Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury
Abstract
:1. Introduction
2. Materials and Methods
3. The Main Characteristics of AUD/PTSD
4. Molecular Toxicology and Pathophysiological Mechanisms of AUD/PTSD
4.1. Metabolomics in AUD/PTSD
4.2. Changes in Inflammatory Cytokines
4.3. Neuroendocrine Alterations
4.4. Altered Signaling Transduction Pathways in the Brain
4.5. Genetic and Epigenetic Changes in the Brain
5. A Variety of Possible Hypotheses Leading to AUD/PTSD
5.1. Metabolic Dysfunction Hypothesis
5.2. Inflammation Hypothesis
5.3. Neuroendocrine Alterations Hypothesis
5.4. Genetic Changes Hypotheses
5.5. Integrated Hypotheses
6. Implications and Further Research Directions
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Item | Diagnostic Criteria or Characteristics |
---|---|
The diagnostic criteria of AUD (DSM-5) | The DSM-5 defines AUD as a problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least 2 of the following 11 symptoms occurring within 12-months [38,39,40].
|
The diagnostic criteria of PTSD (DSM-5) | Under DSM-5, for those older than six years of age, PTSD includes four clusters of symptoms [41]:
|
The characteristics of AUD/PTSD | The main characteristics of comorbidity between PTSD and AUD following TBI:
|
Change Composition | Effect | State | Reference |
---|---|---|---|
Metabolism/Pharmacokinetics | |||
Catalase | Ethanol oxidation in cortical brain tissue↑ | PTSD | [56] |
CYP2E1 | Oxidative alcohol and acetaldehyde metabolism↑ | AUD, AUD/PTSD | [57] |
Glutamate | Forebrain reward circuit; Forebrain glutamate↑ | AUD, AUD/PTSD | [58] |
Cholesterol | Synaptogenesis, and synaptic communication↓ | AUD | [59] |
Phosphatidylethanol | Brain lipid membranes | AUD | [60] |
alpha 6-nicotinic acetylcholine | Target sensitivity↓ | AUD | [61] |
Inflammatory factors | |||
CRP | CRP levels in the clinically elevated range↑ | PTSD, AUD/PTSD | [62] |
TLR4 | Microglia activation/neuroinflammation↑ | AUD | [63] |
IL-6 | Immunosuppressive effects↑ | PTSD | [64] |
Neuroendocrine components | |||
5-HT | Receptor responsiveness↑ Dopamine transmission↑ | AUD | [65] |
Serotonin transporter | Moderate associations between TBI and PTSD | PTSD | [66] |
BDNF Val66Met | Alcohol dependence | AUD | [67] |
BDNF Met/Met genotype | Post-deployment PTSD score changes | PTSD | [68] |
IGF-1 | Plasma concentrations↓ | AUD/PTSD | [69] |
Gut-brain peptides | Regulate addictive behaviors | AUD/PTSD | [70] |
Genes | Cause | State | Reference |
---|---|---|---|
DNA | |||
MCP-1 | Methylation changes | Chronic AUD | [143] |
CYP2E1 | Gene expression changes | Chronic AUD hippocampus ↑ | [144] |
SNP changes | Epigenetic changes | PTSD | [62] |
Polygenic | Induced gene changes | PTSD | [145] |
Methylation | Gene changes | Higher risk PTSD | [143] |
RNA | |||
lncRNAs | Synaptic plasticity | Adolescence | [146] |
microRNAs | Neuroadaptations | Chronic AUD | [147] |
miR-130a | miRNA expression alters | Prefrontal cortex AUD | [147] |
miR-142 | Neuroinflammation ↓ | Alleviate PTSD | [148] |
Chromosome | |||
11q14.2 | Brain structural variation | AUD behavior | [149] |
rs3852144 | Emotional memory formation | PTSD development | [150] |
Transcriptomics and genetics | |||
Atf3, c-Fos, Egr1, Npas4 | Reduced downregulation | AUD after TBI | [151] |
GRIN3B | mRNA level | Biomarker of PTSD | [152] |
Gadd45b, Gadd45c | Upregulation | TBI | [151] |
Parental AUD | More likely offspring AUD | AUD | [153] |
Subcategories | Characteristics of Participants or Animals | Assessments and Tests | Main DATA Findings | Reference |
---|---|---|---|---|
Epidemiological data | A representative US non-institutionalized civilian adult (≥18 years) sample (N = 36,309) as the 2012-2013 NESARC-III. | DSM-5 for AUD | AUD prevalence of 12-months and lifetime were 13.9% and 29.1%, respectively. | [12] |
A national sample of US adults (N = 2953) recruited from an online panel. | DSM-5 for PTSD | PTSD prevalence of lifetime, past 12-months, and past 6-months was 8.3%, 4.7%, and 3.8%, respectively. | [29] | |
A stratified sample of 10,641 participants as part of the Australian national survey of mental health and wellbeing. | The composite international diagnostic interview | AUD is responsible for 24.1% of substance-use problems in PTSD. (DSM-substance-use disorders and ICD-10 personality disorders). | [30] | |
Metabolism data | Rat cortical contusion model. | The activity of catalase | Three-fold increase in catalase activities in a time course. | [56] |
The enzymes of ethanol oxidation in the homogenates from the perfused brains of rats and mice. | Gas chromatography | About 60% of the ethanol oxidation process in rodent brains may be attributed to catalase. | [83] | |
Severe TBI in rats. | Microdialysis determination | Extracellular glutamate levels increased 9-fold compared with uninjured control rats. | [97] | |
Inflammatory factor data | A total of 2600 warzone-deployed marines. | Plasma CRP concentration | Each 10-fold increment in CRP concentration was associated with an odds ratio of a nonzero outcome (presence vs. absence of any PTSD symptoms) of 1.51- and 1-fold increase in outcome with a nonzero value (extent of symptoms when present) of 1.06. | [102] |
C57BL/6 mice and mice deficient in MCP-1 exposed to ethanol. | MCP-1 levels | Ethanol-induced microglial activation, neuroinflammation, and a drastic increase in the mRNA and protein levels of MCP-1. | [63] | |
Patients with an injury severity score and abbreviated injury scale of the head of at least 3 were included upon arrival in the emergency room and grouped according to positive BAC (>0.5%, BAC) vs. less than 0.5% alcohol (no BAC). | Systemic IL-6 levels | Systemic IL-6 levels and leukocyte counts (IL-6: 65.0 ± 8.0 vs. 151.8 ± 22.3; leukocytes: 10.2 ± 0.9 vs. 13.2 ± 0.8, both p < 0.05) were significantly lower in BAC-positive patients. | [64] | |
Neuroendocrine component data | A total of 635 African-American substance-dependent men were recruited. | 5-HT levels,5-HT transporter gene | The HTR3B Ser129 allele and low 5-HTTLPR activity had an additive effect on alcohol + drug dependence (OR = 6.0 (2.1–16.6)) that accounted for 13% of the variance. | [65] |
Both pre- and post-deployment data on 231 of 458 soldiers were analyzed. | BDNF Met/Met genotype | The BDNF Met/Met genotype accounted for 22% of the variance of post-deployment PTSD scores (R (2) = 0.22, p < 0.001). | [68] | |
Abstinent AUD patients (N = 91) and healthy control subjects (N = 55). | Plasma concentrations of BDNF, IGF-1, and IGFBP-3 | AUD patients displayed a high prevalence of dual diagnosis (39.3%) and comorbid substance-use disorders (40.7%). Plasma BDNF and IGF-1 concentrations were significantly lower in the alcohol group than in the control group (p < 0.001). | [69] | |
Genetic data | Genome-wide miRNA and mRNA expression were examined in postmortem PFCs of 23 European and Australian AUD cases and 23 matched controls using the Illumina HumanHT-12 v4 Expression BeadChip array. | Target gene prediction, gene set enrichment analysis, and DAVID functional annotation clustering analysis | Two miRNAs and 787 coding genes were differentially expressed in the PFC of AUD cases. Downregulation of miR-130a may lead to altered expression of a number of genes in the PFC of AUD. | [147] |
A total of 924 Northern Ugandan rebel war survivors; identified seven suggestively significant SNPs; p ≤ 1 × 10−5 for lifetime PTSD risk. | Genome-wide association studies | Emotional memory formation seems to decline with the increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. | [150] | |
Danish nationwide registers; 15,477 offspring with parental AUD and 154,392 reference individuals from the general population. | Parental AUD was defined as registration for AUD treatment. AUD in offspring was identified from medical, pharmacy, treatment, and cause of death registers. | Paternal AUD plus other mental disorders (hazard ratio (HR) = 2.27, 95% confidence interval (CI): 2.10–2.46) and paternal AUD alone (HR = 2.21, 95% CI: 2.07–2.36) were associated with higher offspring AUD risk. | [153] |
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Wang, Z.; Luo, C.; Zhou, E.W.; Sandhu, A.F.; Yuan, X.; Williams, G.E.; Cheng, J.; Sinha, B.; Akbar, M.; Bhattacharya, P.; et al. Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury. Int. J. Mol. Sci. 2023, 24, 8805. https://doi.org/10.3390/ijms24108805
Wang Z, Luo C, Zhou EW, Sandhu AF, Yuan X, Williams GE, Cheng J, Sinha B, Akbar M, Bhattacharya P, et al. Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury. International Journal of Molecular Sciences. 2023; 24(10):8805. https://doi.org/10.3390/ijms24108805
Chicago/Turabian StyleWang, Zufeng, Chengliang Luo, Edward W. Zhou, Aaron F. Sandhu, Xiaojing Yuan, George E. Williams, Jialu Cheng, Bharati Sinha, Mohammed Akbar, Pallab Bhattacharya, and et al. 2023. "Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury" International Journal of Molecular Sciences 24, no. 10: 8805. https://doi.org/10.3390/ijms24108805