Allen Brain Atlases 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. Cerebellum and neocortex[ edit ] The role of the CB1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the cerebellum and neocortex , two regions associated with the coordination and initiation of movement. 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, in effect exciting the postsynaptic cell. This forms a feedback loop between the positive and negative metabotropic receptors , which can maintain a relatively similar homeostasis with any neuron connected through an electrical synapse. Alternatively, in some rare cases CB1 receptor activation may be coupled to Gs proteins, which stimulate adenylate cyclase. Effects vary based on the endocannabinoid molecule: Targeting this receptor with rimonabant has been found to prevent the THC-induced enhancement of DA release in the nucleus accumbens shell from food, suggesting that these receptors may be involved in determining the hedonic value of food.
Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids , whereas an enhancement of movement may occur upon moderate dosages. TM has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement. Another report, however, suggests that inhibition of intestinal motility may also have a CB2 -mediated component. In females , it is present in the ovaries , oviducts myometrium , decidua , and placenta. This is the genesis of its appetite-stimulating effects, colloquially called "the munchies. Cerebellum and neocortex[ edit ] The role of the CB1 receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the cerebellum and neocortex , two regions associated with the coordination and initiation of movement. It has also been implicated in the proper development of the embryo. This finding is consistent with the localization of CB1 receptors to the terminals of central and peripheral neurons, and the established mediation of both excitatory and inhibitory neurotransmitters acetylcholine , noradrenaline , dopamine , 5-HT , GABA , glutamate , D-aspartate , and cholecystokinin. This inhibition grows more pronounced when considered with the effect of activated CB1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. Basal ganglia[ edit ] CB1 receptors are expressed throughout the basal ganglia and have well-established effects on movement in rodents. Targeting this receptor with rimonabant has been found to prevent the THC-induced enhancement of DA release in the nucleus accumbens shell from food, suggesting that these receptors may be involved in determining the hedonic value of food. Upon activation, CB1 receptor exhibits its effects mainly through activation of Gi , which decreases intracellular cAMP concentration by inhibiting its production enzyme , adenylate cyclase , and increases mitogen-activated protein kinase MAP kinase concentration. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release. Signals on this track are also transmitted to the periaqueductal gray PAG of the midbrain. CB1 activation has been shown to effect specific kinematic variables in rodents, such as the rate of applied force during lever pressing,  and the amplitude but not timing of whisker movements. These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. Endocannabinoids released by a depolarized neuron bind to CB1 receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. As in the hippocampus , these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Through an opposing mechanism of action A2A elevates cAMP , together, they may serve to regulate cardiac blood supply, and thus output. The expression of these receptors is believed to modulate neurotransmitter release in a manner that prevents the development of excessive neuronal activity, reducing pain and other inflammatory symptoms. These receptors are densely located in cornu ammonis pyramidal cells, which are known to release glutamate. Effects vary based on the endocannabinoid molecule: These effects were eliminated by the application of the CB1 antagonist AM , illustrating that this receptor is essential for modulating the function of the stress response. In a rodent neuropathic pain model, increased expression of these receptors was seen in thalamic neurons, the spinal cord, and dorsal root ganglion. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception.
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