Pharmacology, PsychoGenics, Inc., 765 Old Saw Mill River Rd., Tarrytown, NY 10591, USA.
Behav Brain Res. 2010 Mar 17;208(1):258-64. doi: 10.1016/j.bbr.2009.12.006. Epub 2009 Dec 16.
Both the GABA(B) receptor positive modulator GS39783 and the GABA(B) receptor antagonist CGP46381 exhibit anxiolytic-like properties in animal models. In the present studies, the effects of GS39783 and CGP46381 in the modified Geller-Seifter task were assessed. First, the predictive validity of the task was confirmed by assessing the effects of multiple anxiolytic and non-anxiolytic compounds on punished and unpunished responding.
Rats were trained in the modified Geller-Seifter task. After successful acquisition of the task, chlordiazepoxide, diazepam, MPEP, haloperidol, GS39783, 8-OH-DPAT, alprazolam and CGP46381 were tested consecutively. For each test compound, doses were administered in a randomized, counter-balanced, within-subjects design. Drug tests were performed only when rats exhibited baseline performance (the punished and time-out response rates were less than 10% of the unpunished response rate).
Chlordiazepoxide, diazepam, alprazolam and MPEP released punished responding with variable effects on unpunished responding. Haloperidol had a small but significant effect on punished responding at an intermediate dose, and decreased unpunished responding at the highest dose tested. In contrast, administration of the GABA(B) receptor positive modulator GS398783 or the GABA(B) receptor antagonist CGP46381 at doses up to 30 mg/kg had no effects on either punished or unpunished responding. The 5-HT(1A) agonist 8-OH-DPAT did not release punished responding, but significantly decreased unpunished responding at the highest dose tested.
The modified Geller-Seifter task generally exhibits good predictive validity for anxiolytic-like compounds. Neither GABA(B) receptor positive allosteric modulation nor blockade exhibited anxiolytic-like properties in the modified Geller-Seifter task. The 5-HT(1A) partial agonist buspirone was similarly ineffective.
GABA（B）受体正向变构调节剂 GS39783 和 GABA（B）受体拮抗剂 CGP46381 在动物模型中均表现出抗焦虑样特性。在本研究中，评估了 GS39783 和 CGP46381 在改良 Geller-Seifter 任务中的作用。首先，通过评估多种抗焦虑和非抗焦虑化合物对受罚和不受罚反应的影响，证实了该任务的预测有效性。
大鼠在改良 Geller-Seifter 任务中接受训练。在成功获得任务后，依次测试氯氮卓、地西泮、MPEP、氟哌啶醇、GS39783、8-OH-DPAT、阿普唑仑和 CGP46381。对于每个测试化合物，均以随机、平衡、个体内设计给药。仅当大鼠表现出基线性能（受罚和超时反应率低于未受罚反应率的 10%）时，才进行药物测试。
氯氮卓、地西泮、阿普唑仑和 MPEP 释放受罚反应，对未受罚反应有不同的影响。氟哌啶醇在中等剂量下对受罚反应有较小但显著的影响，在测试的最高剂量下降低了未受罚反应。相比之下，GABA（B）受体正向变构调节剂 GS398783 或 GABA（B）受体拮抗剂 CGP46381 给药剂量高达 30mg/kg 对受罚或未受罚反应均无影响。5-HT（1A）激动剂 8-OH-DPAT 未释放受罚反应，但在测试的最高剂量下显著降低了未受罚反应。
改良 Geller-Seifter 任务通常对具有抗焦虑样特性的化合物具有良好的预测有效性。GABA（B）受体正向变构调节或阻滞在改良 Geller-Seifter 任务中均未表现出抗焦虑样特性。5-HT（1A）部分激动剂丁螺环酮也同样无效。
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