Anandamide system

Evidence for an Interaction between the Cannabinoid-Anandamide System and Other Neuroreceptor Systems... 

The cannabinoid-anandamide system interacts with several neuroreceptor systems (Table 18.1). 

The high levels recorded in the basal ganglia and cerebellum, regions that coordinate motor functions, strongly suggest that the cannabinoid-anandamide system is involved in this activity. This is supported by the wide spectrum of neurological effects of cannabis or THC in laboratory animals (impaired coordination and balance, decreased muscle tone and reflexes, and, at higher doses, tremor, myoclonic jerks, muscle spasms, and convulsions). In humans, uncoordinated movements, muscle weakness, and tremulousness are frequently observed after cannabis use. 

Despite the recent advances in molecular biology, the mechanisms of action and the physiological functions of the anandamide system remain obscure. It would appear that the cannabinoid receptors and the anandamides reside within the neurons. Thus unlike the classical neurotransmitters noradrenaline and serotonin, the anandamides are not released into the synaptic cleft and are not involved in intemeuronal communication. Instead the anandamides modulate the excitability and inhibitory responsiveness of neurons by acting on cannabinoid hetero-ceptors located on inhibitory and excitatory terminals. In this way, the... 

Endocannabinoids are endogenous mediators acting via the binding to, and activation of, cannabinoid receptors, CBX and CB2 [1]. iV-arachidonoy 1-ethanol-amine (AEA, anandamide) and 2-arachidonoyl-glycerol (2-AG) (Fig. 1) are the two most studied endocannabinoids. In the nervous system, endocannabinoids act as... 

In addition, anandamide was found to parallel classical cannabinoid pharmacology in a series of nonbehavioral experimental systems. In isolated MVD, (Pertwee, 1992) and guinea pig ileum, it inhibited electrically evoked twitch responses (Pertwee, 1995). Moreover, anandamide was shown to decrease intraocular pressure in rabbits (Pate, 1995), to reduce sperm-fertilizing capacity in sea urchins by inhibition of the acrosome reaction (Schuel, 1994), and to produce hypotension in rats (Varga, 1995). 

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

A competitive version of ABPP identifies the target(s) and assesses the selectivity of an enzyme inhibitor in biological systems by gauging how well the inhibitor slows the enzyme s reaction with an ABP. For example, fluorophosphonate ABP 3 was used to profile the selectivity of fatty acid amide hydrolase (FAAH) inhibitors within the serine hydrolase superfamily [27] (FAAH hydrolyzes endocannabinoids such as anandamide). Serine hydrolases that exhibited reduced labeling by the probe in the presence of inhibitor were scored as targets of the inhibitor. Urea FAAH inhibitors exemplified by PF-3845 (5) that covalently modify the active-site serine nucleophile of FAAH were found to be exquisitely selective for FAAH in brain and liver... 

The presence of cannabinoid receptors in the immune system has led to consideration of the effects of cannabis on its function. Cannabinoid receptors have been found in spleen cells (Kaminski et al. 1992). Activation of these receptors would inhibit their function in the immune response. Similar suppressant effects occur on lymphocytes (Diaz et al. 1993). THC and anandamide inhibit macrophage-mediated tumor necrosis (Cabral et al. 1995). Despite these effects, their functional significance remains to be determined. These effects are most likely subtle. 

Welburn PJ, Starmer GA, Chesher GB, Jackson DM. (1976). Effect of cannabinoids on the abdominal constriction response in mice within cannabinoid interactions. Psychopharmacoiogia. 46(1) 83-85. Welch SP. (1997). Characterization of anandamide-induced tolerance comparison to delta 9-THC-induced interactions with dynorphinergic systems. Drug Aicohoi Depend. 45(1-2) 39-45. 

Welch SP. (1997). Characterization of anandamide-induced tolerance comparison to delta 9-THC-induced interactions with dynorphinergic systems. Drug Alcohol Dependence. 45(1-2) 39-45. 

Functional interactions between the nicotinic and cannabinoid systems have been proposed (Cohen et al. 2002) and several studies have tested the applicability of these ideas to nicotine discrimination. However cannabinoid agonists acting at cannabinoid CBi and CB2 receptors have failed to generalise with nicotine (Zaniewska et al. 2006). Results with the anandamide uptake and fatty acid amide hydrolase inhibitors AM-404 and URB 597, that elevate brain concentrations of endogenous cannabinoids, were also negative. Furthermore, neither the CBi receptor... 

Anandamide inhibited the specific binding of [ H]-HU-243 to synaptosomal membranes in a manner typical of competitive ligands, with an inhibition constant (K ) of 39.0 + 5.0 nM. In this system, the of tsP-THC, a psychoactive compound of cannabis, was 46.0 + 3-0 nM. These were exciting results — the psychoactive compound from a higher plant and a chemically completely different compound in the brain were found to bind to the same brain receptor at about the same level of activity. Soon after the identification of anandamide, this compound was tested for its pharmacological activity. Anandamide administered i.p. in mice, caused... 

THC was first isolated from hashish in 1964 by Raphael Mechoulam (1930-) and Yehiel Gaoni at the Weizmann Institute. Mechoulam had obtained 5 kg hashish from Israeli police officials and the earliest scientific work on THC and cannabinoids used this source. In the early 1990s, the specific brain receptors affected by THC were identified. These receptors are activated by a cannabinoid neurotransmitter called arachidonylethanolamide, known as anandamide. Anandamide was named by Mechoulam using ananda, which is the Sanskrit word for ecstasy. Anandamide is thought to be associated with memory, pain, depression, and appetite. THC is able to attach to and activate anandamide receptors. These receptors are actually called THC receptors rather than anandamide receptors because researchers discovered that THC attaches to these receptors before anandamide was discovered. The areas of the brain with the most THC receptors are the cerebellum, the cerebral cortex, and the limbic system. This is why marijuana affects thinking, memory, sensory perception, and coordination. 

Other potentially novel antidepressants in clinical testing target different neurotransmitter systems, including sigma receptors, peptides such as neurotensin or chole-cystokinin, and endogenous reward systems such as anandamide. These are in their very early testing phase. 

The second section on clinical science has been increased by two chapters to accommodate the increase in the numbers of drugs and advances in knowledge about psychiatric disorders. Three new neurotransmitter systems are introduced and illustrated substance P and the neurokinin family nitric oxide and the endocannabi-noids such as anandamide (the brain s own marijuana ). Also amplified is coverage of the classical neurotransmitter systems, especially intercommunications now illustrated between serotonin and dopamine and between norepinephrine/noradrenaline and serotonin. Also included are numerous new illustrations of noradrenergic and cholinergic pathways. 

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. 

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). 

---