Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, PO Box 410, 405 30, Gothenburg, Sweden.
Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden.
J Neural Transm (Vienna). 2022 Apr;129(4):395-407. doi: 10.1007/s00702-022-02487-4. Epub 2022 Mar 24.
Interventions that elevate glycine levels and target the glycine receptor (GlyR) in the nucleus Accumbens (nAc) reduce ethanol intake in rats, supposedly by acting on the brain reward system via increased basal and attenuated ethanol-induced nAc dopamine release. Glycine transport across the blood brain barrier (BBB) appears inefficient, but glycine-containing dipeptides elevate whole brain tissue dopamine levels in mice. This study explores whether treatment with the glycine-containing dipeptides leucine-glycine (Leu-Gly) and glycine-leucine (Gly-Leu) by means of a hypothesized, facilitated BBB passage, alter nAc glycine and dopamine levels and locomotor activity in two rodent models. The acute effects of Leu-Gly and Gly-Leu (1-1000 mg/kg, i.p.) alone or Leu-Gly in combination with ethanol on locomotion in male NMRI mice were examined in locomotor activity boxes. Striatal and brainstem slices were obtained for ex vivo HPLC analyses of tissue levels of glycine and dopamine. Furthermore, the effects of Leu-Gly i.p. (1-1000 mg/kg) on glycine and dopamine output in the nAc were examined using in vivo microdialysis coupled to HPLC in freely moving male Wistar rats. Leu-Gly and Gly-Leu did not significantly alter locomotion, ethanol-induced hyperlocomotor activity or tissue levels of glycine or dopamine, apart from Gly-Leu 10 mg/kg that slightly raised nAc dopamine. Microdialysis revealed no significant alterations in nAc glycine or dopamine levels when regarding all rats as a homogenous group. In a subgroup of rats defined as dopamine responders, a significant elevation of nAc dopamine (20%) was seen following Leu-Gly 10-1000 mg/kg i.p, and this group of animals presented lower baseline dopamine levels compared to dopamine non-responders. To conclude, peripheral injection of glycine-containing dipeptides appears inefficient in elevating central glycine levels but raises accumbal dopamine levels in a subgroup of rats with a lower endogenous dopamine tone. The tentative relationship between dopamine baseline and ensuing response to glycinergic treatment and presumptive direct interactions between glycine-containing dipeptides and the GlyR bear insights for refinement of the glycinergic treatment concept for alcohol use disorder (AUD).
干预物提高甘氨酸水平并靶向伏隔核（nAc）中的甘氨酸受体（GlyR），可减少大鼠的乙醇摄入量，据称这是通过增加基础和减弱乙醇诱导的 nAc 多巴胺释放来作用于大脑奖励系统。甘氨酸穿过血脑屏障（BBB）的转运似乎效率低下，但含有甘氨酸的二肽可提高小鼠全脑组织中的多巴胺水平。本研究探讨了通过假设的促进 BBB 通透性的方式用含有甘氨酸的二肽亮氨酸-甘氨酸（Leu-Gly）和甘氨酸-亮氨酸（Gly-Leu）治疗是否会改变两种啮齿动物模型的 nAc 甘氨酸和多巴胺水平以及运动活动。在运动活动箱中检查了 Leu-Gly 和 Gly-Leu（1-1000mg/kg，ip）单独或 Leu-Gly 与乙醇联合对雄性 NMRI 小鼠运动的急性影响。获得纹状体和脑干切片，用于组织中甘氨酸和多巴胺水平的离体 HPLC 分析。此外，通过在自由移动的雄性 Wistar 大鼠中使用 HPLC 结合的体内微透析研究了 Leu-Gly（1-1000mg/kg，ip）对 nAc 中甘氨酸和多巴胺输出的影响。除了 10mg/kg Gly-Leu 轻微增加 nAc 多巴胺外，Leu-Gly 和 Gly-Leu 均未显著改变运动、乙醇诱导的过度运动活动或组织中的甘氨酸或多巴胺水平。当将所有大鼠视为同质组时，微透析显示 nAc 甘氨酸或多巴胺水平没有明显变化。在定义为多巴胺反应者的大鼠亚组中，Leu-Gly 10-1000mg/kg ip 后 nAc 多巴胺水平显著升高（20%），并且该组动物的基础多巴胺水平低于多巴胺非反应者。总之，外周注射含有甘氨酸的二肽似乎不能有效提高中枢甘氨酸水平，但会在具有较低内源性多巴胺张力的大鼠亚组中升高伏隔核多巴胺水平。多巴胺基础水平与甘氨酸能治疗反应之间的暂定关系以及含有甘氨酸的二肽与 GlyR 之间的假定直接相互作用为酒精使用障碍（AUD）的甘氨酸能治疗概念的细化提供了见解。
