Endocannabinoid system
[9][10] The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.
For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement.
Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades.
[35][36] In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.
[38] While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system.
Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.
While there have been some papers that have linked concurrent stimulation of dopamine and CB1 receptors to an acute rise in cyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration[42] by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase (MAP kinase).
[43][44] Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs.
[44] The molecular mechanisms of the endocannabinoid system are primarily concerned with certain voltage-gated and ligand-gated channels, which can be directly affected by cannabinoids.
One study found that the high-dose treatment of rats with the synthetic cannabinoid HU-210 over several weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories, but did not investigate the effects on short-term or long-term memory.
[30] The study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated.
2-AG was found to act on presynaptic CB1 receptors to mediate retrograde STD following activation of L-type calcium channeles, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced LTD.[30] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales.
By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.
[60] For example, mice without leptin not only become massively obese but express abnormally high levels of hypothalamic endocannabinoids as a compensatory mechanism.
A related study examined the effect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution.
While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.
[59] The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport.
Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves.
Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.
[29] At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.
[29] As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuli-processing in the periphery and dorsal root ganglion.
Modulation of the endocannabinoid system by metabolism to N-arachidinoyl-phenolamine (AM404), an endogenous cannabinoid neurotransmitter, has been discovered to be one mechanism[71] for analgesia by acetaminophen (paracetamol).
[75] Administration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.
[78] The endocannabinoid system is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards.
[79][80] The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants,[81] and detection of arachidonic acid (AA) indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around 500 million years ago (Cambrian).
The two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in gymnosperms, lycophytes and few monilophytes, show AA is an evolutionarily conserved signalling molecule that acts in plants in response to stress similar to that in animal systems.
[85] Serinolamide A is a cannabinoid structurally related to endocannabinoids found in cyanobacteria such as Lyngbya majuscula and other species in the Oscillatoria family.
