Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders

Abstract

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

Keywords: endocannabinoid system; method; molecular alteration; psychiatric disorders.

Figure 1

Schematic representation of the main methods used for identifying alterations in the ECS. AEA: anandamide; 2-AG: 2-arachidonoylglycerol; CB1r: cannabinoid 1 receptor; CB2r: cannabinoid 2 receptor; DAGL: diacylglycerol lipase; EMT: endocannabinoid membrane transporter; FAAH: fatty acid amide hydrolase; GTPyS: GTPgammaS or guanosine 5′-O-(γ-thio) triphosphate; LC-MS / MS: liquid chromatography-tandem mass spectrometry; MAGL: monoacylglycerol lipase; NarPE: N-arachidonoyl phosphatidylethanolamine; NAPE-PLD: N-acylphosphatidylethanolamine specific phospholipase D; NAT: N-acyl-transferase; NGS: next-generation sequencing (genomics); PET: positron emission tomography; q-PCR: real-time polymerase chain reaction; SNPs: single nucleotide polymorphisms; TLC: thin-layer chromatography.

Figure 2

Main findings regarding the alterations of the ECS components in animal models and patients with anxiety and post-traumatic stress disorder. 2-AG: 2-arachidonoylglycerol; AEA: anandamide; AMY: amygdala; CB1r: cannabinoid receptor 1; CNR1: gene encoding CB1r; CNR2: gene encoding CB2r; CPu: caudate putamen; FAAH: fatty acid amide hydrolase; HIPP: hippocampus; PFC: prefrontal cortex; VS: ventral striatum. Note: Anxiety-related studies are in black, and post-traumatic stress disorder studies are in blue.

Figure 3

Main findings regarding the alterations of ECS components in animal models and patients with depression. 2-AG: 2-arachidonoylglycerol; ACC: anterior cingulate cortex; AEA: anandamide; CB1r: cannabinoid receptor 1; CNR1: gene encoding CB1r; FAAH: gene encoding fatty acid amide hydrolase; FSL: Flinders Sensitive Line rats; HIPP: hippocampus; HYP: hypothalamus; MDD: major depressive disorder; MGLL: gene encoding MAGL; NAcc: nucleus accumbens; PFC: prefrontal cortex; SSRI: selective serotonin reuptake inhibitors; ST: striatum; WKY: Wistar Kyoto rats.

Figure 4

Main findings regarding the alterations of the ECS components in animal models and patients with schizophrenia. 2-AG: 2-arachidonoylglycerol; ACC: anterior cingulate cortex; AEA: anandamide; AMY: amygdala; CB1r: cannabinoid receptor 1; CB2r: cannabinoid receptor 2; Ctx: cortex; CSF: cerebrospinal fluid; DAGL: diacylglycerol lipase; DLPFC: dorsolateral prefrontal cortex; FAAH: fatty acid amide hydrolase; HIPP: hippocampus; HIP: hypothalamus; MAGL: monoacylglycerol lipase; NAcc: nucleus accumbens; NAPE-PLD: N-acyl phosphatidylethanolamine phospholipase; OEA: ethanolamide; PCC: posterior cingulate cortex; PFC: prefrontal cortex.

Figure 5

Main findings regarding the alterations of the ECS components in animal models and patients with autism spectrum disorders. AEA: anandamide; CB1r: cannabinoid receptor 1; CB2r: cannabinoid receptor 2; FAAH: fatty acid amide hydrolase; HIPP: hippocampus; NAPE-PLD: N-acyl phosphatidylethanolamine phospholipase, NAE: N- acetyl ethanolamine.

Figure 6

Main findings regarding the alterations of the ECS components in animal models and patients with attention deficit hyperactivity disorder. AEA: anandamide; CB1r: cannabinoid receptor 1; FAAH: fatty acid amide hydrolase; HIPP: hippocampus; Ctx: cortex.

Figure 7

Main findings regarding the alterations of the ECS components in animal models and patients with eating disorders. 2-AG: 2-arachidonoylglycerol; AEA: anandamide; CB1r: cannabinoid receptor 1; CNR1: gene encoding CB1r; HIPP: hippocampus; HYP: hypothalamus; BED: binge eating disorders; AN: Anorexia nervosa; DG: dentate gyrus; Nacc: nucleus accumbens; PFC: prefrontal cortex; FCTx: frontal cortex, TCtx: temporal cortex; BEB: binge eating behavior.