GABAA receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress:: Possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders
GABAA receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress:: Possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders
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DOI：
10.1080/10253890701200997
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发表时间：
2007-01-01
影响因子：
2.3
通讯作者：
Pinna, Graziano
中科院分区：
文献类型：
--
作者：
Matsumoto, Kinzo;Puia, Giulia;Pinna, Graziano
实验室动物长期的社会隔离会导致应激，这会诱发各种行为异常，包括攻击性增加、焦虑相关行为、认知缺陷和过度运动。这些疾病中的许多与精神疾病中发现的症状相似，例如抑郁症，焦虑症，经前烦躁和创伤后应激障碍（PTSD）。最近的研究表明，社会隔离超过4周的雄性小鼠表现出：（a）GABA（A）受体（GABA（A）- R）对GABA（A）-R的GABA模拟药物给药的反应性降低;（B）3 α，5 α-四氢孕酮的生物合成下调（3 α，5 α-THP）（别孕烯醇酮：ALLO），一种神经甾体，对GABA对GABA（A）-R的作用具有强效正变构调节作用;和（c）GABA（A）-R亚单位表达的改变（即α 1/α 2和γ 2亚单位减少，α 4和α 5亚单位增加）。选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀（FLX）及其同类物去甲氟西汀（Nor-FLX），当以nmol/kg剂量全身给药时，使脑ALLO含量降低和GABA（A）-R对GABA模拟药物（即戊巴比妥）的反应性降低正常化，并且还以立体特异性方式减弱社交隔离小鼠的攻击行为。虽然这些化合物抑制离体血清素再摄取到脑组织中，但它们的SSRI活性需要高μ mol/kg剂量范围，并且不是立体特异性的。这些研究表明，在社会隔离的小鼠中，GABA（A）-R信号转导的异常归因于ALLO产生的下调和异五聚体GABA（A）-R亚基组装组成的转换。因此，ALLO生物合成的正常化可能是开发有效治疗与神经类固醇生物合成下调相关的精神疾病的药物的新靶点。
Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders ( PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)- R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and(c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha 1/alpha 2 and gamma 2 subunits and an increase of alpha 4 and alpha 5 subunits).The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high mu mol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentamericGABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.