Preclinical studies have made a convincing case for the efficacy of cannabinoid agents not only in experimental brain ischemia, but also in models of Parkinson’s disease and other forms of degenerative brain disorders. Also highlighted during the conference were various derivatives of cannabidiol. Particularly interesting in this regard was the compound -7-hydroxy-4#- dimethylheptyl-cannabidiol a hy droxylated, dimethylheptylated cannabidiol, structurally related to HU-210. Like D9 -THC, 7-OH-DMH-CBD is a potent inhibitor of electrically evoked contractions in the mouse vasdeferens. However, 7-OH-DMH-CBD does not significantly bind to either CB1 or CB2 receptors and its inhibitory effects on muscle contractility are not blocked by CB1 or CB2 receptor antagonists, suggesting that the compound may target an as-yet-uncharacterized cannabinoid-like receptor. This hypothesis is reinforced by pharmacological experiments, which suggest that 7-OH-DMH-CBD displays anti-inflammatory and in testinal-relaxing properties, but does not exert overt psychoactive effects in mice. However, the nature of this hypothetical receptor and its relationship to other cannabinoid-like sites in the vasculature and in the brain hippocampus remains to be determined.A large number of pharmaceutical companies have started active CB1 antagonist programs, mostly as a result of the clinical success of SR141716A ,cannabis grow equipment the first CB1 antagonist to be developed. This molecule has successfully completed Phase III studies and is anticipated to become available within a year for the treatment of obesity and tobacco addiction. Rimonabant is an inverse CB1 agonist with a Ki of 11 nM at the CB1 receptors and 1640 nM at CB2. Additional agents currently in development include SLV-326 and LY320135 .

However, all of these compounds are inverse agonists.Examples of this class are the compounds O-2654 and AM5171 . As noted above, therapeutic areas for cannabinoid antagonists include obesity, drug addiction and perhaps CNS disorders.The mechanism by which cannabinoid antagonists exert their anti-obesity effects is still not fully understood.First, there is a loss of appetite.Second, there is an increase in metabolic rate and a loss of fat mass. These effects may be linked, on the one hand, to the ability of rimonabant to affect corticotropin-releasing hormone , as suggested by the fact that CB1 receptors colocalize with CRH receptors in the hypothalamus. This may be significant for explaining the drug’s effects on appetite drive, as it is known that CRH is anorexigenic. On the other hand, mice that lack CB1 receptors display a hyperactivity of the hypothalamic pituitary-adrenal axis, with increases in both ACTH and corticosterone. This phenotype may be important in regard to overall metabolic rate. Another possible mediator of the long-lasting effect on body weight reduction unrelated to altered food intake is the adipocyte, because CB1 receptor activation causes lipogenesis, which is blocked by rimonabant.CB1 cannabinoid receptors are present on the cell surface of neurons within the brain reward circuitry. Furthermore, endocannabinoids may be released from dopamine neurons in the ventral tegmental area , and from medium spiny neurons in the nucleus accumbens of the brain reward circuit. Additionally, endocannabinoids and D9 -THC activate CB1 receptors and by doing so regulate reward strength and drug craving. Though we do not know how this occurs, it is likely that these mechanisms extend to all drugs of abuse, because collectively these drugs show the propensity to increase VTA dopamine neuron activity, which might be coupled to augmented endocannabinoid production from the dopamine neurons themselves.

Finally, cannabinoid receptor antagonists block the effects of endocannabinoids in these reward circuits. Preclinical work shows that priming injections of cannabinoid agonists reinstate heroin-seeking behavior after a prolonged period of abstinence in rats trained to self-administer heroin. The cannabinoid antagonist rimonabant fully prevents heroin-induced reinstatement of heroin-seeking behavior. Additionally, rimonabant significantly attenu ates cannabinoid-induced reinstatement of heroin seeking behavior. All these findings clearly support the hypothesis of a functional interaction between opioid and cannabi noid systems in the neurobiological mechanisms of relapse and might suggest a potential clinical use of cannabinoid antagonists for preventing relapse to heroin abuse. It has also been shown that cannabinoid antagonists can prevent drug reinstatement with co caine, alcohol, and nicotine. Thus, it seems that the future of cannabinoid antagonists in substance abuse treatment is particularly promising, especially in the clinical setting, where poly drug abuse is exceedingly more common than isolated single-drug abuse.The available data suggest that CB1 antagonism produces relatively mild side effects in people. Yet several potential risks were discussed and three in particular received a great deal of attention. First, the possibility of neuropsychiatric sequelae, such as anhedonia and anxi ety: preclinical studies have consistently shown such effects in animals, though they have not yet been observed in the clinic. Second, pain and hyperalgesia, because of the pervasive role played by the endocannabinoid system in the control of pain processing. Last, hypertension, as indicated by the contribution of the endocannabinoids to blood pressure regulation and the pressor effects of rimonabant in animal models of hypertension.The endocannabinoid signaling system differs from classical neurotransmitter systems, picking up where classical neurotransmitters leave off.

That is, the activation of receptors initiates a series of chemical events that leads to the release of endocannabinoids from the postsynaptic spine e the final step of which is the enzymatic production and subsequent release of anandamide and/or 2-AG. Once released, the endocannabinoids are then directed to the presynaptic cell and the CB1 receptor responds by inhibiting further release of that cell’s neurotransmitters. The termination of this cascade is accomplished via a transporter that internalizes the endocannabinoids, after which intracel lular enzymes such as fatty-acid amide hydrolase break them down. There is a general consensus that endocannabinoids are transported into cells via a facilitated diffusion mechanism. This process may differ both kinetically and pharmacologically from cell to cell. In brain neurons, endocannabinoid transport is blocked by certain agents, which include the compounds AM404, OMDM-8 and AM1172 . However, the pharmacological properties of these drugs in vivo are only partially understood. Once inside cells, endocannabinoids are hydrolyzed by three principal enzyme systems. FAAH is a key enzyme of anandamide deactivation in the brain. Potent and selective FAAH inhibitors have been developed and shown to exert profound antianxiety and antihyperten sive effects in animals. The latter effects were discussed at length at the workshop, highlighting the important role of anandamide in two important examples of vascular allostasis e shock and hypertension. In addition to FAAH, another amide hydrolase has been recently characterized, which may participate in the degradation of anandamide and other fatty-acid ethanolamides such as oleoylethanolamine . This amidase prefers acid pH values and has a different tissue distribution than FAAH, being notably high in lung, spleen and inflammatory cells. Inhibitors of this enzyme are being developed. Finally, 2-AG is hydrolyzed by an enzymatic system separate from FAAH, which probably involvesa monoacylglycerol lipase recently cloned from the rat brain. Inhibitors of this enzyme are currently under development.What are the therapeutic advantages and draw backs of using a direct agonist vs. an indirect agonist? Several parallels can be drawn to the well-known SSRIs , which have shown such powerful and useful therapeutic applications in effecting indirect agonism of the serotonergic system. Indeed,mobile grow system there is ample evidence that pharmacological profiles for the indirectly-acting agonists can generally be attributed to enhanced selectivity based on more localized action. A prime reason for favoring the indirect agonism approach is the possibility of obtaining new drugs devoid of the psychoactive effects and perceived abuse potential of directly acting CB1 agonists.

If we accept the postulate of on-demand modulation of endo cannabinoid signaling as contributing to some disease states, we are likely to witness the development of more specific medications acting indirectly such as inhibitors of cannabinoid uptake or breakdown.In addition to producing a well-described series of somatic effects – such as decreased motor activity, increased feeding, and analgesia – CB1 cannabinoid receptors also appear to play important, albeit complex, roles in neuropsychiatric disease. Emerging evidence indicates that modulation of CB1 receptor signaling may be useful for the treatment of several mental disorders, such as depression, anxiety, and addiction. This review will focus on the literature suggesting a role for modulation of endogenous cannabinoid signaling in the treatment of depression. Excellent reviews on the contribution of the endocannabinoids to anxiety and addiction have been recently published.Depression is a psychiatric disorder characterized in humans by the core symptoms of depressed mood and/or loss of pleasure or interest in most activities Other characteristics include, but are not limited to, changes in body weight, sleeping patterns, psychomotor behavior, energy level, and cognitive functioning. The overlap between the physiological functions altered by depression and those affected by cannabinoid receptor signaling is striking, and suggests that activation of this system may have important effects on the regulation of mood disorders. In fact, prolonged cannabis consumption and cannabis withdrawal in people are often associated with depression, but whether marijuana usecontributes to the development of this disorder is still a matter of debate . These considerations have prompted numerous researchers to investigate the endocannabinoid system as it relates to depression and mood disorders. There is now persuasive evidence from several areas of research, outlined in this article, which suggests a role for the endocannabinoid system in the normal regulation of mood, as well as in the pathogenesis and treatment of depression and other stress-related disorders. First of all, studies of both animals and humans suggest that alterations in endocannabinoid signaling may participate in depression-related behaviors. Moreover, direct modulation of cannabinoid CB1 receptor signaling, by natural or synthetic agonists, as well as antagonists, can produce effects on stress-responses and mood related behavior. Finally, several enzymes responsible for the metabolism of endocannabinoids have been identified, leading to the development of drugs that indirectly enhance cannabinoid receptor signaling by blocking endocannabinoid deactivation. These pharmacological tools have substantiated the notion that augmentation of endogenous cannabinoid signaling may promote stress-coping behavior, both under normal and pathophysiological conditions. Together, the evidence indicates that the endogenous cannabinoid system is a modulator of mood states and a promising target for the treatment of stress-related mood disorders such as depression. The best characterized endogenous cannabinoid ligands, arachidonoylethanolamide and sn-2-arachidonoylglycerol are produced in an activity dependent manner and appear to locally modulate synaptic transmission in the nervous system via presynaptic activation of the Gαi/o-protein coupled cannabinoid CB1 receptor. Anandamide and 2-AG also bind to and activate the Gαi/o-protein coupled cannabinoid CB2 receptor, but the possible roles of this receptor in the central nervous system are only beginning to be understood. The pattern of distribution of CB1 receptors is reflective of the proposed roles for this system in the modulation of pain perception, affective states, stress responses, motor activity, and cognitive functioning. CB1 is found at highest concentrations in the hippocampus, basal ganglia, neocortex, cerebellum and anterior olfactory nucleus. Moderate levels of the receptor are also present in the basolateral amygdala, hypothalamus, and midbrain periaqueductal gray. Initially, the CB2 receptor was found to be localized predominantly in peripheral tissues and particularly in immune cells, but recent articles have reported CB2 mRNA expression in the brainstem and CB2 immunohistochemical staining throughout the brain. Unlike many traditional neurotransmitters, the endocannabinoid ligands are lipid-derived amphipathic messengers that are not stored in vesicles. Rather, they appear to be produced from precursor components within the cellular membrane. In the best characterized synthesis pathway, the anandamide precursor, N-arachidonoyl-phosphatidylethanolamine , is formed by an N-acyltransferase -catalyzed transfer of an arachidonic acid moiety from the sn-1 position of phosphatidylcholine to the amine group of phosphatidylethanolamine. NAPEs are then cleaved by a NAPE-specific phosopholipase D , an isoform of which has recently been cloned, to produce anandamide. Alternatively, NAPEs can be hydrolyzed by a phopholipase C enzyme to generate phosphoanandamide, which is then dephosphorylated by a phosphatase, such as the protein tyrosine phosphatase PTPN22, to yield anandamide. The biological deactivation of anandamide is likely a two-step process, whereby the lipid mediator is transported into cells by a presently uncharacterizedentity, and then hydrolyzed by the membrane-bound enzyme fatty-acid amide hydrolase to form ethanolamine and arachidonic acid. Two main biochemical pathways exist, which can potentially generate 2-AG. The 2-AG precursor, 1,2-diacyl-sn-glycerol , can be formed from phosphoinositides such as phosphatidylinositol-4,5-bisphosphate by the action of a PI-specific PLC. Two isoforms, α and β, of the enzyme diacylglycerol lipase have been shown to form 2-AG from DAG .