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

点击翻译按钮获取中文摘要

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.