Will therapeutic dosing of fatty acid amino hydrolase inhibitors disrupt neuronal

描述（由申请人提供）：这是一份响应PAR-08-216“发育药理学”的R21申请。减缓内源性大麻素anandamide降解的抑制剂在治疗焦虑、抑郁和疼痛方面显示出巨大的希望，并且后两种适应症正在临床试验中。这些抑制剂通过阻断脂肪酸酰胺水解酶（FAAH）的水解，导致主要通过CB1大麻素受体增强内源性大麻素信号传导，从而增加大麻素水平。FAAH抑制剂的急性副作用描述良好且相对温和。然而，FAAH抑制剂正在开发用于慢性使用，这些药物的长期影响，特别是在大脑发育过程中对大脑的影响，研究很少，也没有很好地理解。内源性大麻素如anandamide在整个身体的许多生理过程中起着关键作用。其中一个过程是神经发育，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的遗传或药理破坏会改变中枢神经系统的发育。拟议的研究将使用小鼠和多学科方法来确定治疗活性剂量的FAAH抑制剂是否会提高胚胎脑内anandamide和相关n -酰基酰胺的水平，足以损害神经发育和后来的中枢神经系统功能（行为和神经元兴奋性），通过解决两个特定目标：治疗剂量的FAAH抑制剂会抑制胚胎脑FAAH活性导致神经发育异常吗？我们将使用质谱法来确定FAAH抑制剂的治疗剂量是否会增加发育中的大脑中的anandamide和相关的n -酰基酰胺。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。大麻素受体在这些过程中的参与将使用药理学或基因敲除方法进行评估。目标2。围产期服用FAAH抑制剂是否会导致成年期行为和突触功能/可塑性的持续损害？小鼠将在整个围产期使用第一个特定目标中确定的FAAH抑制剂治疗。这些老鼠将在成年后以特定性别的方式接受焦虑、药物偏好、空间学习和恐惧条件反射的行为测试。此外，我们将检查突触可塑性和兴奋/抑制平衡在成年期。通过完成这两个目标，我们将深入了解FAAH阻断对神经发育的影响，并将为妊娠期间FAAH抑制的潜在后果提供有价值的数据。

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.