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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: Comparisons with zolpidem, lorazepam, and TPA023.
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Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: Comparisons with zolpidem, lorazepam, and TPA023.

机译：TPA023B，亚型选择性γ-氨基丁酸（A）/苯并二氮杂类调节剂的新型区分刺激效果：与唑吡坦，劳拉西m和TPA023的比较。

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摘要

Anxiolytics with fewer unwanted effects may be created by varying GABAergic efficacy at the BZ binding site across GABA(A) receptor subtypes. TPA023 and TPA023B have in vitro antagonist efficacy at alpha(1) subtypes and partial-agonist efficacy at alpha(2/3) subtypes. TPA023B has partial-agonist efficacy at alpha(5); TPA023 has none. Drug discrimination procedures were used to determine whether the novel GABA(A) 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 alpha(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 alpha(1) efficacy plus reductions in alpha(2/3) efficacy permits anxiolysis but decreases BZ-like interoceptive stimulus effects.
机译：通过改变跨GABA（A）受体亚型的BZ结合位点处的GABA能效率，可以创建具有较少不良作用的抗焦虑药。 TPA023和TPA023B在alpha（1）亚型具有体外拮抗剂功效，而在alpha（2/3）亚型具有部分激动剂功效。 TPA023B在alpha（5）具有部分激动剂功效; TPA023没有。使用药物区分程序确定新的GABA（A）受体功效概况是否会在BZ位配体的主观效应模型中得到反映。训练大鼠以区分TPA023，TPA023B，非选择性BZ抗焦虑劳拉西m或alpha（1）-选择性催眠唑吡坦。劳拉西m，唑吡坦和TPA023的辨别是在少于50个疗程中得知的。尽管进行了各种程序操作，TPA023B训练组在160节训练后仍未显示出获得TPA023B歧视的证据。接受唑吡坦或劳拉西-训练的大鼠均未推广至TPA023B。然而，在相同的剂量范围内，受TPA023训练的大鼠完全和剂量依赖地泛化为TPA023B。在劳拉西m，唑吡坦和TPA023组中进行TPA023B测试后，恢复标准判别性能的培训次数随剂量的增加而增加，这可能是由于残留TPA023B的影响所致。与以前的数据一起，目前的结果表明，消除alpha（1）功效加上降低alpha（2/3）功效可以进行抗焦虑治疗，但可以降低BZ样的感受性刺激作用。

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