Gerak Lisa R, Stevenson Michael W, Winsauer Peter J, Moerschbaecher Joseph M
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112-1393, USA.
Psychopharmacology (Berl). 2004 Apr;173(1-2):195-202. doi: 10.1007/s00213-003-1717-2. Epub 2004 Jan 22.
Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators.
The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators.
Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation.
Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves.
The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.
尽管γ-氨基丁酸A（GABA(A)）受体的正向调节剂通常会产生相似的行为效应，无论GABA(A)受体复合物上的哪个调节位点介导这些效应，但已观察到神经活性甾体与其他正向GABA(A)调节剂的效应之间存在一些差异。
本研究旨在比较一种神经活性甾体与其他正向GABA(A)调节剂的行为效应。
大鼠在重复习得和反应链执行的多重程序下做出反应，反应通过二阶固定比率2的食物呈现程序维持。
孕烷醇酮、氟硝西泮、戊巴比妥和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮剂量依赖性地降低了反应率，并增加了多重程序两个组成部分中的错误百分比。尽管孕烷醇酮、戊巴比妥和氯胺酮的降低反应率和增加错误的效应在数量上彼此相似，但氟硝西泮在降低反应率方面效果较差，而在增加错误方面比其他三种药物更有效。3.2mg/kg的孕烷醇酮剂量增强了氟硝西泮和戊巴比妥的效应，使剂量-效应曲线向左移动2至3倍。相比之下，孕烷醇酮并未改变氯胺酮的剂量-效应曲线。
神经活性甾体孕烷醇酮的破坏效应在质量上与其他正向GABA(A)调节剂以及氯胺酮的效应相似；然而，孕烷醇酮对氟硝西泮和戊巴比妥而非氯胺酮效应的增强，强调了GABA(A)受体在孕烷醇酮行为效应中的重要性。
