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

重度抑郁症（MDD）和创伤后应激障碍（PTSD）是高度共病的， 暴露于压力源是他们发展的一个促成因素。他们在治疗上与 选择性5-羟色胺再摄取抑制剂（SSRIs）是最常见的药物治疗， 尽管它们的功效是适度的。对于这些疾病的更好治疗存在严重的未满足的需求。当下 重复发现NMDA受体拮抗剂氯胺酮在患者中具有快速和持续的疗效， 难治性抑郁症（TRD）的治疗产生了巨大的影响。它也可能对患者有快速的疗效 慢性创伤后应激障碍由于氯胺酮的副作用，这将是有用的，以确定药物，模拟 氯胺酮的有益临床作用而不产生其不良作用。我们最近在啮齿类动物身上证明， 腹侧海马（vHipp）是氯胺酮抗抑郁（AD）样反应的关键靶点。 相比之下，氯胺酮对非海马通路的直接作用可能涉及其某些不良反应。 方面的影响.因此，我们已经开始研究靶向Hipp的药物的作用， 它们所作用的受体亚型的定位。γ-氨基丁酸的α 5亚基 酸受体A亚型（GABAA）具有优先的海马定位和选择性负变构， 已经开发了α 5-GABAA受体的NAM。它们对脑电输出的影响 海马体中的神经元预期与氯胺酮类似。我们最近报道说， 这种药物L-655，708复制了氯胺酮的持续AD样作用，但既没有增强作用， 拟精神病或焦虑样作用。 为了扩展这些观察，我们将研究L-655，708对应激诱导行为的影响， 模仿抑郁症或创伤后应激障碍的症状压力程序将是管理 不可避免的休克（IS）的大鼠在连续两天。对照组大鼠将接受逃避性休克（ES）。压力- 将使用以下参数测量诱导的行为缺陷：1）强迫游泳试验; 2）电击探针 防御性掩埋; 3）女性尿嗅试验（FUST）; 4）注意定势转移试验（AST）。这四 程序评估在这些疾病中观察到的特定行为缺陷，例如，快感缺乏的FUST或 AST用于认知障碍。L-655，708对这些行为的影响将在以下情况下进行评估： 在ES或IS之前（即，预防）或在ES或IS之后（即，治疗）。化学遗传学（DREADD）方法将 用于评估来自vHipp-内侧前额叶皮层（mPFC）的通路激活和来自 vHipp-延髓核（NAc），无论是直接还是通过其投射到mPFC，都是必要的， L-655、708对FST和FUST的影响。我们的主要假设是， 选择性α-5 NAMs将预防和/或克服由以下原因引起的各种持续性行为缺陷： 不可避免的休克（IS）。此外，Hipp将是L-655，708及其激活mPFC的初始靶点 和/或NAc将参与其产生的各种行为效应。

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.