Long-term impact of alcohol on the brain

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While researchers have found that moderate alcohol consumption in older adults is associated with better cognition and well-being than abstinence,[1] excessive alcohol consumption is associated with widespread and significant brain lesions. The effects can manifest much later—mid-life Alcohol Use Disorder has been found to correlate with increased risk of severe cognitive and memory deficits in later life.[2][3] Alcohol related brain damage is not only due to the direct toxic effects of alcohol; alcohol withdrawal, nutritional deficiency, electrolyte disturbances, and liver damage are also believed to contribute to alcohol-related brain damage.[4] The long-term effects of excessive alcohol consumption on brain chemistry is an important cause of chronic fatigue.[5]

Adolescent brain development[edit]

Consuming large amounts of alcohol over a period of time can impair normal brain development in humans.[6] Deficits in retrieval of verbal and nonverbal information and in visuospatial functioning were evident in youths with histories of heavy drinking during early and middle adolescence.[7][8]

During adolescence critical stages of neurodevelopment occur, including remodeling and functional changes in synaptic plasticity and neuronal connectivity in different brain regions. These changes may make adolescents especially susceptible to the harmful effects of alcohol. Compared to adults, adolescents exposed to alcohol are more likely to exhibit cognitive deficits (including learning and memory dysfunction). Some of these cognitive effects, such as learning impairments, may persist into adulthood.[9]

Mechanisms of action[edit]

Neuroinflammation[edit]

Ethanol can trigger the activation of astroglial cells which can produce a proinflammatory response in the brain. Ethanol interacts with the TLR4 and IL-1RI receptors on these cells to activate intracellular signal transduction pathways. Specifically, ethanol induces the phosphorylation of IL-1R-associated kinase (IRAK), ERK1/2, stress-activated protein kinase (SAPK)/JNK, and p38 mitogen-activated protein kinase (p38 MAPK). Activation of the IRAK/MAPK pathway leads to the stimulation of the transcription factors NF-kappaB and AP-1. These transcription factors cause the upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression.[10] The upregulation of these inflammatory mediators by ethanol is also associated with an increase in caspase 3 activity and a corresponding increase in cell apoptosis.[10][11] The exact mechanism by which various concentrations of ethanol either activates or inhibits TLR4/IL-1RI signaling is not currently known, though it may involve alterations in lipid raft clustering [12] or cell adhesion complexes and actin cytoskeleton organization.[13]

Changes in dopaminergic and glutamatergic signaling pathways[edit]

Intermittent ethanol treatment causes a decrease in expression of the dopamine receptor type 2 (D2R) and a decrease in phosphorylation of 2B subunit of the NMDA receptor (NMDAR2B) in the prefrontal cortex, hippocampus, nucleus accumbens, and for only D2R the striatum. It also causes changes in the acetylation of histones H3 and H4 in the prefrontal cortex, nucleus accumbens, and striatum, suggesting chromatin remodeling changes which may mediate long-term alterations. Additionally, adolescent rats pre-exposed to ethanol have higher basal levels of dopamine in the nucleus accumbens, along with a prolonged dopamine response in this area in response to a challenge dose of ethanol. Together, these results suggest that alcohol exposure during adolescence can sensitize the mesolimbic and mesocortical dopamine pathways to cause changes in dopaminergic and glutamatergic signaling, which may affect the remodeling and functions of the adolescent brain.[14] These changes are significant as alcohol’s effect on NMDARs could contribute to learning and memory dysfunction (see Effects of alcohol on memory).

Inhibition of hippocampal neurogenesis[edit]

Excessive alcohol intake (binge drinking) causes a decrease in hippocampal neurogenesis, via decreases in neural stem cell proliferation and newborn cell survival.[15][16] Alcohol decreases the number of cells in S-phase of the cell cycle, and may arrest cells in the G1 phase, thus inhibiting their proliferation.[15] Ethanol has different effects on different types of actively dividing hippocampal progenitors during their initial phases of neuronal development. Chronic alcohol exposure decreases the number of proliferating cells that are radial glia-like, preneuronal, and intermediate types, while not affecting early neuronal type cells; suggesting ethanol treatment alters the precursor cell pool. Furthermore, there is a greater decrease in differentiation and immature neurons than there is in proliferating progenitors, suggesting that the abnormal decrease in the percentage of actively dividing preneuronal progenitors results in a greater reduction in the maturation and survival of postmitotic cells.[16]

Additionally, alcohol exposure increased several markers of cell death. In these studies neural degeneration seems to be mediated by non-apoptotic pathways.[15][16] One of the proposed mechanisms for alcohol’s neurotoxicity is the production of nitric oxide (NO), yet other studies have found alcohol-induced NO production to lead to apoptosis (see Neuroinflammation section).

References[edit]

  1. ^ Lang, I.; Wallace, R. B.; Huppert, F. A.; Melzer, D. (2007). "Moderate alcohol consumption in older adults is associated with better cognition and well-being than abstinence". Age and Ageing 36 (3): 256. doi:10.1093/ageing/afm001. PMID 17353234.  open access publication - free to read
  2. ^ Caroline Cassels (July 30, 2014). "Midlife Alcohol Abuse Linked to Severe Memory Impairment". Medscape (WebMD LLC). 
  3. ^ Kuźma, E. B.; Llewellyn, D. J.; Langa, K. M.; Wallace, R. B.; Lang, I. A. (2014). "History of Alcohol Use Disorders and Risk of Severe Cognitive Impairment: A 19-Year Prospective Cohort Study". The American Journal of Geriatric Psychiatry 22 (10): 1047. doi:10.1016/j.jagp.2014.06.001.  edit
  4. ^ Neiman, J. (Oct 1998). "Alcohol as a risk factor for brain damage: neurologic aspects". Alcohol Clin Exp Res 22 (7 Suppl): 346S–351S. doi:10.1111/j.1530-0277.1998.tb04389.x. PMID 9799959. 
  5. ^ Avellaneda Fernández, A.; Pérez Martín, A.; Izquierdo Martínez, M.; Arruti Bustillo, M.; Barbado Hernández, FJ.; de la Cruz Labrado, J.; Díaz-Delgado Peñas, R.; Gutiérrez Rivas, E.; Palacín Delgado, C.; Rivera Redondo, Javier; Ramón Giménez, José Ramón (2009). "Chronic fatigue syndrome: aetiology, diagnosis and treatment". BMC Psychiatry. 9 Suppl 1: S1. doi:10.1186/1471-244X-9-S1-S1. PMC 2766938. PMID 19857242. 
  6. ^ Tapert SF, Brown GG, Kindermann SS, Cheung EH, Frank LR, Brown SA (February 2001). "fMRI measurement of brain dysfunction in alcohol-dependent young women". Alcohol. Clin. Exp. Res. 25 (2): 236–45. doi:10.1111/j.1530-0277.2001.tb02204.x. PMID 11236838. 
  7. ^ Squeglia LM, Jacobus J, Tapert SF (January 2009). "The influence of substance use on adolescent brain development". Clin EEG Neurosci 40 (1): 31–8. PMC 2827693. PMID 19278130. 
  8. ^ Brown SA, Tapert SF, Granholm E, Delis DC (February 2000). "Neurocognitive functioning of adolescents: effects of protracted alcohol use". Alcohol Clin Exp Res. 24 (2): 164–71. doi:10.1111/j.1530-0277.2000.tb04586.x. PMID 10698367. 
  9. ^ Guerri, C.; Pascual, M. A. (2010). "Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence". Alcohol 44 (1): 15–26. doi:10.1016/j.alcohol.2009.10.003. PMID 20113871.  edit
  10. ^ a b Blanco Am, V. S. S.; Vallés, S. L.; Pascual, M.; Guerri, C. (2005). "Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes". Journal of immunology (Baltimore, Md. : 1950) 175 (10): 6893–6899. doi:10.4049/jimmunol.175.10.6893. PMID 16272348.  edit
  11. ^ Pascual, M.; Blanco, A. M.; Cauli, O.; Miñarro, J.; Guerri, C. (2007). "Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats". European Journal of Neuroscience 25 (2): 541–550. doi:10.1111/j.1460-9568.2006.05298.x. PMID 17284196.  edit
  12. ^ Fernandez-Lizarbe, S.; Pascual, M.; Gascon, M. S.; Blanco, A.; Guerri, C. (2008). "Lipid rafts regulate ethanol-induced activation of TLR4 signaling in murine macrophages". Molecular Immunology 45 (7): 2007–2016. doi:10.1016/j.molimm.2007.10.025. PMID 18061674.  edit
  13. ^ Guasch, R. M.; Tomas, M.; Miñambres, R.; Valles, S.; Renau-Piqueras, J.; Guerri, C. (2003). "RhoA and lysophosphatidic acid are involved in the actin cytoskeleton reorganization of astrocytes exposed to ethanol". Journal of Neuroscience Research 72 (4): 487–502. doi:10.1002/jnr.10594. PMID 12704810.  edit
  14. ^ Pascual, M.; Boix, J.; Felipo, V.; Guerri, C. (2009). "Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat". Journal of Neurochemistry 108 (4): 920–931. doi:10.1111/j.1471-4159.2008.05835.x. PMID 19077056.  edit
  15. ^ a b c Morris, S. A.; Eaves, D. W.; Smith, A. R.; Nixon, K. (2009). "Alcohol inhibition of neurogenesis: A mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model". Hippocampus 20 (5): 596–607. doi:10.1002/hipo.20665. PMC 2861155. PMID 19554644.  edit
  16. ^ a b c Taffe, M. A.; Kotzebue, R. W.; Crean, R. D.; Crawford, E. F.; Edwards, S.; Mandyam, C. D. (2010). "Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates". Proceedings of the National Academy of Sciences 107 (24): 11104–11109. doi:10.1073/pnas.0912810107. PMC 2890755. PMID 20534463.  edit