Brain
CB1 receptors are expressed most densely in the central nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain. Endocannabinoids released by a depolarized neuron bind to CB1 receptors on either pre-synaptic glutamatergic or GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated inhibition, effectively exciting the postsynaptic cell.
In theory, the excitatory effects of reducing GABA release and inhibitory effects of reducing glutamate release should cancel each other out with no net effect postsynaptically; however, it is clear that cannabinoids do affect neuronal activity. This suggesting that their efficacy is based on the unequal expression of glutamatergic and GABAergic neurons, in a manner that varies in different regions of the brain. The decreased global activity results in less spontaneous action potentials in the absence of presynaptic activity. This creates less noise globally, attenuating both positive and negative feedback loops, which are created by a local dominance of either glutamate or GABA, respectively. This effect is because CB1 distribution is largely limited to the termini of neurons. As endocannabinoids are rapidly hydrolyzed by FAAH, they can only effectively agonize receptors immediately pre or post synaptically. This results in localized activity compared to the monoamine GPCRs. Exogenous agonists, however, significantly alter the natural function of this receptor, due to their relative metabolic persistence. The corresponding higher level of receptor activation results in an excessive level of receptor downregulation and thus dysfunction of the endocannabinoid system. Varying levels of CB1 expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei and other subcortical regions (e.g. the septal region), cerebellar cortex, and brainstem nuclei (e.g. the periaqueductal gray).
Read more about this topic: Cannabinoid Receptor Type 1, Expression
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