Biomarkers of the Endocannabinoid System in Substance Use Disorders
Abstract
:1. Introduction
2. Methods
3. Endocannabinoid Components as Potential Biomarkers in SUD
3.1. Alcohol-Related Disorders
3.1.1. Gene Polymorphisms of ECS Components
3.1.2. Gene and Protein Function/Expression Changes of ECS Components
3.1.3. Neuroimaging of ECS Components
3.1.4. Concluding Remarks—ECS and Alcohol-Related Disorders
3.2. Cannabis-Related Disorders
3.2.1. Gene Polymorphisms of ECS Components
3.2.2. Gene and Protein Function/Expression Changes of ECS Components
3.2.3. Neuroimaging of ECS Components
3.2.4. Concluding Remarks—ECS and Cannabis-Related Disorders
3.3. Opioid-Related Disorders
3.3.1. Gene Polymorphisms of ECS Components
3.3.2. Gene and Protein Function/Expression Changes of ECS Components
3.3.3. Concluding Remarks—ECS and Opioid-Related Disorders
3.4. Stimulant-Related Disorders
3.4.1. Gene Polymorphisms of ECS Components
3.4.2. Gene and Protein Function/Expression Changes of ECS Components
3.4.3. Concluding Remarks—ECS and Stimulant-Related Disorders
3.5. Tobacco-Related Disorders
3.5.1. Gene Polymorphisms of ECS Components
3.5.2. Gene and Protein Function/Expression Changes of ECS Components
3.5.3. Neuroimaging of ECS Components
3.5.4. Concluding Remarks—ECS- and Tobacco-Related Disorders
3.6. Hallucinogen-Related Disorders
3.6.1. Gene and Protein Function/Expression Changes of ECS Components
3.6.2. Concluding Remarks—ECS and Hallucinogen-Related Disorders
4. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Alcohol-Related Disorders | |||||
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
Gene Polymorphisms | |||||
Alcoholic dependent patients (n = 137, males) Spanish population | Whole blood | Genotyping | Hare’s Psychopathy Checklist Revised (PCL-R) and TaqIA of the SLC6A3 gene, 3′-UTR microsatellites of CNR1 and C385A FAAH SNP and | Strong positive correlation between PCL-R Factor 1, TaqIA SNP, CNR1 and FAAH genes | [34] |
Heavy drinkers (n = 88, males) | Saliva | Genotyping | Craving Visual Analogue Scale for alcohol and 48-bp VNTR of DRD4 and rs2023239 SNP of CNR1 | ↓ craving in DRD4 long VNTR than in short VNTR | [35] |
Healthy adolescents (n = 2087) Mostly European descent | Whole blood | Genotyping | AUDIT questionnaire and 7 SNPs of CNR1, NAPE, FAAH, MGLL and DAGLA | SNPs rs9343525 Cnr1 and rs507961 Mgll strongly correlated with AUDIT score | [36] |
Patients with alcoholism (n = 729) and healthy controls (n = 799) Japanese population | Whole blood | Genotyping | 5 SNPs of FAAH and 14 SNPs of MGLL | No associations were observed between any of the SNPs and the alcoholism | [37] |
Patients with alcoholism (n = 785) and healthy controls (n = 487) Japanese population | Whole blood | Genotyping | Q63R polymorphism of CNR2 gene and DSM IIIR diagnostic criteria for alcohol dependence | The polymorphism was associated with alcoholism | [38] |
Patients with CD, OD and/or AD (n = 550) and healthy controls (n = 451) European American population | Whole blood | Genotyping | 10 SNPs of CNR1 gene and DSM IIIR or DSM IV diagnostic criteria for drug dependence | SNP3^G and SNP8^T/T were associated with both AD and DD | [39] |
Alcohol patients (n = 298; 187 with AD and 111 with AA) and healthy controls (n = 155) Spanish population | Whole blood | Genotyping | 3 SNPs of CNR1 gene: rs6454674, rs1049353 and rs806368. | ↓ risk with rs6454674-rs1049353-rs806368 haplotype | [40] |
Patients with AD (n = 121) and controls (n = 136) Caucasian population | Whole blood | Genotyping | Identification of CNR1 gene 1359 alleles | ↑ risk to develop alcohol withdrawal delirium with the homozygous genotype Cnr1 1359A/A | [41] |
Patients with AD (n = 196) and control subjects (n = 210) Caucasian population | Whole blood | Genotyping | Identification of CNR1 gene 1359 alleles | No association was found between the polymorphism and alcohol withdrawal-induced seizures | [42] |
Alcoholics (n = 10) and matched controls (n = 10) | Postmortem brain tissue (Brodmann areas 9 and 10) | Genotyping | Identification of CNR1 gene rs2023239 SNP | ↑ susceptibility to changes in the mesocorticolimbic circuitry involved in AD in individuals with the C allele | [43] |
177 subjects Spanish population | Saliva | Genotyping | Screening of CNR1, FAAH, DRD2, ANKK1, COMT and OPRM1 genes polymorphisms | ↑ risk of AD in patients with C385A Faah genotype | [44] |
Patients with AD (n = 497) and healthy controls (n = 389) American population | Whole blood | Genotyping | Exploration of the involvement of CNR1 rs806368, rs1049353, rs6454674, rs2180619 and FAAH rs324420 SNPs on sleep quality in individuals with AD | C allele carriers (CC/AC) of CNR1 rs6454674 had greater sleep disturbances | [45] |
Patients with AD (n = 952) criteria and healthy controls (n = 482) European American and African American population | Whole blood | Genotyping | Identification of FAAH Pro129Thr, rs324420 polymorphism | ↑ frequency of Thr129 allele in European American AD population, but not in African Americans | [46] |
Heavy drinking youth patients (n = 302) | Whole blood | Genotyping | Identification of FAAH C385A alleles | FAAH AC or AA genotypes were associated with more drinking days and more frequent heavy episodic drinking | [47] |
C57BL/6J mice | Knock-in containing the human C385A FAAH SNP | Ethanol binge drinking model | Ethanol consumption | ↑ ethanol intake and preference in FAAH A/A mice than in WT FAAH C/C mice | [48] |
Gene and Protein Changes | |||||
Animal Studies | |||||
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
C57/BJ6 male mice | Two-bottle choice paradigm (2, 4, 8, 16 and 32% of ethanol each 3 days) | qPCR | CB2R gene expression analyses | ↑ alcohol preference was associated with ↓ CB2R gene expression in the MB | [38] |
Male Wistar rats | 3 g/kg of ethanol, p.o., acute | In situ hybridization | Changes on TH, PENK and CB1R gene expressions | ↑ TH gene expression in VTA and SN ↑ PENK gene expression in CPu, NAcc C and S, AMY C and M, VMN and PVN ↓ CB1R gene expression in CPu, AMY C and VMN | [49] |
Male Wistar rats | 10% v/v ethanol for 52 days, chronic | In situ hybridization | Changes on CB1R gene expression | ↓ CB1R gene expression in CPu, VMN and CA1 and CA2 fields of HIPP ↑ CB1R gene expression in the DG | [50] |
Male Long-Evans rats | Ethanol vapor exposure 14 h/day, to achieve 150–250 mg/dL BEC for 8–12 weeks | WB and qPCR | Changes on ECS components in the lateral habenula | ↑ MGLL and DAGLB, and ↓ CB1R gene expression ↑ MAGL and ↓ CB1R protein levels | [51] |
C57BL/6J embryos into host CD1 mothers | ECR1 disruption by CRISPR/CAS9 method + two bottle choice paradigm | qPCR | Changes on CB1R gene expression in different brain regions | ↓ CB1R gene expression in the HIPP but not in the hypothalamus, accompanied with reduced ethanol intake | [52] |
Wistar female rats and their male pups | MS + forced ethanol consumption (10%) | WB | Evaluation of CB1R and CB2R protein levels | ↑ CB1R in the VS and ↓ in the FCx in MS rats = CB2R in all regions in MS rats | [53] |
Ethanol-preferring (AA) and non-preferring (ANA) male rats | Ethanol self-administration | In situ hybridization and qPCR | Analyses of ECS components in different brain regions | ↓ CB1R protein binding by in-situ hybridization ↓ FAAH and MGLL in the PFC ↓ FAAH protein levels in the PFC | [54] |
Male and female Wistar rats | Ethanol vapor exposure (14 h/day, 6 weeks) | qPCR | ECS components in BLA and vmPFC | ↓ CNR1, DAGLA and MGLL in the BLA in males ↓ CNR1 in the BLA in females ↓ NAPE-PLD in vmPFC in males | [55] |
Male Wistar rats | Chronic or intermittent ethanol treatment (10% w/v) and withdrawal (at 6 h and 24 h) | qPCR | ECS components in AMY | ↓ FAAH gene expression after continuous ethanol exposure and 24 h of withdrawal ↑ NAPE-PLD gene expression after continuous exposure and 6 h of withdrawal ↓ MGLL gene expression after intermittent exposure and 24 h of withdrawal | [56] |
Male Wistar rats | Intermittent alcohol exposure | qPCR | ECS components in PFC, ST, AMY and dorsal and ventral HIPP | ↓ CNR1 in AMY and ST ↓ CNR2 in HIPP and ST ↑ NAPE-PLD in PFC and ↓ in the AMY | [57] |
Clinical Studies | |||||
CA, AS and C patients | Post-mortem brain tissue (Ventral striatum) | WB | CB1R and FAAH enzyme levels | ↓ CB1R, FAAH activity and levels in CA | [58] |
Alcohol users (7) and non-users (7) | MDDC | qPCR and Flow cytometry | Changes on CB1R, CB2R and GPR55 gene and protein expression levels | ↑ CB2R and GPR55 gene expression in MDDC of alcohol users Ethanol treatment increased both target’s gene expression levels | [59] |
Neuroimaging | |||||
Animal Studies | |||||
Male Wistar rats | Ethanol administration (acute: 4 g/kg, i.p.; chronic: liquid diet containing ethanol 7.2 % v/v) | PET ([18F]MK-9470) | CB1R binding | ↑ CB1R density in the NAcc after acute ethanol ↓ CB1R density in the Hipp and CPu after chronic ethanol, effect reversed after 7 and 14 days of abstinence | [60] |
Clinical Studies | |||||
Patients with AD (n = 8) and healthy controls (n = 8) | Scans at least 4 weeks after the last drink | PET ([11C]OMAR) | CB1R binding | ↑ CB1R density in the Amy, Hipp, putamen, insula, anterior and posterior cingulate cortices, and orbitofrontal cortex of patients with AD | [61] |
In-patients with AD | 2 scans: within 3–7 days of admission from ongoing drinking, and after 2–4 weeks of supervised abstinence | PET ([18F]FMPEP-d2) | CB1R binding | 1st scan: ↓ CB1R density in patients with AD and negatively correlated with years of alcohol abuse 2nd scan: ↓ CB1R density in patients with AD (similar result as in the 1st scan) | [62] |
Healthy social drinkers (n = 20), alcoholic patients (n = 26) and healthy subjects (n = 17) | Acute intravenous ethanol administration vs. chronic heavy drinking | PET ([18F]MK-9470) | CB1R binding | ↑ CB1R density after acute intravenous ethanol injection ↓ CB1R density in chronic drinking patients | [63] |
Patients with AD (n = 23) and healthy controls (n = 25) | Scans 3–7 days and 2–4 weeks after abstinence | PET ([C-11]CURB) | FAAH binding | ↓ FAAH density in alcoholic patients during early abstinence (3–7 days) No changes after 2–4 weeks of abstinence | [64] |
Cannabinoid Use Disorders | |||||
---|---|---|---|---|---|
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
Gene Polymorphisms | |||||
Cannabis dependent patients | Whole blood | Genotyping | CNR1 SNP rs1049353 | Positive association with CD symptoms ↓ anterior cingulum volume by structural MRI | [67] [68] |
CNR1 SNP rs806380 | No association Positive association with CD symptoms | [67] [69,70] | |||
CNR1 SNP rs806368 | Positive association with CD symptoms | [69] | |||
Daily marijuana smokers | Whole blood | Genotyping | CNR1 rs2023239 (allele G) | Positive correlation with significant withdrawal and craving | [71] |
- | fMRI | ↑ activity in OFC, IFG, ACG | [72] | ||
Heavy cannabis users | - | fMRI | CNR1 rs2023239 (allele G) | Small hippocampal volume | [73] |
Heavy cannabis users | - | fMRI | CNR1 rs1406977 | ↑ connectivity in the left ventrolateral PFC ↓ working memory | [74] |
Schizophrenic patients with CUD | Whole blood | Genotyping | CNR1 SNP rs12720071 (allele G) | Small parietal white matter volume | [75] |
CNR2 rs2501431 | An association with the MAPK14 SNP rs12199654 (A-allele carriers) and small cerebral and lobar white matter volumes Positive correlation with CUD | [76] [77] | |||
CNR2 rs12744386 and rs35761398 | High risk for schizophrenia | [78] | |||
Street drug users | Whole blood | Genotyping | FAAH rs324420 (allele A) | Positive correlation with street drug use | [79] |
Healthy adult volunteers | - | fMRI | ↑ ventral STR reactivity and ↓ AMY reactivity + correlation between STR reactivity and ↑ impulsivity trait − correlation between AMY reactivity and anxiety traits | [80] | |
Cannabis dependent patients | Whole blood | Genotyping | FAAH rs324420 (allele C) | ↑ bias to appetite stimuli | [81] |
↑ risk for CUD | [72,82,83] | ||||
Positive correlation with craving | [71] | ||||
fMRI | ↑ activation of OFC, ACG and NAc | [72] | |||
Children with sexual abuse and cannabis dependent symptoms | Whole blood | Genotyping | MGLL SNP rs604300 | Positive association with stress adaptation | [84] |
Gene and protein changes | |||||
Animal studies | |||||
Rats Wistar rats | CP-55,940 (0.4 mg/kg, i.p., 11 days) | In situ hybridization | CB1R mRNA in CPu | ↓ CNR1 at 11 days of administration | [85] |
Δ9-THC (5 mg/kg, i.p.; 14 days) | ↓ CNR1 at 14 days of administration | [86] | |||
Wistar rats | Δ9-THC (10 mg/kg, i.p., 5 days) | In situ hybridization | CB1R mRNA in CPu | ↑ CNR1 | [87] |
Long-Evan rats | Δ9-THC (1.5 mg/kg, i.p., every third day, from PNDs 28 to 49) | Fluorescent immunosorbent assay | CB1R mRNA in PFC | ↓ CNR1 | [88] |
LC-MS analysis of endogenous cannabinoids | 2-AG levels in PFC | ↑ 2-AG | |||
Swiss Albino mice | Spontaneous CP-55,940 withdrawal (0.5 mg/kg/12 h; i.p.; 6–7 days) | In situ hybridization | Brain CB1R mRNA levels | ↑ CNR1 in NAc, VMN, CeA, HIPP (CA1) | [89,90] |
C57Bl/6J mice | Spontaneous CP-55,940 withdrawal (0.5 mg/kg/12 h; i.p.; 7 days) | qPCR | CB2R mRNA in NAc | ↓ CNR2 | [91] |
Wistar rats | Δ9-THC (5 mg/kg; i.p.; 14 days) | [35S] GTPgammaS binding autoradiography [3H] CB1R-agonist receptor autoradiography | Brain CB1R binding | ↓ CB1R binding in striatum, limbic forebrain and cerebellum | [86] |
CP-55,940 (1, 3 and 10 mg/kg; i.p; 2 weeks) and Δ9-THC (10 mg/kg; i.p.; 2 weeks) | [92] | ||||
Δ9-THC (6.4 mg/kg; i.p.; 7 days) | [93] | ||||
NIH Swiss Mice Sprague-Dawley rats | Δ9-THC (30 mg/kg; i.p.) | [94] | |||
Δ9-THC (10 mg/kg; i.p.; 21 days) | [95] | ||||
Wistar rats | Δ9-THC (3 mg/kg; i.p.; 3 days) | ↑ CB1R binding cerebellum and HIPP | [96] | ||
Long Evans rats | Δ9-THC 1.5 mg/kg; i.p.; PND 28-49) | GC-MS | Brain AEA levels | ↑ AEA in NAcc | [88] |
Wistar rats | Δ9-THC (10 mg/kg; i.p.; 8 days) | ↑ AEA in limbic forebrain areas | [97,98] | ||
FAAHC/A mice (C57Bl/6J background) | Acute THC (1 mg/kg) | Immunohistochemistry Immunoelectron microscopy | Analysis of CB1R, GABA and Glu terminals in NAcc and mPFC | ↑ CB1R ↑ GABAergic terminals VTA ↑ Glu terminals VTA | [99] |
Clinical studies | |||||
THC dependent patients | PBMCs | qPCR and methylation-specific PCR | CB1R mRNA in PBMCs | ↑ CNR1 Hypomethylation of CNR1 promoter | [100] |
Healthy volunteers | Plasma Acute single THC administration (20 mg/kg) | LC-MS | Endogenous cannabinoids | ↓ AEA, 2-AG, PEA and OEA | [101] |
Cannabis dependent patients | - | fMRI | FAAH and MGLL | Changes in white matter associated with regional MAGL gene expression (posterior cingulate, parietal cortex, basal ganglia, temporal cortex) | [102] |
Postmortem brain tissue | qPCR | ||||
Neuroimaging | |||||
Clinical studies | |||||
Cannabis smokers not seeking treatment (n = 30, males) and control subjects (n = 28, males) | Scans the first day after admission and approximately 4 weeks after abstinence | PET ([18F]FMPEP-d2) | CB1R binding | ↓ CB1R density in cannabis smokers CB1R density returned to normal levels after 4 weeks of abstinence from cannabis | [103] |
Chronic cannabis users (n = 10) and age-matched healthy subjects (n = 10) | Scan within the first week following the last cannabis consumption | PET ([18F]MK-9470) | CB1R binding | ↓ CB1R density in the temporal lobe, anterior and posterior cingulate cortex and NAcc in chronic cannabis users | [104] |
Healthy volunteers (n = 14) | THC administration (10 mg, oral, acute) vs. placebo Scans at baseline and long-term after THC exposure | PET ([11C]MePPEP) | CB1R binding | The severity of THC-induced anxiety was directly correlated with the baseline availability of CB1R in the amygdala | [105] |
Cannabis dependent patients (n = 11) and healthy controls (n = 19) | Scans at baseline and after 2 and 28 days of monitored abstinence | PET ([11C]OMAR) | CB1R binding | Negative correlation between CB1R availability and withdrawal symptoms after 2 days of abstinence. No significant group differences in CB1R availability in cannabis dependents after 28 days of abstinence | [106] |
Chronic, frequent cannabis users (n = 10) and healthy controls (n = 22) | Scans during early abstinence in frequent cannabis users | PET ([11C]CURB) | FAAH binding | ↓ FAAH density in cannabis users Lower FAAH was associated with higher trait impulsiveness FAAH binding is dependent on the genetic FAAH polymorphism rs324420 (C385A) | [107] |
Cannabis users (n = 14) and healthy controls (n = 18) | Scans after recent cannabis consumption | PET ([11C]CURB) | FAAH binding | FAAH binding was 12% lower in cannabis users. Lower FAAH binding was related to greater use of cannabis throughout the past year | [108] |
Cannabis use disorder patients (n = 10, females) and healthy controls (n = 17) | Scans after 3 days of monitored cannabis abstinence | PET ([11C]OMAR) | CB1R binding | ↓ CB1R in female patients with cannabis use disorder in specific brain regions (Hipp, Amy, cingulate, and insula). CB1R binding in the Amy was negatively correlated with mood changes (anger/hostility) during abstinence | [109] |
Opioid-Related Disorders | |||||
---|---|---|---|---|---|
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
Gene Polymorphisms | |||||
Former heroin addicts | Whole blood | Genotyping | FAAH SNP 385C>A CNR1 SNP 18087-18131(TAA)8–17 CNR1 SNP 1359G>A CNR1 genotype pattern | No association Long repeats (≥14) associated with heroin addiction Protection from heroin addiction with allele 1359A and genotype 1359AA 1359G>A and 6274A>T associated with heroin addiction | [126] |
Opiate-dependent outpatients under stable methadone treatment | Whole blood | Genotyping | CNR1 SNP rs2023239 | Minor C allele of rs2023239 associated with a protective effect against lifetime MDD | [127] |
Gene and Protein Changes | |||||
Animal Studies | |||||
Swiss mice | Morphine (8–45 mg/kg, s.c., 5 days) | [3H]-CP55,940 autoradiography [35S] GTPγS binding autoradiography | CB1r binding WIN-55,212-2-stimulated [35S] GTPγS binding | ↓ CB1r in the Globus pallidus ↑ CB1r function in the SN and central gray substance | [128] |
Wistar rats | Morphine (10–100 mg/kg, i.p., 6 days) | [3H]-CP55,940 autoradiography [35S] GTPγS binding autoradiography In situ hybridization GC-MS | CB1r binding WIN-55,212-2-stimulated [35S] GTPγS binding CB1r mRNA levels AEA levels | ↑ CB1r in medial CPu, septum and NAcc ↓ CB1r in the midbrain and cerebral cortex ↑ CB1r function in the cerebral cortex ↓ CB1r function in the brainstem ↓ CNR1 gene expression in the CPu and cerebellum ↑ CNR1 gene expression in the CA2 region of the Hipp and septum No changes | [129] [130] [129] [130] |
Sprague-Dawley rats | Morphine (5 mg/kg, s.c., 4.5 days) | [3H]-CP55,940 autoradiography [35S] GTPγS binding autoradiography GC-MS | CB1r binding CP-55,940-stimulated [35S] GTPγS binding AEA and 2-AG levels | ↓ CB1r in the cerebellum and Hipp ↓ CB1r function in the NAcc ↓ 2-AG levels in NAcc and Hipp No changes in AEA levels | [131] |
Sprague-Dawley rats | Morphine (5 mg/kg, i.p., 5 days) | Proteomics analysis (HPLC-ESI-MS/MS) WB qPCR LC-MS | 32 different proteins related to the ECS DAGL, MAGL, and CB2r protein levels MAGL, CB2r, CB1r mRNA levels AEA and 2-AG levels | ↓ MAGL levels in the VTA No changes ↓ CNR2 gene expression in the VTA No changes | [132] |
Wistar rats | Chronic morphine (10 mg/kg, s.c., 12 days) Acute morphine (10 mg/kg, s.c.) | WB qPCR | CB1r protein levels CB1r mRNA levels | ↑ CNR1 protein expression in the cortex, cerebellum and Hipp ↑ CB1R gene expression in the cortex, cerebellum, Hipp, and PBMCs ↓ CB1R gene expression in the cerebellum ↑ CB1R gene expression in PBMCs | [133] |
Wistar rats | Acute morphine (5 and 10 mg/kg, s.c.) Chronic morphine (10–40 mg/kg, s.c., 5 days) and morphine challenge (5 and 10 mg/kg, s.c.) | LC-MS | AEA and 2-AG levels | ↑ AEA and ↓ 2-AG levels in NAcc (shell) ↑ AEA and ↓ 2-AG levels in NAcc (shell) | [134] |
Sprague-Dawley rats | Chronic morphine (10 mg/kg, s.c., 5 conditioning days during CPP) | qPCR | CB2r mRNA levels | ↑ CNR2 in the cortex, spleen, and PBMCs ↓ CNR2 in the brainstem | [135] |
Sprague-Dawley rats | Morphine withdrawal after chronic exposure (10 mg/kg, s.c., 5 conditioning days during CPP) | WB Immunoelectron microscopy | CB1r protein levels CB1r-positive terminals | ↑ CB1r protein expression in the NAcc ↑ CB1r-positive symmetric synapses | [136] |
Sprague-Dawley rats | Morphine withdrawal after chronic exposure (10 mg/kg, s.c., 7 conditioning days during CPP) | WB | DAGL and MAGL protein levels | ↑ DAGL protein expression in the NAcc No changes in MAGL | [137] |
C57BL/6J mice | Morphine (5, 8, 10, and 15 mg/kg; s.c.; 4 conditioning days during CPP) | qPCR | CB1r, CB2r, FAAH MAGL, NAPE-PLD, DAGL mRNA levels in the dorsal Hipp | CPP expression ↑ FAAH and MGLL and ↓ CNR1 and CNR2 gene expression CPP extinction No changes CPP reinstatement ↓ MGLL and ↑ CNR1 gene expression | [138] |
Sprague-Dawley rats | Behavioral sensitization to morphine (10, 20 y 40 mg/kg, s.c., 3 days + 5 mg/kg s.c. morphine challenge after 2 weeks of withdrawal) | LC-MS β-counter to measure [14C]ethanolamine | AEA and 2-AG levels FAAH activity | ↓ AEA levels in the CPu and Hipp ↑ 2-AG levels in the Hipp No changes | [139] |
Lister-Hooded rats | Heroin self-administration (30 µg/kg/inf, i.v., 2-h daily sessions, 16 days) | [3H]-CP55,940 autoradiography [35S] GTPγS binding autoradiography | CB1r binding CP-55,940-stimulated [35S] GTPγS binding | ↑ CB1r in the Amy and VTA ↑ CB1r function in the PFC, NAcc, CPu, Hipp, and Amy | [140] |
Clinical Studies | |||||
Morphine abusers | Whole blood | qPCR | CB1r and CB2r mRNA levels | ↑ CNR1 and CNR2 in PBMCs | [135] |
Stimulant-Related Disorders | |||||
---|---|---|---|---|---|
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
Gene Polymorphisms | |||||
Cocaine-dependent EA (n = 734) and AA (n = 834) patients | Whole blood | Genotyping | CNR1 SNP rs6454674 rs806368 (allele G) | ↑Interaction effects on the risk of cocaine dependence | [142] |
Cocaine-dependent AA (n = 926) patients | Whole blood | Genotyping | CNR1 SNP rs6454674 rs806368 | Positive association with cocaine dependence | [143] |
Cocaine-dependent AC patients with schizophrenia (n = 45) | Whole blood | Genotyping | CNR1 SNP | Positive association with cocaine dependence | [144] |
Cocaine-dependent AC patients non-schizophrenic (n = 97) | |||||
Cocaine use disorder patients (n = 70) | Whole blood | Genotyping | FAAH rs324420 | Positive association with cocaine use disorder patients ↑Drug effects (high and depression) | [145] |
METH-dependent Chinese Han patients (n = 430) and Control (n = 631) | Whole blood | Genotyping | FAAH rs324420 (allele A) | ↑Risk of METH dependence | [146] |
METH-dependence Malaysian patients | Whole blood | Genotyping | FAAH rs324420 | ↑Risk of METH dependence | [147] |
METH dependence with manic episodes (Total n = 232) | ↑Risk of METH-induced mania | ||||
Gene and protein changes | |||||
Animal studies | |||||
Adult male mice C57BL/6J | Single high dose of METH 30 mg/kg, i.p | LC-MS | Levels of AEA and 2-AG in STR | ↑ Levels of AEA ↓ Levels of 2-AG | [148] |
Adult Dark Agouti rats | Acute MDMA administration 12.5 mg/kg | IHC | CB2R mRNA levels | ↑Expression of CB2 in microglial cells in de PFC | [149] |
Male mice C57BL/6J | Acute cocaine administration 10 mg/kg | qPCR | DAGLα TH in the cerebellum | ↓DAGLα ↑TH | [150] |
CS (10 mg/kg) after chronic administration (20 mg/kg) | WB | FAAH DAGLβ in the cerebellum | ↓FAAH ↓DAGLβ | ||
Male mice C57BL/6J | Pre-treatment (20 mg/kg, 5 days) and treatment (10 mg/kg) after 6 days of extinction | qPCR | CB1R, NAPE-PLD, DAGLα mRNA levels in the Hipp | ↓CNR1 ↓NAPE-PLD ↓DAGLα | [151] |
Male mice C57BL/6J | 2 sessions of crack-cocaine inhalation/day for 11 days | qPCR | FAAH, MAGL, CB1R NAPE-PLD and DALGα mRNA levels in the PFC | ↓FAAH, MGLL, CNR1 | [152] |
Not altered NAPE-PLD and DALGα expression | |||||
Sprague-Dawley rats | CS (15 mg/kg, i.p.) for 7 days (PND 33–39, PND 40–46, PND 47–53) | WB | CB1R and CB2R PFC and Hipp | ↑CB1R ↓CB2R PND 33-39 in PFC | [153] |
Adult male CD1 mice | Cocaine 20 mg/kg, i.p., 7 days | WB | CB1R Cb2 r in PFC | ↓CB1R | [154] |
Drug abusers and controls | PFC/BA9 samples | Not alteration in CB2R | |||
Wistar rats | Cocaine (8 mg/kg/day) in maternally deprived and control animals (PND 28–48) | WB | CB1R in the Hipp | ↑CB1R in Control ↓CB1R in Maternally deprived animals | [155] |
Wistar rats | Cocaine intravenous self-administration for 14 days | IHC | CB1R, CB2R protein expression in the PFC, Amy, VTA, NAcc and Hipp | ↓ CB1R PFC and Amy, ↑CB1R in the VTA ↓CB2R PFC and NAcc | [156] |
Cocaine intravenous self-administration for 14 days after 10 days of extinction | ↑CB1R in the Amy ↓CB2R PFC and NAcc | ||||
Wistar rats | Cocaine intravenous self-administration paradigm and Priming of cocaine (10 mg/kg) | Brain sample (Chromatography and IHC) | AEA, 2-AG (Hipp and NAcc) CB1R and CB2R (PFC, LSN, VTA) NAPEs, OEA and PEA (STR, NAcc, cerebellum and Hipp) | ↑AEA Hipp—PFC ↑2-AG Hipp—NAcc ↑CB1R and CB2R in the PFC and LSN ↓CB1R in the VTA ↑NAPE in the STR ↓OEA and PEA in the NAcc, cerebellum and Hipp | [157] |
Male Sprague-Dawley rats | Cocaine self-administration paradigm 30 days of abstinence | WB | DAGL and MAGL in the NAcc | ↑DAGL and ↓MAGL | [158] |
Male Sprague-Dawley rats | Cocaine self-administration (0.75 mg/kg/infusion) for 6 to 9 days | Ex vivo electrophysiology in VTA | ECS-mediated LTD | Abolished LTD ↓CB1R presynaptic | [159] |
Lewis and F344 rats | Cocaine self-administration (1 mg/kg per infusion, 21 days) | IHC | CB1R and CB2R in Hipp | CB1R Lewis rats < CB1R F344 CB2R Lewis rats > CB2R F344 | [160] |
Naïve WT mice | Single injection of cocaine (10, 20, 30 mg/kg, i.p.) | qPCR ISH | CB2R, D1-MSNs, D2-MSNs in the STR and microglia | No alteration | [161] |
Repeated cocaine administration (10, 20 mg/kg, i.p for 7 days) Cocaine self-administration (1 mg/kg/infusion to 0.5 mg/kg/infusion) | ↑CB2R D1-MSNs > D2-MSNs | ||||
Clinical studies | |||||
Healthy recreational polydrug users (n = 20) | Pre-treatment with ketanserin (40 mg), followed 30 min later by MDMA (75 mg) | Chromatography | AEA and 2-AG | No changes | [162] |
Abstinent cocaine addicts with and without comorbidities (n = 134) | Plasma | Chromatography | NAEs 2-acylglycerols | ↑NAEs ↓2-acylglycerols in Cocaine addicts ↑↑NAE in cocaine addicts with mood and anxiety disorder | [163] |
Recreational cocaine users (n = 48), cocaine dependent users (n = 25), and controls (n = 67) | Hair samples | LC-MS/MS | Cortisone, cortisol, 2-AG, AEA, OEA, and PEA | ↑Cortisone in recreational cocaine users and cocaine dependent users ↓OEA ↓PEA in cocaine dependent users compared to recreational cocaine users and controls No significant differences AEA and 2-AG levels | [164] |
Tobacco-Related Disorders | |||||
---|---|---|---|---|---|
Subjects | Sample/Intervention | Method | Measurement | Main Outcomes | References |
Gene Polymorphisms | |||||
Nicotine dependent patients divided in 2 samples (Virginia Study of Nicotine Dependence (VAND, n = 688) and Virginia Study of Anxiety and Neuroticism (VAANX, n = 961) | Whole blood | Genotyping | CNR1 SNP rs6928499 rs2023239 CNR1 1-1-2 haplotype (SNP rs2023239-rs12720071-rs806368) | Positive association with smoking initiation and nicotine dependence Positive association with nicotine dependence | [169] |
Regular tobacco smokers (n = 104) | Whole blood | Genotyping | CNR1 SNP rs2023239 (allele C) | Positive association with reduced nicotine reinforcement | [170] |
Tobacco smokers (n = 73) | Whole blood | Genotyping | CNR1 TAG haplotype (SNP rs806379-rs1535255-rs2023239) | Homozygous for the major allele of the CNR1 SNP rs806379 attenuated the cognitive disruption induced by nicotine withdrawal | [171] |
Gene and Protein Changes | |||||
Animal Studies | |||||
Male wistar rats | Chronic nicotine (1 mg/kg, s.c., 7 days) | [3H]-CP55,940 autoradiography In situ hybridization GC-MS | CB1r binding CB1r mRNA levels AEA and 2-AG levels | ↑ CB1r in the cerebral cortex ↓ CNR1 gene expression in the septum AEA levels ↑ in the brainstem and limbic forebrain and ↓ in the Hipp, STR and cerebral cortex AEA levels ↑ in the brainstem and ↓ in the Hipp and cerebral cortex | [172] |
Male C57BL/6J mice | Exposure to tobacco smoke from PND3 to PND14 (two 1h exposures per day, 3R4F reference cigarettes) | WB | CB1r, CB2r, NAPE-PLD, DAGL, FAAH, and MAGL protein levels (infancy, adolescence and adulthood) | ↓ CB1r, CB2r, NAPE-PLD, FAAH and ↑ DAGL, MAGL in the brainstem during infancy ↓ CB2r and FAAH in the brainstem during adulthood ↓ NAPE-PLD, MAGL and ↑ FAAH in the STR during infancy ↑ FAAH in the STR during adolescence ↓ NAPE-PLD in the STR during adulthood | [173] |
Male and female Wistar rats | Subchronic nicotine treatment from PND34 to PND43 (0.4 mg/kg/day, i.p.) | WB | CB1r protein levels (short- and long-term effects) | ↑ CB1r in the Hipp of male and female rats (long-term) ↓ CB1r in the STR of male and female rats (long-term) | [174] |
Male and female Wistar rats | Chronic nicotine exposure from PND 28 to PND 43 (0.7 mg/kg, s.c.) | [3H]-CP55,940 autoradiography [35S] GTPγS binding autoradiography | CB1r binding CP-55,940-stimulated [35S] GTPγS binding | ↓ CB1r in the area 3 of the cingulate cortex of male and female adult Rats ↑ CB1r function in the cingulate cortex (areas 1, 3) and Hipp (CA1, CA3) of male adult rats ↑ CB1r function in the cingulate cortex (area 1) of female adult rats | [175] |
Male Sprague-Dawley rats | Nicotine exposure during adolescence (PND30) and adulthood (PND60) (0.4 mg/kg/day, i.p., 7 days) | [3H]-CP55,940 autoradiography | CB1r binding | ↑ CB1r in the cingulate cortex (areas 1, 3), frontal cortex (area 2), VTA and Hipp (dental gyrus and CA3) of adolescent rats | [176] |
Male Sprague-Dawley rats | Nicotine exposure (0.35 mg/kg, s.c., 4 injections 3 days apart) followed by a nicotine challenge after 1- or 3-week injection-free period (0.1 mg/kg, s.c.) | In situ hybridization | CB1r mRNA levels | ↓ CNR1 gene expression in the BLA and CeA of high responder rats | [177] |
Male C57BL/6J mice | Nicotine exposure (3 μg/g body weight, i.p., four times/day during 4 weeks) combined with HFD | qPCR | CB1r mRNA levels | ↑ CNR1 gene expression in the arcuate, paraventricular, ventromedial and dorsomedial nuclei, lateral hypothalamus and Hipp | [178] |
Wistar rats | Nicotine exposure (5.2 mg/kg/day, transdermal patch, 7 days) | LC-MS | AEA levels 2-AG levels | ↓ AEA levels in the Hipp during acute nicotine withdrawal (16 h) ↑ AEA levels in the Amy and hypothalamus during protracted nicotine withdrawal (32 h) No changes from control group | [179] |
Male C57BL/6J mice | Nicotine exposure (25 mg/kg/day, Alzet minipump, 14 days) | LC-MS WB | AEA and 2-AG levels MAGL and DAGL protein levels | ↑ 2-AG levels and no changes in AEA levels in whole brain homogenates ↓ MAGL and no changes in DAGL levels in whole brain homogenates | [180] |
Male Wistar rats | Nicotine self-administration (75 mg/kg per Infusion, 0.1 mL per infusion over 4 s) | LC-MS (in vivo microdialysis) LC-MS (brain bulk tissue) Monitoring of d8-arachidonic acid | AEA, 2-AG, OEA and PEA levels AEA, 2-AG, OEA and PEA levels FAAH activity | ↑ AEA and 2-AG levels in the VTA ↑ AEA levels in the VTA, SNr, NAcc, dorsal STR, PFC and Amy ↑ OEA levels in the SNr and PFC ↑ PEA levels in the SNr, NAcc, dorsal STR and Hipp No changes | [181] |
Neuroimaging | |||||
Animal Studies | |||||
Female Wistar rats | Chronic nicotine exposure (1 mg/kg, i.p., 2 weeks) | PET ([18F]MK-9470) | CB1r binding | No major changes | [182] |
Clinical studies | |||||
Frequent chronic cigarette smokers (n = 18, men) vs. non-smokers (n = 28, men) | - | PET ([18F]FMPEP-d2) | CB1r binding | ↓ CB1r density in tobacco smokers | [183] |
Schizophrenic patients smokers (n = 11, men) and non-smokers (n = 14, men) vs. control subjects (n = 18, men) | - | PET ([(11)C]OMAR) | CB1r binding | ↓ CB1r density in schizophrenics (smokers and non-smokers) ↓ CB1r density in non-smoker schizophrenics | [184] |
Hallucinogen-Related Disorders | |||||
---|---|---|---|---|---|
Drug | Species | Paradigm | Methods | Findings | Reference |
Ayahuasca | Human | Acute (1 mL/kg, p.o.) | LC-MS | ↓ AEA Plasma; 2-AG low reduction follow increased plasma levels (in healthy volunteers) | [187] |
ketamine | Mice | Subchronic (15 mg/kg, i.p., 7 days) | LC-MS qPCR | CPu: ↑ AEA and 2-AG levels. ↓ NAPE | [188] |
CeA: ↑ AEA levels | |||||
NAcc: ↑ 2-AG levels | |||||
PFC: ↑ AEA levels and ↓ 2-AG levels | |||||
Ketamine hyperlocomotion paradigm | qPCR | CPU & PFC: ↓ mRNA of MAGL | |||
Immunoblotting | CPU: ↓ MAGL protein | ||||
PCP | Mice | Acute (post-natal days 7, 9 and 11, s.c.) | Immunohistochemistry | ↓ CB1R in the prelimbic mPFC | [189] |
↑ CB1R in the dental gyrus | |||||
Rat | Sub-chronic (5 mg/kg, 7 days, i.p.) | GC/MS | ↑ AEA in the NAcc (after motor activity test) | [190] | |
Sub-chronic (twice a day 5 mg/kg 7 days i.p.) | GC/MS | ↓ AEA levels in the mPFC and in the Amy but ↑ in NAcc ↑ 2-AG in the NAcc and in the CPu (after social interaction) | [191] | ||
Immunoblotting | ↑ NAPE-PLD expression in mPFC (after social interaction) | ||||
Chronic-intermittent (2.5 mg/kg, i.p., 4 weeks) | Autoradiographic-binding | ↑ CB1R density in Amygdala and VTA; ↓ stimulation in PFC, Hipp, SN, and cerebellum. ↑ stimulation in Globus pallidus. | [192] |
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Navarrete, F.; García-Gutiérrez, M.S.; Gasparyan, A.; Navarro, D.; López-Picón, F.; Morcuende, Á.; Femenía, T.; Manzanares, J. Biomarkers of the Endocannabinoid System in Substance Use Disorders. Biomolecules 2022, 12, 396. https://doi.org/10.3390/biom12030396
Navarrete F, García-Gutiérrez MS, Gasparyan A, Navarro D, López-Picón F, Morcuende Á, Femenía T, Manzanares J. Biomarkers of the Endocannabinoid System in Substance Use Disorders. Biomolecules. 2022; 12(3):396. https://doi.org/10.3390/biom12030396
Chicago/Turabian StyleNavarrete, Francisco, María S. García-Gutiérrez, Ani Gasparyan, Daniela Navarro, Francisco López-Picón, Álvaro Morcuende, Teresa Femenía, and Jorge Manzanares. 2022. "Biomarkers of the Endocannabinoid System in Substance Use Disorders" Biomolecules 12, no. 3: 396. https://doi.org/10.3390/biom12030396