Background

Abnormal reward processing, typically anhedonia, is a hallmark of human depression and is accompanied by altered functional connectivity in reward circuits. Negative allosteric modulators of GABA_A (gamma-aminobutyric acid A) receptors (GABA-NAMs) have rapid antidepressant-like properties in rodents and exert few adverse effects, but molecular targets underlying their behavioral and synaptic effects remain undetermined. We hypothesized that GABA-NAMs act at the benzodiazepine site of GABA_A receptors containing α5 subunits to increase gamma oscillatory activity, strengthen synapses in reward circuits, and reverse anhedonia.

Methods

Anhedonia was induced by chronic stress in male mice and assayed by preferences for sucrose and female urine (n = 5–7 mice/group). Hippocampal slices were then prepared for electrophysiological recording (n = 1–6 slices/mouse, 4–6 mice/group). Electroencephalography power was quantified in response to GABA-NAM and ketamine administration (n = 7–9 mice/group).

Results

Chronic stress reduced sucrose and female urine preferences and hippocampal temporoammonic-CA1 synaptic strength. A peripheral injection of the GABA-NAM MRK-016 restored hedonic behavior and AMPA-to-NMDA ratios in wild-type mice. These actions were prevented by pretreatment with the benzodiazepine site antagonist flumazenil. MRK-016 administration increased gamma power over the prefrontal cortex in wild-type mice but not α5 knockout mice, whereas ketamine promoted gamma power in both genotypes. Hedonic behavior and AMPA-to-NMDA ratios were only restored by MRK-016 in stressed wild-type mice but not α5 knockout mice.

Conclusions

α5-Selective GABA-NAMs exert rapid anti-anhedonic actions and restore the strength of synapses in reward regions by acting at the benzodiazepine site of α5-containing GABA_A receptors. These results encourage human studies using GABA-NAMs to treat depression by providing readily translatable measures of target engagement.

中文翻译：

---

含有 α5 亚基的苯二氮卓位点的 γ-氨基丁酸 A 受体的负变构调节可逆转小鼠应激引起的快感缺失和突触功能减弱

背景

异常的奖励处理，通常是快感缺乏，是人类抑郁症的一个标志，并伴随着奖励回路功能连接的改变。_{GABA A}（γ-氨基丁酸 A）受体（GABA-NAM）的负变构调节剂在啮齿类动物中具有快速抗抑郁样特性，并且几乎没有副作用，但其行为和突触效应背后的分子靶标仍未确定。我们假设 GABA-NAM 作用于含有 α5 亚基的GABA _{A受体的苯二氮卓位点，以增加 γ 振荡活性，增强奖赏回路中的突触并逆转快感缺乏。}

方法

雄性小鼠的快感缺乏是由慢性应激引起的，并通过对蔗糖和雌性尿液的偏好进行测定（n  = 5-7只小鼠/组）。然后准备海马切片用于电生理记录（n  = 1-6 切片/小鼠，4-6 只小鼠/组）。对 GABA-NAM 和氯胺酮给药的脑电图功率进行量化（n  = 7-9 只小鼠/组）。

结果

慢性压力降低了蔗糖和女性尿液偏好以及海马颞氨-CA1 突触强度。外周注射 GABA-NAM MRK-016 可恢复野生型小鼠的享乐行为和 AMPA 与 NMDA 比率。通过使用苯二氮卓位点拮抗剂氟马西尼进行预处理可以防止这些作用。MRK-016 给药增加了野生型小鼠前额皮质的伽马功率，但不是 α5 基因敲除小鼠的伽马功率，而氯胺酮则提高了两种基因型的伽马功率。MRK-016 仅在应激的野生型小鼠中恢复享乐行为和 AMPA 与 NMDA 比率，但在 α5 敲除小鼠中则不然。

结论

_{α5-选择性 GABA-NAM 通过作用于含有 α5 的 GABA A}受体的苯二氮卓位点，发挥快速的抗快感缺乏作用并恢复奖励区域突触的强度。这些结果鼓励人类研究使用 GABA-NAM 通过提供易于翻译的目标参与度测量来治疗抑郁症。