Comparative analysis of fatty acid amide hydrolase and CB1 cannabinoid receptor expression in the mouse brain: Evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling

Fatty acid amide hydrolase (FAAH) catalyses hydrolysis of the endocannabinoid arachiclonoylethanolamide (anandamide) in vitro and regulates anandamide levels in the brain. In the cerebellar cortex, hippocampus and neocortex of the rat brain, FAAH is located in the somata and dendrites of neurons that are postsynaptic to axon fibers expressing the CB1 cannabinoid receptor [Proc R Soc Lond B 265 (1998) 2081]. This complementary pattern of FAAH and CB1 expression provided the basis for a hypothesis that endocannabinoids may function as retrograde signaling molecules at synapses in the brain [Proc R Soc Lond B 265 (1998) 2081; Phil Trans R Soc Lond 356 (2001) 381] and subsequent experimental studies have confirmed this [Science 296 (2002) 678]. To assess more widely the functions of FAAH in the brain and the potential impact of FAAH activity on the spatiotemporal dynamics of endocannabinoid signaling in different regions of the brain, here we have employed immunocytochemistry to compare the distribution of FAAH and CB1 throughout the mouse brain, using FAAH(-/-) mice as negative controls to validate the specificity of FAAH-immunoreactivity observed in wild type animals. In many regions of the brain, a complementary pattern of FAAH and CB1 expression was observed, with FAAH-immunoreactive neuronal somata and dendrites surrounded by CB1-immunoreactive fibers. In these regions of the brain, FAAH may regulate postsynaptic formation of anandamide, thereby influencing the spatiotemporal dynamics of retrograde endocannabinoid signaling. However, in some regions of the brain such as the globus pallidus and substantia nigra pars reticulata, CB1 receptors are abundant but with little or no associated FAAH expression and in these brain regions the spatial impact and/or duration of endocannabinoid signaling may be less restricted than in regions enriched with FAAH. A more complex situation arises in several regions of the brain where both FAAH and CB, are expressed but in a non-complementary pattern, with FAAH located in neurons and/or oligodendrocytes that are proximal but not postsynaptic to CB1-expressing axon fibers. Here FAAH may nevertheless influence endocannabinoid signaling but more remotely. Finally, there are regions of the brain where FAAH-immunoreactive neurons and/or oligodendrocytes occur in the absence of CB1-immunoreactive fibers and here FAAH may be involved in regulation of signaling mediated by other endocannabinold receptors or by receptors for other fatty acid amide signaling molecules. In conclusion, by comparing the distribution of FAAH and CB1 in the mouse brain, we have provided a neuroanatomical framework for comparative analysis of the role of FAAH in regulation of the spatiotemporal dynamics of retrograde endocannabinoid signaling in different regions of the brain. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.