Will therapeutic dosing of fatty acid amino hydrolase inhibitors disrupt neuronal

描述（由申请人提供）：这是响应 PAR-08-216“发育药理学”的 R21 申请。 Inhibitors that slow the degradation of the endocannabinoid anandamide show great promise for treating anxiety, depression, and pain, and are in clinical trials for the latter two indications. These inhibitors increase anandamide levels by blocking its hydrolysis by fatty acid amide hydrolase (FAAH) leading to enhanced endocannabinoid signaling, primarily through CB1 cannabinoid receptors. FAAH 抑制剂的急性副作用很明显且相对轻微。 However, FAAH inhibitors are being developed for chronic use and the long-term effects of these drugs, particularly on the brain as it develops, are poorly studied and not well understood.内源性大麻素（例如 anandamide）在全身的许多生理过程中发挥着关键作用。这些过程之一是神经发育，其中内源性大麻素调节神经发生、神经元迁移和轴突寻路。神经发育过程中内源性大麻素信号传导的遗传或药理学破坏会改变中枢神经系统的发育。 The proposed studies will use mice and a multidisciplinary approach to determine if therapeutically active doses of FAAH inhibitors raise embryonic brain levels of anandamide and related N-acyl amides to levels sufficient to impair neurodevelopment and later CNS function (behavior and neuronal excitability) by addressing two specific aims: Aim 1. Will therapeutic dosing of FAAH inhibitors suppress embryonic brain FAAH activity leading to abnormal neurodevelopment? We will use mass spectrometry to determine if therapeutic doses of FAAH inhibitors increase anandamide and related N-acyl amides in developing brain.然后我们将确定这些 FAAH 抑制剂是否影响神经发生、神经元迁移或轴突寻路。将使用药理学或敲除方法评估大麻素受体在这些过程中的参与。 Aim 2. Will therapeutic dosing of FAAH inhibitors during the perinatal period lead to sustained impairment of behavior and synaptic function/plasticity during adulthood?小鼠将在整个围产期接受第一个具体目标中确定的 FAAH 抑制剂的治疗。 These mice will then undergo behavioral testing as adults in a gender-specific fashion for anxiety, drug preference, spatial learning, and fear conditioning.此外，我们将检查成年期间的突触可塑性和兴奋/抑制平衡。 By completing these two aims we will gain insight into the neurodevelopmental effects of FAAH blockade and will be provided with valuable data on the potential consequences of FAAH inhibition during pregnancy. PUBLIC HEALTH RELEVANCE: Inhibitors of the breakdown of the endogenous cannabinoid, anandamide, are undergoing clinical trials for pain and depression. We have found that perturbation of endocannabinoid signaling, including inhibition of anandamide breakdown, leads to derangements in neurodevelopment.在拟议的工作中，我们将确定治疗剂量的 anandamide 降解抑制剂是否会对神经发育产生不利影响。

DESCRIPTION (provided by applicant): This is an R21 application in response to PAR-08-216, "Developmental Pharmacology". Inhibitors that slow the degradation of the endocannabinoid anandamide show great promise for treating anxiety, depression, and pain, and are in clinical trials for the latter two indications. These inhibitors increase anandamide levels by blocking its hydrolysis by fatty acid amide hydrolase (FAAH) leading to enhanced endocannabinoid signaling, primarily through CB1 cannabinoid receptors. The acute side effects of FAAH inhibitors are well delineated and relatively mild. However, FAAH inhibitors are being developed for chronic use and the long-term effects of these drugs, particularly on the brain as it develops, are poorly studied and not well understood. Endocannabinoids such as anandamide play key roles in numerous physiological processes throughout the body. One of these processes is neurodevelopment where endocannabinoids modulate neurogenesis, neuronal migration, and axonal pathfinding. Genetic or pharmacological disruption of endocannabinoid signaling during neurodevelopment alters CNS development. The proposed studies will use mice and a multidisciplinary approach to determine if therapeutically active doses of FAAH inhibitors raise embryonic brain levels of anandamide and related N-acyl amides to levels sufficient to impair neurodevelopment and later CNS function (behavior and neuronal excitability) by addressing two specific aims: Aim 1. Will therapeutic dosing of FAAH inhibitors suppress embryonic brain FAAH activity leading to abnormal neurodevelopment? We will use mass spectrometry to determine if therapeutic doses of FAAH inhibitors increase anandamide and related N-acyl amides in developing brain. We will then determine if these FAAH inhibitors affect neurogenesis, neuronal migration, or axonal pathfinding. The involvement of cannabinoid receptors in these processes will be evaluated using pharmacological or knockout approaches. Aim 2. Will therapeutic dosing of FAAH inhibitors during the perinatal period lead to sustained impairment of behavior and synaptic function/plasticity during adulthood? Mice will be treated through the perinatal period with FAAH inhibitors identified in the first specific aim. These mice will then undergo behavioral testing as adults in a gender-specific fashion for anxiety, drug preference, spatial learning, and fear conditioning. In addition we will examine synaptic plasticity and excitation/inhibition balance during adulthood. By completing these two aims we will gain insight into the neurodevelopmental effects of FAAH blockade and will be provided with valuable data on the potential consequences of FAAH inhibition during pregnancy. PUBLIC HEALTH RELEVANCE: Inhibitors of the breakdown of the endogenous cannabinoid, anandamide, are undergoing clinical trials for pain and depression. We have found that perturbation of endocannabinoid signaling, including inhibition of anandamide breakdown, leads to derangements in neurodevelopment. In the proposed work we will determine if therapeutic doses of anandamide degradation inhibitors detrimentally affect neurodevelopment.