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1.
Mol Pharmacol ; 78(6): 996-1003, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20855465

RESUMO

Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.


Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Monoacilglicerol Lipases/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Animais , Ativação Enzimática/genética , Ativação Enzimática/fisiologia , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monoacilglicerol Lipases/deficiência , Monoacilglicerol Lipases/fisiologia , Medição da Dor/métodos
2.
J Neurosci ; 30(6): 2017-24, 2010 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-20147530

RESUMO

Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.


Assuntos
Encéfalo/metabolismo , Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Lipase Lipoproteica/genética , Animais , Ácidos Araquidônicos/metabolismo , Encéfalo/citologia , Glicerídeos/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Knockout , Neurogênese , Plasticidade Neuronal , Transdução de Sinais , Medula Espinal/metabolismo , Sinapses/fisiologia
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