MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, pain, Anxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013).
Nicotine exposure in rats increased 2-AG biosynthesis in the ventral tegmental area (VTA). 2-AG reduces GABA signaling, increasing VTA sensitivity to nicotine and increasing sensitization of DA release in the nucleus accumbens. Inhibition of DAGL restored GABA signaling in the VTA, making DAGL an interesting target to treat addictions (Buczynski et al., 2016). Following the same line, morphine withdrawal increased DAGLα expression in rat nucleus accumbens and increased depolarization-induced suppression of inhibition, suggesting that 2-AG mediates this process (Wang et al., 2016). Furthermore, a study testing the effects of cocaine in orexin neurons found very similar results (Tung et al., 2016).
CB1 is the most abundant G-protein coupled receptor in the parts of the brain that are most involved in addictive behavior, suggesting a link. At least one genetic variation/polymorphism in CB1 is linked to increased receptor binding and increased CB1-mediated neuronal activation in the prefrontal cortex (Hutchison et al., 2008). Exposure to alcohol increases activation of the nucleus accumbens, ventromedial prefrontal cortex, orbitofrontal cortex and ventral tegmental area and increases the subjective appreciation of alcohol. Similar linkage to Addiction risk has been reported for the Mu opioid receptor which weakly binds THC and can thus be considered a Cannabinoid receptor(Hutchison et al., 2008; Pertwee et al., 2010).
Post-mortem research suggests that although expression is unaffected, CB1 receptors are hyperactive in the caudate nucleus and hypoactive in the cerebellum of alcoholics (Erdozain et al., 2015).
Blocking the reward signal with CB1 antagonists blocks dopaminergic signaling in the nucleus accumbens and decreases alcohol craving and consumption (reference within: Hutchison et al., 2008).
In one study in rats, chronic stimulation of the endocannabinoid system (Anandamide) reduced addictive behavior (cocaine seeking), suggesting a role for the endocannabinoid system in suppressing Addiction (Chauvet et al., 2014).
Mice genetically deficient for CB2, drink more alcohol (and eat more food), suggesting CB2 could be a target for the treatment of Addiction (Pradier et al., 2015).
Buczynski, M. W., Herman, M. A., Hsu, K.-L., Natividad, L. A., Irimia, C., Polis, I. Y., … Parsons, L. H. (2016). Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proceedings of the National Academy of Sciences of the United States of America, 113(4), 1086-1091. https://doi.org/10.1073/pnas.1522672113
Chauvet, C., Nicolas, C., Thiriet, N., Lardeux, M.V., Duranti, A., and Solinas, M. (2014). Chronic Stimulation of the Tone of Endogenous Anandamide Reduces Cue- and Stress-Induced Relapse in Rats. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP.
Chen, R., Zhang, J., Wu, Y., Wang, D., Feng, G., Tang, Y.-P., … Chen, C. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports, 2(5), 1329-1339. https://doi.org/10.1016/j.celrep.2012.09.030
Erdozain, A.M., Rubio, M., Meana, J.J., Fernández-Ruiz, J., and Callado, L.F. (2015). Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects. J. Psychopharmacol. Oxf. Engl.
Hutchison, K.E., Haughey, H., Niculescu, M., Schacht, J., Kaiser, A., Stitzel, J., Horton, W.J., and Filbey, F. (2008). The incentive salience of alcohol: translating the effects of genetic variant in CNR1. Arch. Gen. Psychiatry 65, 841–850.
Kohnz, R., & Nomura, D. K. (2014). Chemical Approaches to Therapeutically Target the Metabolism and Signaling of the endocannabinoid 2-AG and Eicosanoids. Chemical Society reviews, 43(19), 6859-6869. https://doi.org/10.1039/c4cs00047a
Mulvihill, M. M., & Nomura, D. K. (2013). Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life sciences, 92(8-9), 492-497. https://doi.org/10.1016/j.lfs.2012.10.025
Pertwee, R.G., Howlett, A.C., Abood, M.E., Alexander, S.P.H., Di Marzo, V., Elphick, M.R., Greasley, P.J., Hansen, H.S., Kunos, G., Mackie, K., et al. (2010). International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CBΌ and CB. Pharmacol. Rev. 62, 588–631.
Pradier, B., Erxlebe, E., Markert, A., and Rácz, I. (2015). Interaction of Cannabinoid receptor 2 and social environment modulates chronic alcohol consumption. Behav. Brain Res. 287, 163–171.
Tung, L.-W., Lu, G.-L., Lee, Y.-H., Yu, L., Lee, H.-J., Leishman, E., … Chiou, L.-C. (2016). Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nature Communications, 7, 12199. https://doi.org/10.1038/ncomms12199
Wang, X.-Q., Ma, J., Cui, W., Yuan, W.-X., Zhu, G., Yang, Q., … Gao, G.-D. (2016). The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-α expression following short-term morphine withdrawal. British Journal of Pharmacology, 173(7), 1143-1153. https://doi.org/10.1111/bph.12969