Akhondzadeh S, Stone T W
Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar, Iran.
Pharmacol Res. 1998 Dec;38(6):441-8. doi: 10.1006/phrs.1998.0388.
We have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal slices. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone. It was also shown that glutamate receptor activity or extracellular calcium are not involved in the induction of this type of long-term depression. The present study investigated the possible relation between muscimol-induced long-term depression and barbiturates/benzodiazepine-induced amnesia and attempts to determine the possible effect of pregnenolone sulfate on muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that pentobarbital, benzodiazepines and pregnanolone at concentrations that did not have any effect themselves on the population spike, potentiate the ability of muscimol to induce long-term depression. In addition to this, the long-term depression was either blocked or reversed by pregnenolone sulfate at concentrations (10 microM) where pregnenolone sulfate did not induce any multiple burst or increase of spike size. The results suggest that the potentiation of this type of long-term depression by benzodiazepines and barbiturates can explain the main adverse effect of these drugs, amnesia and cognitive impairment. Moreover, the prevention or reversal of this type of long-term depression by pregnenolone sulfate, may suggest a clinical application of this agent in the management of amnesia or dementia.
我们最近报道了一种通过激活海马切片中的GABAA受体来诱导长期抑制的新方案。这种长期抑制可被荷包牡丹碱逆转，并被诸如alphaxalone等神经甾体增强。研究还表明，谷氨酸受体活性或细胞外钙不参与此类长期抑制的诱导。本研究调查了蝇蕈醇诱导的长期抑制与巴比妥类药物/苯二氮卓类药物诱导的失忆之间的可能关系，并试图确定硫酸孕烯醇酮对蝇蕈醇诱导的长期抑制的可能影响。在对辐射层（0.01 Hz）中的Schaffer侧支纤维进行顺向刺激后，在大鼠海马切片的CA1锥体细胞层进行细胞外记录。观察到，戊巴比妥、苯二氮卓类药物和孕烷醇酮在自身对群体峰电位无任何影响的浓度下，增强了蝇蕈醇诱导长期抑制的能力。除此之外，硫酸孕烯醇酮在浓度为10 microM时（该浓度下硫酸孕烯醇酮不会诱导任何多重爆发或峰电位大小增加），可阻断或逆转长期抑制。结果表明，苯二氮卓类药物和巴比妥类药物对这种类型长期抑制的增强作用可以解释这些药物的主要不良反应，即失忆和认知障碍。此外，硫酸孕烯醇酮对这种类型长期抑制的预防或逆转作用，可能提示该药物在失忆或痴呆管理中的临床应用。
