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).
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 (Hutchison et al., 2008).
In a rat study it was found that the therapeutic effect of amphetamins actually requires CB1 activation (Kleijn et al., 2012)
In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).
Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).
CB1 receptors may be upregulated in an attempt to compensate for reduced endocannabinoid signaling. In line with this, mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with Anorexia and bulimia (Monteleone et al., 2009)
One study in healthy humans linked CB1 polymorphisms (small variations in a gene that are not directly linked to any particular deficit) to variations in the time people spent looking at happy faces (Chakrabarti and Baron-Cohen, 2011).
Interestingly, in another genetic mouse model of mental retardation and Autism (FMR1 knockout), blockade of CB1 normalized cognitive defects (Busquets-Garcia et al., 2013), suggesting CB1 may be a therapeutic target for Autism treatment.
Leukemia cells express functional CB1 and CB2 receptors (Moaddel et al., 2011). Also, other CB1/2 agonists showed Leukemia cell growth and proliferation inhibition (Gallotta et al., 2010; Yrjölä et al., 2015).
CB1 receptors may be upregulated in an attempt to compensate for reduced endocannabinoid signaling. In line with this, mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with Anorexia and bulimia (Monteleone et al., 2009).
Functional Gastro-Intestinal Disorders
Polymorphisms (small, single nucleotide mutations) in the CB1 gene/receptor are linked to the susceptibility to develop Crohn’s Disease, suggesting the involvement of the endocannabinoid system in Crohn’s Disease (Storr et al., 2010). cannabinoid-mediated reduction in gastro-intestinal motility appears to be mediated by CB1 but not CB2 (Aviello et al., 2008). CB1 and TRPV1 signaling are both required for the development of stress-induced visceral hyperalgesia and TRPV4 and TRPA1 may also be involved (Lin et al., 2013).
Another rat study found that endocannabinoid PEA and CB1 were upregulated, PPARα was downregulated and CB2 was unchanged upon induction of Cystitis (Pessina et al., 2014). PEA attenuated pain and bladder voiding. This effect was blocked by CB1 and PPARα antagonists.
CBG can activate α2 receptors and block CB1 and 5-HT1A receptors (Cascio et al., 2010), suggesting CBG does have therapeutic potential in the treatment of Depression. Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and Depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010)
PEA enhances AEA activity at CB1, CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1, CB2 or PPARα-dependent way (Petrosino et al., 2010). In mice CB1 and CB2 suppressed inflammation in allergic contact dermatitis (Karsak et al., 2007).
In rats, THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011). Similarly, CB1 activation decreases synchrony in cortical neurons (Sales-Carbonell et al., 2013). In mice, stimulating CB1 receptors (ACEA) or blocking TRPV1 receptors (capsazepine) protected against PTZ-induced seizures (Naderi et al., 2015). In rats, the synthetic CB1 agonist WIN 55-212-2 was protective against the development of Epilepsy when administered after an episode of status epilepticus (induced by pilocarpine)(Di Maio et al., 2014).
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