glyceryl-2-arachidonate and Schizophrenia

Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anxiety Disorders; Arachidonic Acids; Chronic Pain; Depressive Disorder; Endocannabinoids; Glycerides; Humans; Mental Disorders; Microglia; Multiple Sclerosis; Neuralgia; Neurodegenerative Diseases; Parkinson Disease; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia

Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol 1) is synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary type 1 cannabinoid receptor (CB1R); 3) binds to CB1R, which inhibits gamma-aminobutyric acid release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-β-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-arachidonylglycerol, as well as both greater CB1R receptor binding and lower levels of CB1R messenger RNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered.

Topics: Arachidonic Acids; Cognition; Endocannabinoids; gamma-Aminobutyric Acid; Glycerides; Humans; Interneurons; Prefrontal Cortex; Pyramidal Cells; Receptor, Cannabinoid, CB1; RNA, Messenger; Schizophrenia; Signal Transduction

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptors are the CB1 cannabinoid receptors; however, CB2 cannabinoid receptors, transient receptor potential channels, and peroxisome proliferator activated receptors are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide). Despite similarities in chemical structure, 2-arachidonoyl glycerol and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiologic and pathophysiologic roles to these two endocannabinoids. As a result of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiologic and pathophysiologic roles of the ECS. This review provides an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.

Topics: Arachidonic Acids; Cannabinoid Receptor Agonists; Dronabinol; Endocannabinoids; Glycerides; Humans; Neuronal Plasticity; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia

Epidemiological and experimental evidence suggests that the endocannabinoid system plays a pathophysiological role in schizophrenia. This is reflected by elevated cerebrospinal levels of the endocannabinoid anandamide in schizophrenia and its initial prodromal states.. We analyzed plasma concentrations of anandamide, 2-arachidonoyl-sn-glycerol, palmitoylethanolamide and oleoylethanolamide from 25 twin pairs discordant for schizophrenia, six discordant for bipolar disorder and eight healthy twin pairs to determine hereditary traits.. Twin pairs discordant for schizophrenia or bipolar disorder had significantly higher levels of anandamide and palmitoylethanolamide compared to healthy twins (both P < 0.002). Non-affected twins discordant for schizophrenia, who developed a psychotic disorder within 5 years follow-up showed lower anandamide (P = 0.042) and 2-arachidonoyl-sn-glycerol levels (P = 0.049) than twins who remained healthy.. We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism.

Topics: Adult; Amides; Arachidonic Acids; Bipolar Disorder; Endocannabinoids; Ethanolamines; Female; Genetic Predisposition to Disease; Glycerides; Humans; Male; Middle Aged; Palmitic Acids; Polyunsaturated Alkamides; Prodromal Symptoms; Psychotic Disorders; Schizophrenia; Signal Transduction; Up-Regulation; Young Adult

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

Topics: Amides; Animals; Arachidonic Acids; Cannabidiol; Disease Models, Animal; Endocannabinoids; Ethanolamines; Female; Glycerides; Hippocampus; Interpersonal Relations; Male; Methylazoxymethanol Acetate; Motor Activity; Oleic Acids; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Recognition, Psychology; RNA, Messenger; Schizophrenia

The endocannabinoid system - comprising cannabinoid receptors, endocannabinoid ligands and their synthesis and inactivation enzymes - has been widely implicated in the pathophysiology of schizophrenia. However, little is known regarding the status of the different elements of the endocannabinoid system in the brain of schizophrenic patients. We have previously reported altered endocannabinoid levels in the postmortem brain of subjects with schizophrenia compared with matched controls.. Our aim was to further examine the status of the main elements of the endocannabinoid system in the postmortem prefrontal cortex of the same cohort of subjects.. Gene expression and function of the cannabinoid receptor type-1 (CB1) and the endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been assessed.. A significant decrease in. The present findings reveal an imbalance in the expression and function of different elements of the endocannabinoid system in schizophrenia. This outcome highlights the relevance of the endocannabinoid system in the pathophysiology of schizophrenia and emphasises its elements as potential targets in the search for new therapeutic strategies.

Topics: Adult; Amidohydrolases; Arachidonic Acids; Carbamates; Endocannabinoids; Female; Glycerides; Humans; Male; Middle Aged; Monoacylglycerol Lipases; Prefrontal Cortex; Receptor, Cannabinoid, CB1; Schizophrenia

Cannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.. Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.. Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

Topics: Animals; Arachidonic Acids; Calcium; Cannabinoid Receptor Modulators; Dopamine Agents; Endocannabinoids; Glycerides; Lipoprotein Lipase; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Patch-Clamp Techniques; Prefrontal Cortex; Pyramidal Cells; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia; Signal Transduction; Synapses; Type C Phospholipases

The discovery of blood platelet's ability to release 2-arachidonoyl-glycerol (2-AG), a highly lipophilic cannabinoid molecule may usher in a radical change in our understanding of how the vascular system interacts with the brain. This paper primarily extends Kayai's second messenger imbalance theory of schizophrenia, suggesting that 2-AG is the unidentified second messenger system that Kayai theorized was unbalanced in schizophrenia; furthermore, that a chronic over-release of 2-AG by platelets may be a causal factor in the cognitive deficits associated with negative symptom schizophrenia. Finally, platelet release of 2-AG may also be the causal agent in the cognitive deficits associated with states of high arousal, shock and in other conditions that feature heightened platelet activation. As such, heightened platelet activation may be a profoundly important vector for changing endogenous cannabinoid levels in the brain.

Topics: Antipsychotic Agents; Arachidonic Acids; Blood Platelets; Cannabinoid Receptor Modulators; Cannabinoids; Cognition Disorders; Dopamine; Endocannabinoids; Glycerides; Humans; Marijuana Smoking; Schizophrenia