The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism

Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.     

Retrograde signalling by endocannabinoids

The cannabinoid neurotransmitter system comprises cannabinoid G protein-coupled membrane receptors (CB1 and CB2), endogenous cannabinoids (endocannabinoids), as well as mechanisms for their synthesis, membrane transport and metabolism. Within the brain the marijuana constituent delta9-tetrahydrocannabinol (THC) produces its pharmacological actions by acting on cannabinoid CB1 receptors. THC modulates neuronal excitability by inhibiting synaptic transmission via presynaptic CB1-mediated mechanisms. More recently, it has been established that physiological stimulation of neurons can induce the synthesis of endocannabinoids, which also modulate synaptic transmission via cannabinoid CB1 and other receptor systems. These endogenously synthesised endocannabinoids appear to act as retrograde signalling agents, reducing synaptic inputs onto the stimulated neuron in a highly selective and restricted manner. In this review we describe the cellular mechanisms underlying retrograde endocannabinoid signalling.     

The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders

To date, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol are the best studied endocannabinoids and are thought to act as retrograde messengers in the central nervous system (CNS). By activating presynaptic cannabinoid CB₁ receptors, they can reduce glutamate release in dorsal and ventral striatum (nucleus accumbens) and alter synaptic plasticity, thereby modulating neurotransmission in the basal ganglia and in the mesolimbic reward system. In this review, we will focus on the role of the endocannabinoid system within these neuronal pathways and describe its effect on dopaminergic transmission and vice versa. The endocannabinoid system is unlikely to directly affect dopamine release, but can modify dopamine transmission trough trans-synaptic mechanisms, involving γ-aminobutyric acid (GABA)-ergic and glutamatergic synapses, as well as by converging signal transduction cascades of the cannabinoid and dopamine receptors. The dopamine and endocannabinoid systems exert a mutual control on each other. Cannabinergic signalling may lead to release of dopamine, which can act via dopamine D₁-like receptors as a negative feedback mechanism to counteract the effects of activation of the cannabinoid CB₁ receptor. On the other hand, dopaminergic signalling via dopamine D₂-like receptors may lead to up-regulation of cannabinergic signalling, which is likely to represent a negative feedback on dopaminergic signalling. The consequences of these interactions become evident in pathological conditions in which one of the two systems is likely to be malfunctioning. We will discuss neurological and psychiatric disorders such as Parkinson's and Huntington's disease, drug addiction and schizophrenia. Furthermore, the possible role of the endocannabinoid system in disorders not necessarily depending on the dopaminergic system, such as eating disorders and anxiety, will be described.     

In vivo neurochemical effects induced by changes in endocannabinoid neurotransmission

Neurotropic effects of endo- and exo-cannabinoids are largely caused by their effects on classical neurotransmitter signaling. Pharmacological and molecular tools have been used to selectively target the endocannabinoid system. Endocannabinoids mostly act as retrograde messengers and, upon release from postsynaptic neurons, they modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Generally, increased and decreased endocannabinoid neurotransmission results in decreases and increases in neurotransmitter release, respectively. However, net effects are often pleiotropic, probably owing to the level of regional endogenous tone, transsynaptic mechanisms and cumulative actions. Changes in classical neurotransmitter function can, in turn, modulate endocannabinoid signaling. Importantly, the endocannabinoid system can be altered in response to physiological and pathogenic events and targeted for therapeutic intervention.     

Mechanisms of control of neuron survival by the endocannabinoid system

Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB(1) cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival. Thus, CB(1) receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases. Nonetheless, some studies have reported that cannabinoids can also exert neurotoxic actions. Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB(1) receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB(1) receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB(2) cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation. Altogether, these findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.     

Lipid mediator endocannabinoids in modulating synaptic transmission

Marijuana smoking elicits various psychoactive effects through type 1 cannabinoid receptors (CB(1)Rs) in the brain. CB(1)R is a seven-transmembrane domain. G(i/o)-protein coupled receptors, and is expressed throughout the central nervous system including the hippocampus, cerebellum, striatum and cerebral cortex. Endogenous ligands for CB(1)R (endocannabinoids) are lipid in nature, and anandamide and 2-arachidonoylglycerol (2-AG) are considered to be the two major endocannabinoids. Endocannabinoids are known to function as retrograde messengers at synapses. Endocannabinoids are released from postsynaptic neurons in activity-dependent manners, and retrogradely activate presynaptic CB(1)Rs, resulting in short-term or long-term suppression of synaptic transmission. Endocannabinoid-mediated retrograde signaling is observed at various brain regions and considered as a general mechanism of synaptic modulation in the brain. Endocannabinoid release is triggered by postsynaptic Ca2+ elevation or activation of G(q/11)-protein coupled receptors. Recent studies have demonstrated that 2-AG mediates retrograde signaling at synapses in the brain. Endocannabinoid-mediated retrograde signaling is involved in long-term synaptic plasticity in several brain regions. At behavioral level, endocannabinoid signaling is known to be involved in hippocampus-, amygdala- and cerebellum-dependent learning and memory.     

Endocannabinoid signaling directs periimplantation events

An emerging concept in female reproduction is the role of endocannabinoids, a group of endogenously produced lipid mediators that bind to and activate cannabinoid receptors. Although adverse effects of cannabinoids in female reproduction have been implicated for years, the mechanisms by which they exert these effects remained elusive. With the identification of cannabinoid receptors, endocannabinoid ligands, their key synthetic and hydrolytic pathways, and the generation of knockout mouse models for cannabinoid receptors, a wealth of information is now available regarding the significance of cannabinoid/endocannabinoid signaling in early pregnancy. This review focuses on various aspects of endocannabinoid signaling in preimplantation embryo development and activation, and uterine differentiation during the periimplantation embryo-uterine dialog. It is hoped that a deeper understanding will lead to potential clinical applications of the endocannabinoid system as a target for regulating female fertility.     

Endocannabinoids and food consumption: comparisons with benzodiazepine and opioid palatability-dependent appetite

The endocannabinoid system consists of several endogenous lipids, including anandamide and 2-arachidonoyl-glycerol (2-AG), and constitute a retrograde signalling system, which modulates neurotransmitter release and synaptic plasticity. Specific brain-type cannabinoid receptors (CB₁) are widely distributed in the central nervous system, and are localized presynaptically. Mounting evidence, reviewed here, indicates that cannabinoids can act to increase food consumption, and cannabinoid CB₁ receptor antagonists/inverse agonists reduce food intake and suppress operant responding for food rewards. Hence, endocannabinoids provide the first example of a retrograde signalling system, which is strongly implicated in the control of food intake. Benzodiazepine and opioid palatability-dependent appetite are well-established processes supported by several sources of convergent evidence; they provide pharmacological benchmarks against which to evaluate the endocannabinoids. To date, evidence that endocannabinoids specifically modulate palatability as an affective evaluative process is insufficient and not compelling. Endocannabinoids may have important clinical utility in the treatment of human obesity and forms of eating disorders.     

The endogenous cannabinoid system and the treatment of marijuana dependence

The active principle of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory. Marijuana use may lead to adaptive changes in endocannabinoid signaling, and these changes might contribute to effects of marijuana as well as to the establishment of marijuana dependence. In the present article, I outline current views on how endocannabinoid substances are produced, released, and deactivated in the brain. In addition, I review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of marijuana dependence and other aspects of drug abuse.     

Participation of the cannabinoid system in the regulation of emotional-like behaviour

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. Indeed, recent studies have suggested that the cannabinoid system could represent an important substrate for the control of emotional behaviour, and further research would probably help to identify new promising therapeutic targets. This paper reviews the results obtained in different animal models used to investigate emotional states after the manipulation of the endocannabinoid system. Cannabinoid compounds can induce anxiogenic- and anxiolytic-like responses in rodents depending on the experimental conditions. Studies using knockout mice lacking the CB1 cannabinoid receptors have shown the participation of this receptor in several behavioural responses including anxiety- and depressive-like states. Furthermore, the endocannabinoid system regulates the hypothalamic-pituitary adrenal axis, which is involved in providing an appropriate response to stressful situations. Recent studies have also demonstrated that the endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitter, including opioids, GABA and cholecystokinin that have been classically involved in the control of anxiety-like responses. All this recent information has further clarified the role played by the endogenous cannabinoid system in the control of emotional behaviour and provides data to support a new possible therapeutic use of cannabinoid compounds.     

内源性大麻素—生物合成、信号转导及生物降解

大麻素系统由内源性大麻素、大麻素受体和内源性大麻素失活系统三部分组成,该系统失衡与多种中枢神经系统和免疫系统疾病有关。内源性大麻素水平是衡量大麻素系统活性的主要指标。内源性大麻素代谢途径的深入研究对揭示大麻素系统生理、病理作用以及设计基于该系统的新型治疗药物至关重要。该文综述内源性大麻素的生物合成、信号转导及其降解过程。     

Endocannabinoid regulation of matrix metalloproteinases: implications in ischemic stroke

Stroke is a major cause of morbidity and mortality and follows heart disease and cancer as the third leading cause of death in Western societies [1]. Despite many advances in stroke research and pharmacotherapy, clinical treatment of this debilitating disorder is still inadequate. Recent findings from several laboratories have identified the endocannabinoid signaling pathway, comprised of the endocannabinoid agonist anandamide and its pharmacological targets, CB1 and CB2 cannabinoid receptors and associated anandamide receptors, as a physiological system with capacity to mitigate cardiovascular and cerebrovascular disorders through neuronal and endothelial actions. Variability in experimental stroke models and modes of outcome evaluation, however, have provoked controversy regarding the precise roles of endocannabinoid signals in mediating neural and/or vascular protection versus neurovascular damage. Clinical trials of the CB1 antagonist rimonabant demonstrate that modulation of endocannabinoid signaling during metabolic regulation of vascular disorders can significantly impact clinical outcomes, thus providing strong argument for therapeutic utility of endocannabinoids and/or cannabinoid receptors as targets for therapeutic intervention in cases of stroke and associated vascular disorders. The purpose of this review is to provide updated information from basic science and clinical perspectives on endocannabinoid ligands and their effects in the pathophysiologic genesis of stroke. Particular emphasis will be placed on the endocannabinoids anandamide and 2-arachidonylglycerol and CB1 receptor-mediated mechanisms in the neurovascular unit during stroke pathogenesis. Deficiencies in our knowledge of endocannabinoids in the etiology and pathogenesis of stroke, caveats and limitations of existing studies, and future directions for investigation will be addressed.     

Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area

Intact endogenous cannabinoid signaling is involved in several aspects of drug addiction. Most importantly, endocannabinoids exert pronounced influence on primary rewarding effects of abused drugs, including exogenous cannabis itself, through the regulation of drug-induced increase in bursting activity of dopaminergic neurons in the ventral tegmental area (VTA). Previous electrophysiological studies have proposed that these dopaminergic neurons may release endocannabinoids in an activity-dependent manner to regulate their various synaptic inputs; however, the underlying molecular and anatomical substrates have so far been elusive. To facilitate understanding of the neurobiological mechanisms involving endocannabinoid signaling in drug addiction, we carried out detailed analysis of the molecular architecture of the endocannabinoid system in the VTA. In situ hybridization for sn-1-diacylglycerol lipase-alpha (DGL-alpha), the biosynthetic enzyme of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), revealed that DGL-alpha was expressed at moderate to high levels by most neurons of the VTA. Immunostaining for DGL-alpha resulted in a widespread punctate pattern at the light microscopic level, whereas high-resolution electron microscopic analysis demonstrated that this pattern is due to accumulation of the enzyme adjacent to postsynaptic specializations of several distinct morphological types of glutamatergic and GABAergic synapses. These axon terminal types carried presynaptic CB(1) cannabinoid receptors on the opposite side of DGL-alpha-containing synapses and double immunostaining confirmed that DGL-alpha is present on the plasma membrane of both tyrosine hydroxylase (TH)-positive (dopaminergic) and TH-negative dendrites. These findings indicate that retrograde synaptic signaling mediated by 2-AG via CB(1) may influence the drug-reward circuitry at multiple types of synapses in the VTA.     

Endocannabinoid overload

The signaling capacity of endogenous cannabinoids ("endocannabinoids") is tightly regulated by degradative enzymes. This Perspective highlights a research article in this issue (p. 996) in which the authors show that genetic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), causes marked elevations in 2-AG levels that lead to desensitization of brain cannabinoid receptors. These findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and reveal that excessive 2-AG signaling can lead to functional antagonism of the brain cannabinoid system.     

Cannabinoid physiology and pharmacology: 30 years of progress

Delta9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the "endocannabinoid" agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to G(i/o) to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPgammaS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of gamma-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.     

Blocking cannabinoid activation of FAK and ERK1/2 compromises synaptic integrity in hippocampus

The cannabinoid CB1 receptor allows endocannabinoids to act as intercellular and retrograde messengers in the central nervous system. Endocannabinoid actions have been implicated in both synaptic plasticity and neuroprotection. Here, cannabinergic activation of extracellular signal regulated-kinase (ERK) and focal adhesion kinase (FAK) occurred correspondingly in long-term hippocampal slice cultures. The stable endocannabinoid analogue R-methanandamide activated ERK1/ERK2 subtypes of mitogen-activated protein kinase (MAPK) through the upstream activator MAPK kinase (MEK). R-methanandamide also promoted FAK signaling, but in a MEK-independent manner. Both events of ERK and FAK activation were selectively blocked by N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281), a cannabinoid CB1 receptor antagonist, and the blockage was associated with a gradual decline in synaptic markers. Interestingly, the integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro also caused the disruption of R-methanandamide-mediated ERK and FAK responses and upset the integrity of excitatory synapses. These results suggest that the endocannabinoid system supports synaptic maintenance through linkages with MAPK pathways and integrin-related FAK signaling.     

Corticosteroid–endocannabinoid loop supports decrease of fear-conditioned response in rats

The endocannabinoid (eCB) and glucocorticoid systems contribute to the modulation of emotional states. Noteworthy, glucocorticoid hormones are released by adrenal glands during stressful events and endocannabinoids are released in the brain during fear-conditioned responses. Since it was already suggested that glucocorticoids may trigger the release of endocannabinoids in the brain, our objective was to investigate whether the interaction between these neuromodulatory systems contributes to the decrease of conditioned freezing behavior over successive 9-min exposures to the conditioning context. Present results suggest a bidirectional interdependence between glucocorticoid and endocannabinoid systems. CB₁ receptors blockade prevents glucocorticoid-induced facilitation of conditioned freezing decrease and inhibition of glucocorticoid synthesis renders boosting of endocannabinoid signaling innocuous, while preserving the efficacy of direct CB₁ receptors activation by an exogenous cannabinoid agonist. This suggests that CB₁ receptors are somehow “downstream” to glucocorticoid release, which in its turn, is reduced by CB₁ activation, contributing to the persistent reduction of conditioned freezing responses.     

Therapeutic potential of cannabinoids in CNS disease

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.     

Commentary: Functional Neuronal CB2 Cannabinoid Receptors in the CNS

Cannabinoids are the constituents of the marijuana plant (Cannabis sativa). There are numerous cannabinoids and other natural compounds that have been reported in the cannabis plant. The recent progress in marijuana-cannabinoid research include the discovery of an endocannabinoid system with specific genes coding for cannabinoid receptors (CBRs) that are activated by smoking marijuana, and that the human body and brain makes its own marijuana-like substances called endocannabinoids that also activate CBRs. This new knowledge and progress about cannabinoids and endocannabinoids indicate that a balanced level of endocannabinoids is important for pregnancy and that the breast milk in animals and humans has endocannabinoids for the growth and development of the new born. There are two well characterized cannabinoid receptors termed CB1-Rs and CB2-Rs and these CBRs are perhaps the most abundant G-protein coupled receptors that are expressed at high levels in many regions of the mammalian brain. The expression of CB1-Rs in the brain and periphery and the identification of CB2-Rs in immune cells and during inflammation has been extensively studied and characterized. However, the expression of functional neuronal CB2-Rs in the CNS has been much less well established and characterized in comparison to the expression of abundant brain CB1-Rs and functional neuronal CB2-Rs has ignited debate and controversy. While the issue of the specificity of CB2-R antibodies remains, many recent studies have reported the discovery and functional characterization of functional neuronal CB2-Rs in the CNS beyond neuro-immuno cannabinoid activity.     

Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders.

The activity of the endocannabinoid system, in terms of the levels of the endocannabinoids and of cannabinoid receptors, or of the functional coupling of the latter to a biological response, undergoes to remodelling during pathological conditions. In the CNS, these changes, depending also on the nature of the disorder, can be transient or long-lasting, occur only in those tissues involved in the pathological condition and usually aim at restoring the physiological homeostasis by reducing excitotoxicity, inflammation and neuronal death. However, during chronic disorders, prolonged activation of the endocannabinoid system might also contribute to the symptoms of the pathology. Whilst acute changes of the tissue levels of the endocannabinoids reflect the "on demand" nature of their biosynthesis and release, and hence are effected mostly through regulation of the biosynthetic enzymes, chronic changes seem to be mostly due to longer-lasting alterations in the expression of anabolic and catabolic enzymes. The possibility of obtaining therapeutic advantage from endocannabinoid plasticity in neuropsychiatric and neurological disorders is discussed in this review article.