Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors
Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors
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DOI：
10.1038/npp.2015.112
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发表时间：
2015-10-01
影响因子：
7.6
通讯作者：
Thompson, Scott M.
中科院分区：
文献类型：
--
作者：
Fischell, Jonathan;Van Dyke, Adam M.;Thompson, Scott M.
选择性血清素再摄取抑制剂（SSRI）是治疗抑郁症的主要药物，但 SSRI 只对一半患者有效，并且通常需要几周时间才能缓解症状。 NMDA 受体拮抗剂氯胺酮可发挥快速抗抑郁作用，但具有令人不安的副作用。我们假设 GABA(A) 受体的负变构调节剂会对大脑活动产生与氯胺酮类似的影响，但如果仅针对含有 α 5 亚基（富含于海马和前额皮质）的 GABA(A) 受体，则不会产生那么多副作用。在这里，我们表明，α 5 选择性负调节剂 L-655,708 在全身给药 24 小时内逆转了大鼠两种不同慢性应激范式产生的蔗糖偏好和社交互动测试中享乐行为的变化。另一种 α5 选择性负调节剂 MRK-016 也观察到了类似的效果。 L-655,708 对无应激动物的享乐或开放行为没有影响。在 24 小时内，L-655,708 注射还恢复了应激敏感颞氨-CA1 突触处病理性减弱的兴奋性突触传递强度（通过电生理学测量），并增加了 AMPA 受体 GluA1 亚基的水平（通过蛋白质印迹法测量）。我们认为，L-655,708 快速恢复兴奋性突触强度的能力可能是其快速恢复压力诱导的行为改变的能力的基础，这支持了皮质-中脑边缘奖励途径中多个兴奋性突触功能障碍在一定程度上导致抑郁症发生的证据。含有 α5 亚基的 GABAA 受体的负变构调节剂代表了一类有前途的新型速效且临床可行的抗抑郁化合物。
Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABA(A) receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABA(A) receptors containing alpha 5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the alpha 5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another alpha 5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of alpha 5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.