Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects
Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects
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DOI：
10.1093/ijnp/pyx003
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发表时间：
2017-06-01
影响因子：
4.8
通讯作者：
Lodge, Daniel J.
中科院分区：
文献类型：
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作者：
Carreno, Flavia R.;Collins, Gregory T.;Lodge, Daniel J.
背景资料：以类似于氯胺酮引起的方式选择性增强海马活动可能比氯胺酮具有治疗优势，氯胺酮具有拟精神病和强化作用，可能是由于海马外部的作用（即，脱靶效应）。在这里，我们评估了对含有α 5亚基的γ氨基丁酸A亚型受体L-655，708的负变构调节剂的抗抑郁样反应，因为这些受体在海马中的表达程度比其他脑区大得多。全身给予L-655，708在强迫游泳试验中产生了与氯胺酮相当的持续抗抑郁样作用，并被利多卡因的海马失活所阻断。然而，与氯胺酮，L-655，708并没有影响前脉冲抑制惊吓，也没有保持响应训练的大鼠自我管理静脉注射ketamine.Conclusion：两者合计，这些研究结果表明，激活L-655，708的海马产生抗抑郁样作用的情况下，任何拟精神病或滥用相关的影响。
Background: Selective augmentation of hippocampal activity in ways similar to that caused by ketamine may have therapeutic advantages over ketamine, which has psychotomimetic and reinforcing effects likely due to effects outside the hippocampus (i.e., off-target effects).Methods: Here we evaluated the antidepressant-like response to a negative allosteric modulator of alpha 5 subunit-containing gamma aminobutyric acid subtype A receptors, L-655,708, as these receptors are expressed to a much greater extent in the hippocampus than in other brain areas.Results: Systemic administration of L-655,708 produced a sustained antidepressant-like effect in the forced swim test that was comparable with that of ketamine and was blocked by hippocampal inactivation with lidocaine. However, in contrast to ketamine, L-655,708 did not affect prepulse inhibition of startle, nor did it maintain responding in rats trained to self-administer i.v. ketamine.Conclusion: Taken together, these findings suggest that activation of the hippocampus by L-655,708 produces an antidepressant-like effect in the absence of any psychotomimetic or abuse-related effects.