CHRONIC BARBITURATES-CNS BIOCHEMISTRY

我们最近观察到，急性服用巴比妥类药物 产生环鸟苷酸（环GMP）的显著减少 大鼠小脑中的水平。 经过长期的巴比妥治疗， 小脑环GMP水平仅在存在 小脑和小脑中巴比妥的急性麻醉浓度 血 巴比妥突然停药后小脑环鸟苷酸水平 在同一时间， 与巴比妥戒断综合征相关的自发性惊厥。 这些数据为耐受性的发展提供了强有力的证据， 巴比妥和小脑循环的显著戒断后反应 GMP。 假设停药后环GMP升高 在小脑和其他有待研究的大脑区域， 参与了与巴比妥戒断相关的兴奋增强 综合征 特别是小脑环GMP的升高可能与 戒断抽搐的强直性伸展阶段。 循环GMP水平 小脑受[1]外部兴奋性输入的调节， 据信利用兴奋性氨基酸，例如，谷氨酸和天冬氨酸， 或乙酰胆碱（ACh）作为神经递质和[2] GABA能小脑 中间神经元。 我们最近的数据表明，GABA神经元的数量较少， 重要性 因此，假设急性和慢性 巴比妥类药物对小脑环GMP的影响可能通过以下途径介导： 对这些兴奋性氨基酸和/或ACh通路的作用。 以来 基本的神经元回路以及所涉及的递质更好 与其他大脑区域不同， 小脑被提出作为一个模型，以调查的适应性和 巴比妥类药物中上述兴奋性递质的功能参与 依赖和戒断综合征的表现。 可能 突触前递质合成和释放的变化以及突触后 将研究受体的适应性。

We have recently observed that the acute administration of barbiturates produces a marked reduction in cyclic guanosine monophosphate (cyclic GMP) levels in the rat cerebellum. Following long term barbital treatment, cerebellar cyclic GMP levels are only slightly reduced in the presence of acutely anesthetic concentrations of barbital in the cerebellum and in the blood. Upon abrupt barbital withdrawal cyclic GMP levels in the cerebellum are elevated 2-3 fold at a time coincident with the peak in the number of spontaneous convulsions associated with the barbital abstinence syndrome. These data provide strong evidence for the development of tolerance to barbital and for a marked post withdrawal response of cerebellar cyclic GMP. It is hypothesized that the post withdrawal elevations of cyclic GMP in the cerebellum and in other brain areas to be studied are functionally involved in the enhanced excitation associated with the barbital abstinence syndrome. In particular, elevated cerebellar cyclic GMP may be involved in the tonic-extension phase of abstinence convulsions. Cyclic GMP levels in the cerebellum are regulated by [1] extrinsic excitatory inputs which are believed to utilize excitatory amino acids, e.g., glutamate and aspartate, or acetylcholine (ACh) as neurotransmitters and [2] GABAergic cerebellar interneurons. Our recent data suggest that the GABA neurons are of lesser importance. It is therefore hypothesized that the acute and chronic effects of barbiturates on cerebellar cyclic GMP may be mediated via actions on these excitatory amino acid and/or ACh pathways. Since the basic neuronal circuitry as well as the transmitters involved is better understood in the cerebellum as opposed to other brain areas, the cerebellum is proposed as a model to investigate the adaptations of and the functional involvement of the above excitatory transmitters in barbiturate dependence and the manifestation of the abstinence syndrome. Possible presynaptic changes in transmitter synthesis and release and postsynaptic adaptations in receptors will be investigated.