anandamide and Substance-Related-Disorders

It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Drug Discovery; Endocannabinoids; Glycerides; Humans; Inflammation; Metabolic Diseases; Mood Disorders; Nervous System Diseases; Pain; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance-Related Disorders

The objective of this review is to point out some important facts that we don't know about endogenous cannabinoids - lipid-derived signaling molecules that activate CB1 cannabinoid receptors and play key roles in motivation, emotion and energy balance. The first endocannabinoid substance to be discovered, anandamide, was isolated from brain tissue in 1992. Research has shown that this molecule is a bona fide brain neurotransmitter involved in the regulation of stress responses and pain, but the molecular mechanisms that govern its formation and the neural pathways in which it is employed are still unknown. There is a general consensus that enzyme-mediated cleavage, catalyzed by fatty acid amide hydrolase (FAAH), terminates the biological actions of anandamide, but there are many reasons to believe that other as-yet-unidentified proteins are also involved in this process. We have made significant headway in understanding the second arrived in the endocannabinoid family, 2-arachidonoyl-sn-glycerol (2-AG), which was discovered three years after anandamide. Researchers have established some of the key molecular players involved in 2-AG formation and deactivation, localized them to specific synaptic components, and showed that their assembly into a multi-molecular protein complex (termed the '2-AG signalosome') allows 2-AG to act as a retrograde messenger at excitatory synapses of the brain. Basic questions that remain to be answered pertain to the exact molecular composition of the 2-AG signalosome, its regulation by neural activity and its potential role in the actions of drugs of abuse such as Δ(9)-THC and cocaine. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Endocannabinoids; Humans; Polyunsaturated Alkamides; Receptors, Cannabinoid; Substance-Related Disorders

The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Depression; Disease Models, Animal; Endocannabinoids; Enzyme Inhibitors; Glycerides; Humans; Ligands; Molecular Structure; Monoacylglycerol Lipases; Pain; Polyunsaturated Alkamides; Signal Transduction; Substance-Related Disorders

Cannabinoids represent one of the most widely used hallucinogenic drugs and induce profound alterations in sensory perception and emotional processing. Similarly, the dopamine (DA) neurotransmitter system is critical for the central processing of emotion and motivation. Functional disturbances in either of these neurotransmitter systems are well-established correlates of the psychopathological symptoms and behavioral manifestations observed in addiction and schizophrenia. Increasing evidence from the anatomical, pharmacological and behavioral neuroscience fields points to complex functional interactions between these receptor systems at the anatomical, pharmacological and neural systems levels. An important question relates to whether these systems act in an orchestrated manner to produce the emotional processing and sensory perception deficits underlying addiction and schizophrenia. This review describes evidence for functional neural interactions between cannabinoid and DA receptor systems and how disturbances in this neural circuitry may underlie the aberrant emotional learning and processing observed in disorders such as addiction and schizophrenia.

Topics: Amygdala; Animals; Appetitive Behavior; Arachidonic Acids; Association Learning; Cannabinoids; Central Nervous System Stimulants; Dopamine; Emotions; Endocannabinoids; gamma-Aminobutyric Acid; Humans; Interneurons; Models, Neurological; Models, Psychological; Motivation; Nerve Net; Perception; Polyunsaturated Alkamides; Prefrontal Cortex; Pyramidal Cells; Rats; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Receptors, Dopamine; Reward; Schizophrenia; Sensation; Substance-Related Disorders; Ventral Tegmental Area

In utero exposure to tetrahydrocannabinol, the psychoactive component of marijuana, is associated with an increased risk for neurodevelopmental defects in the offspring by interfering with the functioning of the endocannabinoid (eCB) system. At the present time, it is not clearly known whether the eCB system is present before neurogenesis. Using an array of biochemical techniques, we analyzed the levels of CB1 receptors, eCBs (AEA and 2-AG), and the enzymes (NAPE-PLD, DAGLα, DAGLβ, MAGL, and FAAH) involved in the metabolism of the eCBs in chick and mouse models during development. The findings demonstrate the presence of eCB system in early embryo before neurogenesis. The eCB system might play a critical role in early embryogenesis and there might be adverse developmental consequences of in utero exposure to marijuana and other drugs of abuse during this period.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Chick Embryo; Chromatography, Liquid; Dronabinol; Embryo, Mammalian; Endocannabinoids; Endpoint Determination; Female; Glycerides; Mass Spectrometry; Mice; Neurogenesis; Polyunsaturated Alkamides; Prosencephalon; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB1; Signal Transduction; Substance-Related Disorders

Chronic migraine (CM) and medication-overuse headaches (MOH) are well-recognized disabling conditions affecting a significant portion of the headache population attending centers specialized in treating headaches. A dysfunctioning of the serotonergic system has been demonstrated in MOH and CM patients. Here we report on our assessment of the dysfunctioning of the endocannabinoid system as a potential underlying factor in pathogenic mechanisms involved in CM and MOH.. To test the hypothesis of an impairment in the endocannabinoid system in patients with MOH and CM and to assess its relationship with any disruption of the serotonergic system, we determined the levels of the two main endogenous cannabinoids, anandamide (AEA) and 2-acylglycerol (2-AG), in platelets of 20 CM patients, 20 MOH patients and 20 control subjects and also measured the platelet serotonin levels in the same patients.. We found that 2-AG and AEA levels were significantly lower in MOH patients and CM patients than in the control subjects, without significant differences between the two patient groups. Serotonin levels were also strongly reduced in the two patient groups and were correlated with 2-AG levels, with higher values for MOH patients.. These data support the potential involvement of a dysfunctioning of the endocannabinoid and serotonergic systems in the pathology of CM and MOH. These systems appear to be mutually related and able to contribute to the chronification of both CM and MOH.

Topics: Adult; Arachidonic Acids; Blood Platelets; Cannabinoid Receptor Modulators; Case-Control Studies; Chronic Disease; Endocannabinoids; Female; Glycerides; Headache Disorders, Secondary; Humans; Male; Middle Aged; Migraine without Aura; Polyunsaturated Alkamides; Serotonin; Substance-Related Disorders

Disturbances in the endogenous cannabinoid (ECB) system in schizophrenia may contribute to their enhanced sensitivity to psychoactive substances, and the beneficial effects of second-generation antipsychotics for substance abuse in schizophrenia may involve modulatory effects on ECB. To verify these two assumptions, 29 patients (24 completers) with schizophrenia and substance use disorders (SUD) were treated with quetiapine for 12 weeks, and peripheral ECB levels were measured, using high-performance liquid chromatography/mass spectrometry, in patients (weeks 0, 6 and 12) and 17 healthy volunteers. Baseline anandamide levels were significantly higher in patients, relative to controls. This result is consistent with studies describing ECB dysfunctions in schizophrenia. SUD parameters improved during treatment, but no changes in ECB occurred over time. Improvements in substance abuse were probably not mediated by modulatory effects of quetiapine on ECB. Lastly, baseline anandamide predicted endpoint SUD scores (alcohol/ cannabis). Anandamide is a potential target for medications aimed at relieving SUD in schizophrenia.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Arachidonic Acids; Cannabinoid Receptor Modulators; Chromatography, High Pressure Liquid; Diagnosis, Dual (Psychiatry); Dibenzothiazepines; Endocannabinoids; Female; Humans; Linear Models; Male; Mass Spectrometry; Middle Aged; Polyunsaturated Alkamides; Psychiatric Status Rating Scales; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders

Anandamide, an endogenous ligand for brain cannabinoid CB(1) receptors, produces many behavioral effects similar to those of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB(1) receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB(1) receptors by anandamide could be part of the signaling of natural rewarding events.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cocaine; Endocannabinoids; Infusions, Intravenous; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Saimiri; Self Administration; Stereoisomerism; Substance-Related Disorders

Despite recent data suggesting that the endocannabinoid transmission is a component of the brain reward system and plays a role in dependence/withdrawal to different habit-forming drugs, only a few studies have examined changes in endocannabinoid ligands and/or receptors in brain regions related to reinforcement processes after a chronic exposure to these drugs. Recently, we carried out a comparative analysis of the changes in cannabinoid CB(1) receptor density in several rat brain regions caused by chronic exposure to some of the most powerful habit-forming drugs. In the present study, we have extended this objective by examining changes in the brain contents of arachidonoylethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), the endogenous ligands for cannabinoid receptors, in animals chronically exposed to cocaine, nicotine or ethanol. Results were as follows. Cocaine was the drug exhibiting the minor number of effects, with only a small, but significant, decrease in the content of 2-AG in the limbic forebrain. In contrast, chronic alcohol exposure caused a decrease in the contents of both AEA and 2-AG in the midbrain, while it increased AEA content in the limbic forebrain. This latter effect was also observed after chronic nicotine exposure together with an increase in AEA and 2-AG contents in the brainstem. In contrast, the hippocampus, the striatum and the cerebral cortex exhibited a decrease in AEA and/or 2-AG contents after chronic nicotine exposure. We also tested the effect of chronic nicotine on brain CB(1) receptors, which had not been investigated before, and found an almost complete lack of changes in mRNA levels or binding capacity for these receptors. In summary, our results, in concordance with previous data on CB(1) receptors, indicate that the three drugs tested here produce different changes in endocannabinoid transmission. Only in the case of alcohol and nicotine, we observed a common increase in AEA contents in the limbic forebrain. This observation is important considering that this region is a key area for the reinforcing properties of habit-forming drugs, which might support the involvement of endocannabinoid transmission in some specific events of the reward system activated by these drugs.

Topics: Animals; Arachidonic Acids; Binding Sites; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Cocaine; Endocannabinoids; Ethanol; Glycerides; In Situ Hybridization; Male; Nicotine; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; RNA, Messenger; Substance-Related Disorders

Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide. HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated physical dependence on THC [Delta9-tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Endocannabinoids; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Arachidonic Acids; Brain; Brain Chemistry; Cannabinoids; Endocannabinoids; Euphoria; Humans; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance-Related Disorders