kg flumazenil was 6.51 (SEM = 0.42) for diazepam and 6.57 (SEM = 0.17) for chlordiazepoxide. This value could not be calculated for etizolam because only one monkey was tested with 0.1 mg/kg flumazenil. However, the mean pKB for etizolam considering all monkeys and all doses of flumazenil was 6.58 (SEM = 0.47). Apparent pA2 values for flumazenil with diazepam were 6.02 for one monkey and 7.11 for another. All three BZs tended to increase average latency to respond. Apparent pKB and pA2 analysis may prove useful for elucidating receptor mechanisms involved in the behavioral effects of BZs.
本研究的目的是进一步探究戊巴比妥（PB）的药物辨别效应与苯二氮䓬类药物（BZs）的药物辨别效应之间的关系，并开始收集有关参与BZs这种行为效应的受体机制的药理学信息。对3只恒河猴进行训练，使其在离散试验电击回避程序下能够从生理盐水辨别出戊巴比妥（PB；10mg/kg，腹腔注射），单独给予它们腹腔注射地西泮（0.3 - 10mg/kg）、氯氮䓬（1.0 - 30mg/kg）或艾司唑仑（0.3 - 10mg/kg），并与氟马西尼（0.01 - 1.7mg/kg，肌肉注射）联合使用。在给予生理盐水、PB或BZs前10分钟注射氟马西尼。在所有猴子中，所有三种BZs都能完全替代PB。地西泮效力最强，平均半数有效剂量（ED50）为0.81mg/kg（标准误 = 0.04），而氯氮䓬效力最弱（平均ED50 = 5.78mg/kg，标准误 = 1.22mg/kg）。艾司唑仑的ED50为1.22mg/kg（标准误 = 0.37mg/kg）。用氟马西尼（0.01 - 1.0mg/kg）预处理后，所有猴子对所有三种BZs的PB适宜反应的剂量 - 反应函数均出现与剂量相关的平行右移。对于地西泮，0.1mg/kg氟马西尼时的平均（n = 3）pKB值为6.51（标准误 = 0.42），氯氮䓬为6.57（标准误 = 0.17）。由于仅用一只猴子测试了0.1mg/kg氟马西尼，所以无法计算艾司唑仑的该值。然而，考虑所有猴子和所有氟马西尼剂量时，艾司唑仑的平均pKB为6.58（标准误 = 0.47）。氟马西尼与地西泮的表观pA2值，一只猴子为6.02，另一只为7.11。所有三种BZs都倾向于增加平均反应潜伏期。表观pKB和pA2分析可能有助于阐明参与BZs行为效应的受体机制。
