Selective negative allosteric modulators of alpha 5-GABAA receptors: novel psychotherapeutic drugs

严重抑郁障碍(MDD)和创伤后应激障碍(PTSD)高度并存，两者都 暴露在压力源下是他们发展的一个促成因素。他们在治疗方面有相似之处 选择性5-羟色胺再摄取抑制剂(SSRIs)是治疗这两种疾病最常见的药物治疗，甚至 尽管它们的功效并不大。对这些疾病的更好治疗存在严重的未得到满足的需求。The Now 重复发现NMDA受体拮抗剂氯胺酮对患者既快速又持久有效 随着治疗的进行，耐药抑郁症(TRD)产生了巨大的影响。它也可能对患者产生快速疗效。 患有慢性创伤后应激障碍。由于氯胺酮的不良反应特征，它将有助于识别模仿的药物 氯胺酮的有益的临床效果，而不产生其不良反应。我们最近在啮齿动物身上展示了， 腹侧海马区(VHipp)是抗抑郁药(AD)样氯胺酮反应的关键靶点。 相比之下，氯胺酮对非海马区通路的直接影响可能与其某些不良反应有关 效果。因此，我们开始研究针对HIPP的药物的效果，因为 它们作用的受体亚型在那里的定位。γ-氨基丁酸的α5-亚基 酸性受体A亚型(GABAA)具有较好的海马区定位和选择性负变构 α5-GABA受体的调节剂(NAM)已经开发出来。它们对谷氨酸能输出的影响 预计海马区的神经元将与氯胺酮相似。我们最近报道了一起 这种名为L-655,708的药物复制了氯胺酮持续的AD样作用，但没有增强-， 类似精神分裂--也不会导致焦虑--的效果。 为了扩展这些观察，我们将检查L-655,708对被认为是 模仿符合MDD或PTSD的症状。压力程序将是给药 连续两天给予大鼠不可避免的休克(IS)。对照组大鼠将接受可逃避的休克。压力- 将使用以下参数测量诱发的行为缺陷：1)强迫游泳试验；2)电击探头 防御性掩埋；3)女性尿液嗅觉试验(FUST)；4)注意定势转移试验(AST)。这四个人 程序评估在这些障碍中出现的特定行为缺陷，例如快感缺乏或 AST用于认知障碍。当给予L-655,708对这些行为的影响时，将评估其对这些行为的影响 在ES或IS之前(即，预防)或在ES或IS之后(即，治疗)。化学发生(DREADD)方法将 用于评估来自vHipp-内侧前额叶皮质(MPFC)的通路是否激活，以及来自 VHipp伏核(NAC)直接或通过其向mPFC的投射是 L-655、708对FST和FUST的影响。我们最重要的假设是 选择性α-5NAM将预防和/或克服由以下原因引起的各种持续性行为缺陷 不可避免的震惊(IS)。此外，HIPP将是L-655,708及其激活mPFC的初始目标 和/或NAC将参与其产生的各种行为影响。

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid, with both having exposure to stressors a contributing factor to their development. They share similarities in treatment with selective serotonin reuptake inhibitors (SSRIs) being the most common pharmacological treatment for both, even though their efficacy is modest. There is a serious unmet need for better treatments for these disorders. The now replicated finding that the NMDA receptor antagonist ketamine has both rapid and sustained efficacy in patients with treatment resistant depression (TRD) has had tremendous impact. It may also have rapid efficacy in patients with chronic PTSD. Because of ketamine's adverse effect profile, it would be useful to identify drugs that mimic ketamine's beneficial clinical effects without producing its adverse effects. We recently demonstrated, in rodents, that the ventral hippocampus (vHipp) is a critical target for the antidepressant (AD)-like response to ketamine. By contrast, direct effects of ketamine on non-hippocampal pathways are likely involved in some of its adverse effects. Consequently, we have begun to study effects of drugs targeting the Hipp because of the distinct localization there of the subtypes of receptors on which they act. The α5-subunit of the Gamma Aminobutyric Acid receptor, subtype A (GABAA) has a preferential hippocampal localization and selective negative allosteric modulators (NAMs) of the α5-GABAA receptor have been developed. Their effect on glutamatergic output neurons in the hippocampus would be expected to be similar to that of ketamine. We recently reported that one such drug, L-655,708, replicated the sustained AD-like effect of ketamine but had neither reinforcing-, psychotomimetic- nor anxiogenic-like effects. To extend these observations, we will examine the effects of L-655,708 on stress-induced behaviors thought to mimic symptoms consistent with either MDD or PTSD. The stress procedure will be the administration of inescapable shock (IS) to rats on two consecutive days. Control rats will receive escapable shock (ES). Stress- induced behavioral deficits will be measured using the following parameters: 1) forced swim test; 2) shock probe defensive burying; 3) female urine sniffing test (FUST), and 4) the attentional set-shifting test (AST). These four procedures evaluate specific behavioral deficits seen in these disorders, e.g., the FUST for anhedonia or the AST for cognitive impairment. The effect of L-655,708 on these behaviors will be evaluated when it is given either prior to ES or IS (i.e., prophylaxis) or after ES or IS (i.e., treatment). A chemogenetic (DREADD) approach will be used to evaluate if activation of pathway from the vHipp –medial prefrontal cortex (mPFC) and a circuit from the vHipp – nucleus accumbens (NAc), either directly or via its projection to the mPFC are necessary for the effects of L-655,708 on the FST and FUST respectively. Our overriding hypotheses are that treatment with the selective α-5 NAMs will either prevent and/or overcome a variety of sustained behavioral deficits caused by inescapable shock (IS). Further, the Hipp will be the initial target for L-655,708 and its activation of the mPFC and/or the NAc will be involved in the various behavioral effects it produces.