Reddy D S, Kulkarni S K
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Punjab University, India.
Brain Res. 1997 Mar 28;752(1-2):61-71. doi: 10.1016/s0006-8993(96)01447-3.
This study examined the effects of neurosteroids on the behavior of mice in the mirrored chamber test of anxiety, and determined the potential mechanisms by which neurosteroids alter the behavior in animal models of anxiety. Allopregnanolone (AP) (0.5 and 1 mg/kg) and pregnenolone sulfate (PS) (0.5 and 2 mg/kg) significantly reduced the latency to enter the chamber, and increased both number of entries and total time spent in the chamber in a dose-dependent manner, without affecting the spontaneous locomotor activity. In contrast, dehydroepiandrosterone sulfate (DHEAS) (1 and 2 mg/kg) increased motor activity and caused an anxiogenic response, i.e., an increase in latency to enter the mirrored chamber, and a decrease in the number of entries and time spent in the chamber. Progesterone (PROG) (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (4'-CD) (0.25-1 mg/kg), a specific ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor (MDR), produced a clear dose-dependent anxiolytic response in the mirrored chamber. The AP-, PROG- and 4'-CD-elicited anxiolytic behavior was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a selective benzodiazepine (BZD) antagonist. In contrast, the anxiolytic effect of PS was not blocked by picrotoxin. The 4'-CD-induced anxiolytic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. Nifedipine (2 and 5 mg/kg), a dihydropyridine-type Ca2+ channel blocker, produced a flumazenil-resistant anxiolytic effect. Combined administration of nifedipine (2 and 5 mg/kg) and PS (0.5 and 2 mg/kg) exerted a significant additive effect in the mirrored chamber test. The potent anxiolytic effect of dizocilpine (0.5 and 1 mg/kg), an NMDA receptor antagonist, was blocked by pretreatment with DHEAS (2 mg/kg). Neurosteroids evoked changes in mirrored chamber activities resembling those elicited by triazolam (0.25 and 0.5 mg/kg). However, these effects were seen at doses that did not markedly affect locomotor activity, thereby suggesting these changes in behavior represent anxiolytic actions. Together, these results provide evidence for differential behavioral actions of the neurosteroids AP, PS and DHEAS in the mirrored chamber test of anxiety. The anxiolytic effect of PROG may be imputed to its metabolism to neurosteroid AP, while the 4'-CD-induced anxiolytic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptor. Further, these differential effects reaffirm the contention that neurosteroids could be involved in the homeostasis of stress response.
本研究检测了神经甾体对小鼠在焦虑镜像箱试验中行为的影响，并确定了神经甾体改变焦虑动物模型中行为的潜在机制。别孕烯醇酮（AP）（0.5和1mg/kg）和硫酸孕烯醇酮（PS）（0.5和2mg/kg）显著缩短了进入箱体的潜伏期，并以剂量依赖性方式增加了进入次数和在箱体内停留的总时间，且不影响自发运动活性。相比之下，硫酸脱氢表雄酮（DHEAS）（1和2mg/kg）增加了运动活性并引起致焦虑反应，即进入镜像箱的潜伏期延长，进入次数和在箱体内停留时间减少。孕酮（PROG）（1 - 10mg/kg），一种神经甾体前体，以及4'-氯地西泮（4'-CD）（0.25 - 1mg/kg），一种线粒体地西泮结合抑制剂（DBI）受体（MDR）的特异性配体，在镜像箱试验中产生了明显的剂量依赖性抗焦虑反应。AP、PROG和4'-CD引起的抗焦虑行为被GABA - A氯通道拮抗剂苦味毒（1mg/kg）阻断，但未被选择性苯二氮䓬（BZD）拮抗剂氟马西尼（2mg/kg）阻断。相反，PS的抗焦虑作用未被苦味毒阻断。PK11195（2mg/kg），一种选择性部分MDR拮抗剂，预处理可阻止4'-CD诱导的抗焦虑作用。硝苯地平（2和5mg/kg），一种二氢吡啶型Ca2+通道阻滞剂，产生了氟马西尼抵抗的抗焦虑作用。硝苯地平（2和5mg/kg）与PS（0.5和2mg/kg）联合给药在镜像箱试验中产生了显著的相加效应。NMDA受体拮抗剂地佐环平（0.5和1mg/kg）的强效抗焦虑作用被DHEAS（2mg/kg）预处理阻断。神经甾体引起的镜像箱活动变化类似于三唑仑（0.25和0.5mg/kg）引起的变化。然而，这些效应在不明显影响运动活性的剂量下出现，从而表明这些行为变化代表抗焦虑作用。总之，这些结果为神经甾体AP、PS和DHEAS在焦虑镜像箱试验中的不同行为作用提供了证据。PROG的抗焦虑作用可能归因于其代谢为神经甾体AP，而4'-CD诱导的抗焦虑反应与其刺激MDR的神经甾体生成及随后对GABA - A受体的调节有关。此外，这些不同效应再次证实了神经甾体可能参与应激反应稳态的观点。
