Leonard Stuart T, Gerak Lisa R, Delatte Marcus S, Moerschbaecher Joseph M, Winsauer Peter J
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Behav Pharmacol. 2009 Feb;20(1):33-44. doi: 10.1097/FBP.0b013e3283242f2d.
Despite the knowledge that gamma-aminobutyric acid(A) modulators can affect learning and memory, their capacity for disrupting each of these complex processes is rarely compared, and often mistakenly assumed to occur with identical potency. For these reasons, the effects of flunitrazepam (0.056-3.2 mg/kg), ethanol (0.25-1.5 g/kg), and ethyl-beta-carboline-3-carboxylate (beta-CCE; 1-17.8 mg/kg) were compared in groups of rats responding under baselines that assessed learning and memory separately. The first baseline was a multiple schedule of repeated acquisition and performance of tandem response sequences, whereas the second baseline was a retention or memory procedure where a tandem response sequence was acquired and then retested after a 30-min delay. Under both procedures, responding was maintained under a second-order fixed-ratio-2 schedule of food reinforcement, and incorrect responding (errors) produced a 5-s timeout. With regard to the effects of the three drugs on sequence acquisition (learning), all three drugs dose dependently decreased the overall response rate and increased the percentage of errors. Both flunitrazepam and beta-CCE affected accuracy more potently than response rate, whereas ethanol was equipotent in affecting these two dependent measures. With regard to the effects of these drugs on sequence retention (memory), both flunitrazepam and ethanol dose dependently decreased retention at doses that had little or no effect on sequence acquisition under the multiple schedule, whereas beta-CCE decreased retention and sequence acquisition similarly at the doses tested. Together, these data show that drugs with differing capacities for altering the function of gamma-aminobutyric acid(A) receptors differ in their capacity for disrupting the acquisition and retention of response sequences and that positive modulation of this receptor complex may be more predictive of disruptions in memory than disruptions in learning.
尽管已知γ-氨基丁酸(A)调节剂会影响学习和记忆,但它们干扰这些复杂过程中每一个过程的能力很少被比较,而且常常被错误地认为具有相同的效力。出于这些原因,在分别评估学习和记忆的基线条件下,对氟硝西泮(0.056 - 3.2毫克/千克)、乙醇(0.25 - 1.5克/千克)和β-咔啉-3-羧酸乙酯(β-CCE;1 - 17.8毫克/千克)对大鼠组的影响进行了比较。第一个基线是重复获取和执行串联反应序列的多重时间表,而第二个基线是一个保持或记忆程序,其中获取一个串联反应序列,然后在30分钟延迟后重新测试。在这两种程序下,反应在二级固定比率为2的食物强化时间表下维持,错误反应(失误)会导致5秒的超时。关于这三种药物对序列获取(学习)的影响,所有三种药物均剂量依赖性地降低了总体反应率并增加了错误百分比。氟硝西泮和β-CCE对准确性的影响比反应率更显著,而乙醇在影响这两个相关指标方面效力相当。关于这些药物对序列保持(记忆)的影响,氟硝西泮和乙醇在多重时间表下对序列获取几乎没有影响或没有影响的剂量下,均剂量依赖性地降低了保持率,而β-CCE在测试剂量下同样降低了保持率和序列获取。总之,这些数据表明,具有不同能力改变γ-氨基丁酸(A)受体功能的药物在干扰反应序列的获取和保持方面能力不同,并且该受体复合物的正向调节可能比学习干扰更能预测记忆干扰。