Novel discriminative stimulus effects of TPA023B, subtype-selective γ-aminobutyric-acidA/benzodiazepine modulator: Comparisons with zolpidem, lorazepam, and TPA023
- 作者：Stephen J. Kohut ; Nancy A. Ator
- 关键词：GABA ; Subtype selectivity ; Anxiolytic ; Drug discrimination ; Abuse liability ; Benzodiazepine ; Lorazepam ; Zolpidem ; TPA023 ; TPA023B ; Training ; Rat
- 刊名：Pharmacology Biochemistry and Behavior
- 出版年：2008
- 期刊代码：219_00913057
- 类别：med
- 出版时间：July 2008
- 卷：90
- 期：1
- 页码：65-73
- 文件大小：658 K
摘要
Anxiolytics with fewer unwanted effects may be created by varying GABAergic efficacy at the BZ binding site across GABAA receptor subtypes. TPA023 and TPA023B have in vitro antagonist efficacy at 
1 subtypes and partial-agonist efficacy at 2/3 subtypes. TPA023B has partial-agonist efficacy at 5; TPA023 has none. Drug discrimination procedures were used to determine whether the novel GABAA receptor efficacy profiles would be reflected in a model of subjective effects of BZ-site ligands. Rats were trained to discriminate TPA023, TPA023B, the nonselective BZ anxiolytic lorazepam, or the 1-selective hypnotic zolpidem. The lorazepam, zolpidem, and TPA023 discriminations were learned in < 50 sessions. The TPA023B training group showed no evidence of acquiring the TPA023B discrimination after 160 sessions despite various procedural manipulations. Neither zolpidem- nor lorazepam-trained rats generalized to TPA023B. Within the same dose range, however, TPA023-trained rats generalized fully and dose-dependently to TPA023B. Number of training sessions to regain criterion discrimination performance following TPA023B tests in the lorazepam, zolpidem, and TPA023 groups increased as a function of dose, likely due to effects of residual TPA023B. Together with previous data, the present results suggest that elimination of 1 efficacy plus reductions in 2/3 efficacy permits anxiolysis but decreases BZ-like interoceptive stimulus effects.
1 subtypes and partial-agonist efficacy at 2/3 subtypes. TPA023B has partial-agonist efficacy at 5; TPA023 has none. Drug discrimination procedures were used to determine whether the novel GABAA receptor efficacy profiles would be reflected in a model of subjective effects of BZ-site ligands. Rats were trained to discriminate TPA023, TPA023B, the nonselective BZ anxiolytic lorazepam, or the 1-selective hypnotic zolpidem. The lorazepam, zolpidem, and TPA023 discriminations were learned in < 50 sessions. The TPA023B training group showed no evidence of acquiring the TPA023B discrimination after 160 sessions despite various procedural manipulations. Neither zolpidem- nor lorazepam-trained rats generalized to TPA023B. Within the same dose range, however, TPA023-trained rats generalized fully and dose-dependently to TPA023B. Number of training sessions to regain criterion discrimination performance following TPA023B tests in the lorazepam, zolpidem, and TPA023 groups increased as a function of dose, likely due to effects of residual TPA023B. Together with previous data, the present results suggest that elimination of 1 efficacy plus reductions in 2/3 efficacy permits anxiolysis but decreases BZ-like interoceptive stimulus effects.