MD - PSYCHIATRY
DNB - PSYCHIATRY
FIPR - NIMHANS
PAPER I
Q 3 DESCRIBE IN DETAIL THE ENDOCABINNOID SYSTEM ?
A 3 DEFINITION
1 The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the mammalian brain and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors.
2 Known as “the body’s own cannabinoid system”, the ECS is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory, and in mediating the psychoactive effects of cannabis.
3 The ECS is also involved in voluntary exercise and may be related to the evolution of the runner’s high in human beings and related aspects of motivation or reward for locomotor activity in other animals.
HISTORY
Two primary endocannabinoid receptors have been identified - CB1, first cloned in 1990; and CB2, cloned in 1993.
A ) CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), Anandamide, as well as its mimetic phytocannabinoid, THC.
B ) One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD.
C ) 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management.
COMPONENTS
1 The endogenous arachidonate-based lipids,anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG) - these are known as “endocannabinoids” and are physiological ligands for the cannabinoid receptors.
2 Endocannabinoids are alleicosanoids
3 The enzymes that synthesize and degrade the endocannabinoids, such as fatty acid amide hydrolase or monoacylglycerol lipase.
4 The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems.
5 The neurons, neural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized from the endocannabinoid system.
6 The endocannabinoid system has been studied using genetic and pharmacological methods.
A ) These studies have revealed that cannabinoids act as neuromodulators for a variety of processes, including motor learning, appetite and pain sensation among other cognitive and physical processes.
B ) The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system, which mediates many of the same functions, both physical and cognitive.
C ) Moreover, CB1 is colocalized on orexin projection neurons in the lateral hypothalamusand many output structures of the orexin system, where the CB1 and orexin receptor 1(OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer
7 Cannabinoid binding sites exist throughout the central and peripheral nervous systems.
A ) The two most relevant receptors for cannabinoids are the CB1and CB2 receptors, which are expressed predominantly in the brain and immune system respectively.
B ) Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression.
1 - 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.
2 In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans ( vv imp )
3 A recent analysis of cannabinoid binding in CB1 and CB2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.
A ) Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response
B ) In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55 (a regulator ofneuroimmune function), and GPR119.
C ) CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla vv imp
MECHANISM OF ACTION - ( synthesis , release and degradation )
1 During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron.
2 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.
3 Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.
A ) Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized.
B ) This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.
4 Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase.
A ) This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE).
B ) Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.
C ) This process is mediated by bile acids.
D ) 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
E ) Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation.
F ) Vv imp - Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine ormonoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol.
1 - arachidonic acid is a substrate for leukotriene and prostaglandinsynthesis
2 - Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.
E ) A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates.
1 - 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.
F ) Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane.
G ) Cannabinoids reduce calcium influx by blocking the activity of voltage-dependent N-, P/Q-and L-type calcium channels
H ) In addition to acting on calcium channels, activation of Gi/o andGs, the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulatepotassium channel activity.
I ) Recent studies have found that CB1 activation specifically facilitates potassium ion flux through GIRKs, a family ofpotassium channels.
J ) Immunohistochemistry experiments demonstrated that CB1 is co-localized with GIRK and Kv1.potassium channels, suggesting that these two may interact in physiological contexts
K ) In the central nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input.
1 - This mechanism, known as presynaptic inhibition, occurs when a postsynaptic neuron releases endocannabinoids in retrograde transmission, which then bind to cannabinoid receptors on the presynaptic terminal.
2 - CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron.
3 - CB1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e. through Gi/o-mediated inhibition ofadenylyl cyclase and protein kinase A.
4 - Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons
FUNCTIONS
1 - Memory -
A ) has a role in potentiating short term into long term memory
2 - Hippocampal neurogenesis -
A ) In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.
3 - Induction of synaptic depression - causes depression -
A ) 2-AG was found to act on presynaptic CB1 receptors to mediate retrogradeshort-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggeredautocrine signalling onto postsynapic TRPV1receptors that induced long-term depression (LTD).
B ) Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors - These findings provide the brain a direct mechanism to selectively inhibit neuronal excitability over variable time scales.
C ) By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs.
4 - Apetite regulation -
A ) THC acts via CB1 receptors in the hypothalamic nuclei to directly increase appetite.
B ) hypothalamic neurons tonically produce endocannabinoids that work to tightly regulatehunger.
The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood
C ) endocannabinoids affect taste perception in taste cells
1 - In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response.
2 - cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior
5 - In maintaining energy balance and homeostasis -
A ) While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful.
B ) So , The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis(HPA axis) to repeated exposure to restraint stress - prevents hyperexcretion of stress hormones like cortisol
6 - For controlling stress response
7 - For exploration , social behaviour and anxiety -
A ) Prolonged, systemic exposure to cannabinoids has often been associated with anti-social effects -
Glutaninergic and gabaergic - has anxiolytic effects but in appropriate amount not excessively
8 - For appropriate immune function -
A ) endocannabinoid functions as both neuromodulators and immunomodulators in the immune system.
B ) It serves as an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.
C ) Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophages, neutrophils, and BM cells
1 - These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthyIgM levels.
9 - In multiple sclerosis -
A ) Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain.
B ) CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein.
1 - vv imp Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function
2 2-AG stimulates proliferation of a microglial cell line by a CB2receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis
10 - In maintaining ANS -
A ) CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs.
B ) Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves.
C ) endocannabinoid regulates the intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.
11 - For analgesia -
A ) 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.
B ) 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.
C ) The endocannabinoid most researched in pain is palmitoylethanolamide.
1 - Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GPR55 receptor.
2 - Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications and found to be safe and effective.
12 - For thermoregulation -
A ) Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.
B ) TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM.
C ) Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation
13 - In sleep -
A ) Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects.
B ) Intercerebroventricular administration of anandamide has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.
C ) Administration of anandamide into thebasal forebrain has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.
D ) REM sleep deprivation in has been demonstrated to increase CB1 receptor expression in the central nervous system.
E ) Furthermore, anandamide levels possess a circadian rhythm