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.
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.
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