PDF(Pubmed)
Abstract：
The serotonin (5-hydroxytryptamine (5-HT))-mediated system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous studies showed that stress and drug exposure can modulate the dorsal raphe nucleus (DRN)-5-HT system via γ-aminobutyric acid (GABA)A receptors. Moreover, GABAA receptor-mediated inhibition of serotonergic DRN neurons is required for stress-induced reinstatement of opioid seeking.
To further test the role of GABAA receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABAA α1 subunit to manipulate GABAA receptors in either the DRN or the entire population of 5-HT neurons. The GABAA α1 subunit is a constituent of the most abundant GABAA subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons.
Our results showed that mice with DRN-specific knockout of α1-GABAA receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABAA receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety.
Our data suggest that GABAA receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.
To further test the role of GABAA receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABAA α1 subunit to manipulate GABAA receptors in either the DRN or the entire population of 5-HT neurons. The GABAA α1 subunit is a constituent of the most abundant GABAA subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons.
Our results showed that mice with DRN-specific knockout of α1-GABAA receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABAA receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety.
Our data suggest that GABAA receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.
摘要：
■5-羟色胺（5-羟色胺（5-HT））介导的系统在与压力相关的精神疾病和药物滥用中起着重要作用。我们先前的研究表明，应激和药物暴露可以通过γ-氨基丁酸（GABA）A受体调节背中缝核（DRN）-5-HT系统。此外，GABAA受体介导的5-羟色胺能DRN神经元的抑制是应激诱导的阿片样物质寻求的恢复所必需的。
■为了进一步测试5-HT系统中GABAA受体在应激和阿片类药物敏感行为中的作用，我们目前的研究产生了GABAAα1亚基有条件遗传缺失的小鼠，以操纵DRN或整个5-HT神经元群体中的GABAA受体。GABAAα1亚基是大脑中最丰富的GABAA亚型的组成部分，也是5-HTDRN神经元中表达最高的亚基。
■我们的结果表明，DRN特异性敲除α1-GABAA受体的小鼠在焦虑和抑郁样行为以及游泳应激诱导的恢复测试中表现出正常表型。吗啡条件的位置偏好。相比之下,具有5-HT神经元特异性敲除α1-GABAA受体的小鼠在基线时表现出抗焦虑表型，并且对吗啡戒断后引起的焦虑的敏感性增加。
■我们的数据表明，5-HT神经元上的GABAA受体有助于焦虑样行为以及这些行为对阿片类药物戒断的敏感性。
■为了进一步测试5-HT系统中GABAA受体在应激和阿片类药物敏感行为中的作用，我们目前的研究产生了GABAAα1亚基有条件遗传缺失的小鼠，以操纵DRN或整个5-HT神经元群体中的GABAA受体。GABAAα1亚基是大脑中最丰富的GABAA亚型的组成部分，也是5-HTDRN神经元中表达最高的亚基。
■我们的结果表明，DRN特异性敲除α1-GABAA受体的小鼠在焦虑和抑郁样行为以及游泳应激诱导的恢复测试中表现出正常表型。吗啡条件的位置偏好。相比之下,具有5-HT神经元特异性敲除α1-GABAA受体的小鼠在基线时表现出抗焦虑表型，并且对吗啡戒断后引起的焦虑的敏感性增加。
■我们的数据表明，5-HT神经元上的GABAA受体有助于焦虑样行为以及这些行为对阿片类药物戒断的敏感性。
