不同偶联模式的兴奋性氨基酸受体所介导非洲爪蟾卵母细胞跨膜电流的相互影响

目的 研究不同偶联模式的兴奋性氨基酸受体所介导非洲爪蟾卵母细胞跨膜电流的相互影响.方法 用异硫氰酸胍-酚-氯仿法从成年大鼠脑中提取总RNA,以寡聚脱氧胸苷酸纤维素亲和层析法分离出mRNA并注射入非洲爪蟾卵母细胞使表达,通过全细胞双电极电压钳位法,分别以M-胆碱受体Carb,谷氨酸离子型受体激动剂kainate(KA),代谢Ⅰ型受体激动剂quisqualate(QA)及代谢Ⅲ型受体激动剂L-phosphoserine(L-SOP)两两同时灌流有受体表达的非洲爪蟾卵母细胞.结果 3种偶联模式的受体激动后产生的膜电流具有交叉脱敏现象.结论 在多种受体共存的细胞中,受体之间可能存在着广泛的相互作用.     

兴奋性氨基酸受体所介导细胞钙电流特征及其中L-SOP的作用途径

目的:研究兴奋性氨基酸受体各亚型所介导非洲爪蟾卵母细胞跨膜电流的特征及其中Ⅲ型受体激动剂L-SOP的作用途径.方法:用异硫氰酸胍-酚-氯仿法从成年大鼠脑中提取总RNA,以寡聚脱氧胸苷酸纤维素亲和层析法分离出mRNA并注射入非洲爪蟾卵母细胞使表达,以全细胞双电极电压钳位法灌流此卵母细胞.结果:100 μM KA(kainate)(离子型)产生一主峰电流后缓慢下行,成为一稳定电流平台,最终脱敏,脱敏时间平均为37.57 min.2 μM QA(quisqualate)(代谢Ⅰ型)产生一峰值电流后转为一持续性钙振荡或直接出现钙振荡,振荡维持时间为(6.72±1.33)min,脱敏时间均随激动剂浓度的增加而缩短.0.8 mM L-SOP(L-phosphoserine)(代谢Ⅲ型)灌流产生规律性电流振荡,振荡时间为(20.17±8.47)min.此振荡电流可被代谢Ⅰ型受体拮抗剂L-AP3所拮抗.结论:离子型、代谢Ⅰ型及代谢Ⅲ型受体均产生各自特征电流模型;L-SOP不仅是Ⅲ型受体的激动剂,而且是Ⅰ型受体的弱的激动剂,即细胞振荡电流是L-SOP通过Ⅰ型受体的作用途径而产生.     

The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration

RATIONALE: Substances acting as agonists of group II mGlu receptors with joint group I mGlu receptor antagonist effects, or group II mGlu receptors agonists, were shown to induce antianxiety-like effect in rats after intrahippocampal administration. OBJECTIVE: The present study was undertaken to establish whether a more selective group I, II, III mGlu receptors agonists/antagonists induce anxiolytic-like effects after injection to the hippocampus. METHODS: (S)-4-Carboxyphenylglycine [(S)-4CPG] and 7-(hydroxyimino)cyclopropan[b]chromen-1alpha-carboxylic ethyl ester (CPCCOEt), selective antagonists at group I mGlu receptors, or (+)1S, 2S, 5R, 6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), two selective agonists of group II mGlu receptors, as well as (1S, 2S, 4S, 5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), an agonist at all three groups of mGlu receptors and L-serine-O-phosphate (L-SOP), an agonist at group III mGlu receptors, were used. All compounds were administered into the CA1 region of the dorsal hippocampus. The conflict drinking Vogel test in rats was used to estimate the anxiolytic-like effects of all the compounds. RESULTS: After intrahippocampal administration, both selective group I mGlu receptors antagonists (S)-4CPG and CPCCOEt, as well as the selective agonists of group II mGlu receptors LY 354740 and L-CCG-I, and an agonist of group III mGlu receptors, L-SOP, induced anticonflict effects. CONCLUSION: Selective antagonists of group I mGlu receptors and agonists of group II and group III mGlu receptors exhibit anxiolytic-like activity in the conflict drinking test. It seems that the hippocampus may be one of the brain structures involved in the anticonflict effect of mGlu receptor agonists/antagonists.     

New perspectives in glutamate and anxiety

Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue.A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies.Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits.The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions.