Departments of Pharmacology (LRG and CPF) and Psychiatry (CPF), The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA,
Psychopharmacology (Berl). 2014 Jan;231(1):181-90. doi: 10.1007/s00213-013-3218-2. Epub 2013 Aug 15.
Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA(A) receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA(A), N-methyl-D-aspartate (NMDA), σ₁, or 5-HT₃ receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.
The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA(A) receptors might contribute to its discriminative stimulus effects.
Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.
Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA(A) receptors, such as extrasynaptic GABA(A), NMDA, σ₁, and 5-HT₃ receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA₂ values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.
While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABA(A) receptors, they indicate a primary and possibly exclusive role of synaptic GABA(A) receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA(A) receptors.
神经活性甾体和苯二氮䓬类药物可以通过作用于突触 GABA(A) 受体上的不同结合位点来正向调节 GABA。尽管这些受体被认为介导了苯二氮䓬类药物和神经活性甾体的行为效应，但其他受体（例如，突触外 GABA(A)、N-甲基-D-天冬氨酸 (NMDA)、σ₁或 5-HT₃受体）可能有助于神经活性甾体的效应，从而解释了不同阳性调节剂之间的差异。
本研究将神经活性甾体孕烷醇酮确立为鉴别刺激物，以确定其鉴别刺激物效应是否除了对突触 GABA(A) 受体的正向调节作用之外还有其他作用。
四只恒河猴在刺激-终止的固定比率 10 程序下，对 5.6 毫克/千克孕烷醇酮进行鉴别。
作用于苯二氮䓬、巴比妥或神经活性甾体位点的阳性调节剂产生了≥80%的孕烷醇酮杠杆反应，而主要作用于突触外 GABA(A) 受体以外的受体的药物，如突触外 GABA(A)、NMDA、σ₁和 5-HT₃受体，则产生了载体杠杆反应。氟马西尼拮抗了苯二氮䓬咪达唑仑和氟硝西泮，Schild 分析得出斜率没有偏离单位，pA₂值分别为 7.39 和 7.32。氟马西尼没有改变孕烷醇酮的鉴别刺激效应。
虽然这些结果不排除孕烷醇酮作用于突触外 GABA(A) 受体以外的受体的可能性，但它们表明突触 GABA(A) 受体在其鉴别刺激效应中具有主要且可能是排他性的作用。报道的苯二氮䓬类药物和神经活性甾体的作用差异不是由于它们在突触 GABA(A) 受体上的作用不同所致。
