Endocannabinoids neurotransmitter

Let us consider a concrete example arachidonic acid, an unsaturated fatty acid that plays an important role in neurochemistry as a part of the endocannabinoid neurotransmitter anan-damide (see Chapter 5). Arachidonic acid is the polyunsaturated fatty acid containing 20 carbon atoms and 4 double bonds. To write its structure, we will start with a simple chain with 20 carbons. At one end we will put the -COOH group, and the terminal -CH3 group at the other end ... 

The elucidation of synaptic mechanisms involving endocannabinoids has revealed some surprises. Indeed, endocannabinoids are released in the extracellular space from postsynaptic neurons in response to a rise in intracellular Ca. Then, endocannabinoid neurotransmitters travel backward across synapses, and eventually stimulate CBl receptor on the presynaptic neuron. The main effect of endocannabinoids on presynaptic neurons is to decrease the release of either the inhibitory y-aminobutyric acid (GABA) or the excitatory glutamate neurotransmitters, resulting in a control of a broad range of physiological functions including food intake, fear,and anxiety. ... 

Our last example concerns anandamide, an endocannabinoid neurotransmitter derived from arachidonic acid (Fig. 5.10). 

Immediately after synthesis, endocannabinoids are released in the extracellular space, where they then act on the same or neighboring cells as autocrine or paracrine mediators (Di Marzo, 1999). Experimental evidence thus far indicates that anandamide and 2-AG, unlike other classical neurotransmitters, are not stored in vesicles. First, anandamide basal concentrations are extremely low (5-10 pmol/g), 100 to 10,000 times lower than those of classical neurotransmitters (Cadas, 1997). Second, stimulus-dependent anandamide release is linked with de novo NAPE and... 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

Anandamide is one of these endocannabinoids and a member of a new chemical class of neurotransmitters, which is not a monoamine, not an amino acid, and not... 

THE BRAIN S OWN MARIJUANA-LIKE NEUROTRANSMITTER The very high potency and structure of the cannabinoids contained within the marijuana plant enable them to cross the blood—brain barrier and bind to a receptor for the brain s very own endogenous cannabinoid neurotransmitter system. If this were not true, then the marijuana plant would be popular only for its use in making rope, paper, and cloth. The two currently identified neurotransmitters compounds (and there are probably more) in this system are anandamide, from the Sanskrit word amnia () meaning bliss, and 2-AG (2-arachidonoyl-glycerol). Unlike the other neurotransmitters that I ve discussed, these two endocannabinoids are not stored in synaptic vesicles. 

Rather, they are both produced within neurons and released to flow backward across the synapse to find their receptors, designated as CBi and CBz. There are probably more of these CB receptors for marijuana in the human brain than for any other known neurotransmitter. The great abundance of these receptors and their widespread location gives an indication of importance of the endocannabinoid system in the regulation of the brain s normal functioning. 

When marijuana is ingested or inhaled, THC binds to cannabinoid receptors throughout the brain and body, where it mimics the actions of internally produced neurotransmitters, such as the endocannabinoid known as anandamide. Anandamide is named after the Sanskrit word ananda, which means bliss. ... 

A fifth pathway, finally, is the well-established secretion of small membrane-permeable mediators by diffusion. This mechanism is used for the secretion of nitric oxide, endocannabinoids, and other important lipidic or gaseous neurotransmitters. The major point of regulation of release here is the synthesis of the respective compounds, not their actual secretion. 

Presynaptic G-protein coupled receptors for a large number of neurotransmitters, both autoreceptors and receptors for extrinsic signals, suppress Ca2+-channel gating in response to an action potential. This mechanism of action appears to be the dominant mechanism involved in short-term plasticity mediated by presynaptic receptors. A typical example is depolarization-induced suppression of inhibition (DSI), which is the short-term suppression of presynaptic GABA-release induced by the depolarization of the postsynaptic cell (Diana and Marty, 2004). DSI is caused when the postsynaptic depolarization causes the release of endocannabinoids from the postsynaptic cell, and the endocannabinoids then bind to presynaptic CB1 receptors whose activation suppresses presynaptic Ca2+-channels. Like many other forms of presynaptic suppression mediated by activation of presynaptic receptors, this effect is short-lasting (in the millisecond range). The precise mechanisms by which Ca2+-channels are suppressed appear to vary between receptors, but the outcome is always a very effective short-term decrease in synaptic signaling. 

Endocannabinoids are lipophilic biomolecules, which complicates our understanding of mechanisms of release of these substances. Most neurotransmitters are released from cells via vesicular mechanisms, and such a mechanism has even been suggested to underlie dopamine release from postsynaptic elements in ventral tegmental area (VTA) dopaminergic neurons (Beckstead et al. 2004). Endocannabinoids would not be packaged into the lumen of a vesicle like hydrophilic molecules. 

Cannabinoid and endocannabinoid-induced synaptic depression is observed in both the peripheral nervous system and the CNS. Indeed, A9-THC inhibition of transmitter release was first demonstrated in mouse vas deferens (Graham et al. 1974), and further evidence for presynaptic inhibition has been obtained using this preparation (Ishac et al. 1996 Pertwee and Fernando 1996) and in the myenteric plexus (Coutts and Pertwee 1997 Kulkami-Narla and Brown 2000). In addition, anandamide was first characterized as an EC based on its actions in the mouse vas deferens (Devane et al. 1992). Subsequently, CB1 receptor-mediated inhibition of release of several neurotransmitters has been documented in various regions of the PNS (see Szabo and Schlicker 2005 for review). Cannabinoids also inhibit neural effects on contraction in the ileum (Croci et al. 1998 Lopez-Redondo et al. 1997), although it is not clear that this is effect involves direct inhibition of neurotransmitter release (Croci et al. 1998). The CB1 receptor has been localized to enteric neurons, and thus the effect on ileum certainly involves actions on these presynaptic neurons. In addition, anandamide produces ileal relaxation via a non-CBl, non-CB2-mediated mechanism (Mang et al. 2001). 

Edwards DA, Kim J, Alger BE (2006) Multiple mechanisms of endocannabinoid response initiation in hippocampus. J. Neurophysiol. 95(l) 67-75 Elmslie KS (2003) Neurotransmitter modulation of neuronal calcium channels. J Bioenerg Bio-membr 35(6) 477-89... 

What is an endocannabinoid What evidence exists that these substances act as neurotransmitters ... 

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