Cancer, neurogenerative diseases, ischemic injuries, inflammation, pain, anxiety, nausea, and drug-withdrawal symptoms could possibly be treated by MAGL inhibitors, which showed potential therapeutic action (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013).
Biosynthesis of 2-AG was increased in the ventral tegmental area (VTA) after rats were exposed to nicotine. GABA signaling is reduced by 2-AG, leading to an increased VTA sensitivity to nicotine and increased sensitization of DA release in the nucleus accumbens. GABA signaling in the VTA was restored by DAGL suppression, suggesting that DAGL can be a good target when treating addictions (Buczynski et al., 2016).
Following the same line, DAGLα expression in rat nucleus accumbens and depolarization-induced suppression of inhibition were increased by morphine withdrawal. This suggests that 2-AG plays a role in mediating this process (Wang et al., 2016). Moreover, very similar results were found in a study that focused to test the effects of cocaine in orexin neurons (Tung et al., 2016).
CB1 is a member of the G protein-coupled receptor and can be found in the parts of the brain that mostly play a role in addictive behavior. It was shown that increased receptor binding and increased CB1 -mediated neuronal activation in the prefrontal cortex can be connected to at least one genetic variation/polymorphism in CB1 (Hutchison et al., 2008). Activation of the nucleus accumbens, ventromedial prefrontal cortex, orbitofrontal cortex, and ventral tegmental area as well as subjective appreciation of alcohol can be increased by alcohol exposure. Similar linkage to addiction risk showed that interaction between THC and Mu opioid receptor is weak, suggesting that Mu opioid can be considered as a cannabinoid receptor (Hutchison et al., 2008; Pertwee et al., 2010).
Post-mortem research proposes that though the expression is not affected, CB1 receptors have been shown to have hyperactivity in the caudate nucleus and hypoactive in the cerebellum of alcoholics (Erdozain et al., 2015).
Dopaminergic signaling in the nucleus accumbens can be blocked and alcohol craving and consumption can be reduced through blocking the reward signal with CB1 antagonists (reference within Hutchison et al., 2008).
In one study in rats, addictive behavior (cocaine-seeking) can be reduced via chronic stimulation of the endocannabinoid system (Anandamide). This proposes that the endocannabinoid system can be involved in inhibiting addiction (Chauvet et al., 2014).
Mice that drink more alcohol and eat more food have been shown to be genetically deficient for CB2. This proposes that CB2 could be a target to treat addiction (Pradier et al., 2015).