Maitre M
Centre de Neurochimie, Laboratoire de Neurobiologie Moléculaire des Interactions Cellulaires, UPR 416 CNRS, Strasbourg, France.
Prog Neurobiol. 1997 Feb;51(3):337-61. doi: 10.1016/s0301-0082(96)00064-0.
gamma-Hydroxybutyrate is a metabolite of GABA which is synthesized and accumulated by neurons in brain. This substance is present in micromolar quantities in all brain regions investigated as well as in several peripheral organs. Neuronal depolarization releases gamma-hydroxybutyrate into the extracellular space in a Ca(2+)-dependent manner. Gamma-hydroxybutyrate high-affinity receptors are present only in neurons, with a restricted specific distribution in the hippocampus, cortex and dopaminergic structures of rat brain (the striatum in general, olfactory bulbs and tubercles, frontal cortex, dopaminergic nuclei A9, A10 and A12). Stimulation of these receptors with low amounts of gamma-hydroxybutyrate induces in general hyperpolarizations in dopaminergic structures with a reduction of dopamine release. However, in the hippocampus and the frontal cortex, it seems that gamma-hydroxybutyrate induces depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. Some of the electrophysiological effects of GHB are blocked by NCS-382, a gamma-hydroxybutyrate receptor antagonist while some others are strongly attenuated by GABAB receptors antagonists. Gamma-hydroxybutyrate penetrates freely into the brain when administered intravenously or intraperitoneally. This is a unique situation for a molecule with signalling properties in the brain. Thus, the gamma-hydroxybutyrate concentration in brain easily can be increased more than 100 times. Under these conditions, gamma-hydroxybutyrate receptors are saturated and probably desensitized and down-regulated. It is unlikely that GABAB receptors could be stimulated directly by GHB. Most probably, GABA is released in part under the control of GHB receptors in specific pathways expressing GABAB receptors. Alternatively, GABAB receptors might be specifically stimulated by the GABA formed via the metabolism of gamma-hydroxybutyrate in brain. In animals and man, these GHBergic and GABAergic potentiations induce dopaminergic hyperactivity (which follows the first phase of dopaminergic terminal hyperpolarization), a strong sedation with anaesthesia and some EEG changes with epileptic spikes. It is presumed that, under pathological conditions (hepatic failure, alcoholic intoxication, succinic semialdehyde dehydrogenase defects), the rate of GHB synthesis or degradation in the peripheral organ is modified and induces increased GHB levels which could interfere with the normal brain mechanisms. This pathological status could benefit from treatments with gamma-hydroxybutyric and/or GABAB receptors antagonists. Nevertheless, the regulating properties of the endogenous gamma-hydroxybutyrate system on the dopaminergic pathways are a cause for the recent interest in synthetic ligands acting specifically at gamma-hydroxybutyrate receptors and devoid of any role as metabolic precursor of GABA in brain.
γ-羟基丁酸是γ-氨基丁酸（GABA）的一种代谢产物，由大脑中的神经元合成并积累。在所有研究的脑区以及几个外周器官中，这种物质以微摩尔量存在。神经元去极化以Ca(2+)依赖的方式将γ-羟基丁酸释放到细胞外空间。γ-羟基丁酸高亲和力受体仅存在于神经元中，在大鼠脑的海马体、皮质和多巴胺能结构（一般为纹状体、嗅球和结节、额叶皮质、多巴胺能核A9、A10和A12）中有受限的特定分布。用少量γ-羟基丁酸刺激这些受体通常会导致多巴胺能结构超极化，多巴胺释放减少。然而，在海马体和额叶皮质中，γ-羟基丁酸似乎会诱导去极化，伴有环磷酸鸟苷（cGMP）积累和肌醇磷酸周转率增加。γ-羟基丁酸（GHB）的一些电生理效应被γ-羟基丁酸受体拮抗剂NCS-382阻断，而其他一些效应则被GABAB受体拮抗剂强烈减弱。静脉注射或腹腔注射γ-羟基丁酸时，它可自由穿透进入大脑。对于在大脑中具有信号传导特性的分子来说，这是一种独特的情况。因此，大脑中的γ-羟基丁酸浓度很容易增加1倍以上。在这些条件下，γ-羟基丁酸受体饱和，可能会脱敏和下调。γ-羟基丁酸不太可能直接刺激GABAB受体。很可能，在表达GABAB受体的特定途径中，GABA部分是在γ-羟基丁酸受体的控制下释放的。或者，GABAB受体可能被大脑中γ-羟基丁酸代谢产生的GABA特异性刺激。在动物和人类中，这些γ-羟基丁酸能和GABA能增强作用会诱导多巴胺能亢进（这在多巴胺能终末超极化的第一阶段之后）、强烈的镇静和麻醉作用以及一些伴有癫痫样棘波改变的脑电图变化。据推测，在病理状态（肝功能衰竭、酒精中毒、琥珀酸半醛脱氢酶缺陷）下，外周器官中γ-羟基丁酸的合成或降解速率会发生改变，导致γ-羟基丁酸水平升高，这可能会干扰正常的脑机制。这种病理状态可能受益于γ-羟基丁酸和/或GABAB受体拮抗剂的治疗。然而，内源性γ-羟基丁酸系统对多巴胺能途径的调节特性是近期人们对特异性作用于γ-羟基丁酸受体且在大脑中不具有任何作为GABA代谢前体作用的合成配体产生兴趣的原因。
