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After many years of heavy drinking, alcohol produces pathological alterations in the brain. In many alcoholics these changes culminate in massive social deterioration and disorders of memory and learning. Severe cognitive impairments occur in approximately 10% of heavy drinkers. The most serious cognitive deficit that develops in alcoholics is the alcoholic Korsakoff's syndrome, characterised by an irreversible memory loss for recent events and personality deterioration. An important issue that has been frequently discussed is how alcohol alters neural systems in the brain, and whether these alterations could underlie the psychological and cognitive disturbances associated with alcoholism. Nowadays this problem can be approached by innovative research using molecular and epigenetic analyses.
Alcoholic dementia is the second leading course of adult dementia in Western countries, accounting for 10% of the cases, and still represents an unresolved problem. So far, no effective pharmacotherapy for memory problems associated with alcoholism is available.
New molecular findings in alcoholism
Molecular studies on substance addiction are predominantly based on animal experiments. However, it seems very promising to put emphasis on the human brain, analyzing post-mortem human tissues obtained from human alcoholics and control patients and then verifying the human molecular findings in animal models of alcohol-induced cognitive deficits. Using these models yields significant insight into brain pathophysiology and aims to develop pharmacotherapy for this disorder.
Alcoholism and endogenous opioid systems
The main research focus is on the endogenous opioid systems, which include three opioid receptors – the mu-, delta- and kappa- (KOR) receptor types – and the endogenous opioid peptides – endorphins, enkephalins and dynorphins – that activate these receptors. These peptides are derived from opioid precursor proteins (proopiomelanocortin, proenkephalin, prodynorphin). Molecular dysregulations in the endogenous opioid systems are supposed to play a critical role in the development of alcoholism and associated cognitive impairment. This is supported by clinical practice, since the opioid antagonist naltrexone, which blocks effects of the endogenous opioid peptides, is widely used in the management of alcoholism. Furthermore, dynorphins which predominantly act as agonists of kappa-opioid receptors (KOR) have been implicated in cognitive impairment especially that associated with aging.
Therefore, in patients with chronic alcoholism the endogenous opioid systems in neurocognitive brain structures were characterised by molecular methods. With regard to messenger-RNA levels of the opioid receptor genes and genes coding for the opioid precursor proteins, strong and significant differences were observed in prodynorphin, but not in other opioid genes, between the post-mortem tissues of alcoholics and control subjects. In chronic alcoholics, prodynorphin expression was upregulated in the prefrontal cortex and hippocampus and, consistently, dynorphins – mature peptide products of this gene – were elevated in the same brain structures.
Do elevated dynorphins in fact contribute to cognitive dysfunction?
When rats were treated with high doses of ethanol, dynorphin content in the prefrontal cortex and hippocampus was increased – a finding that was obviously similar to that obtained in human alcoholics. Importantly, ethanol treatment impaired animal behaviour in learning and memory tests. In next animal experiment a drug that selectively binds to the KOR receptor and blocks the effects of endogenous dynorphins, a KOR antagonist, was injected into ethanol-treated rats. Strikingly, this compound prevented the development of learning and memory deficits induced by alcohol. This indicates that upregulated dynorphins may play a crucial role in impairing learning and memory.
Cycles of alcohol intoxication and withdrawal appear to stimulate the generation of dynorphins in the hippocampus and prefrontal cortex in rats as well as in human alcoholics. As a neurobiological feedback, elevated dynorphins may inhibit release of neurotransmitters such as glutamate and acetylcholine, which are essentially required for learning and memory. Thus, inhibition of their secretion by upregulated dynorphins may result in functional cognitive deficit.
Elevated dynorphins, endogenous kappa-opioid agonists widely expressed in the central nervous system, may play a role in the cognitive deficit in alcoholics, or contribute to the development of alcohol dependence.
Epigenetic dysregulations in the endogenous opioid systems
Persistent activation of prodynorphin expression induced by chronic alcohol consumption may underlie cognitive impairment in alcoholics. To address the molecular mechanism of enduring upregulation of prodynorphin, an epigenetic approach was undertaken. Epigenetic analyses investigate heritable changes in gene function that occur without a change in DNA. Essential for normal development, epigenetic controls become misdirected in many human diseases. An epigenetic change may influence the expression of the genome. The key property of epigenetic regulatory marks is that they retain stability for cell life time. However, external factors may reprogram epigenetic patterns and thus affect gene regulation. Methylation of cytosines in DNA is a critical component of epigenetic regulation of gene expression.
Analysis of cytosine DNA methylation in the prodynorphin gene demonstrated that several cytosines in this gene are differentially methylated in the prefrontal cortex of chronic alcoholics. Methylation level of one of them (C3) was strongly decreased in alcoholics suggesting that the C3 containing DNA sequence is a target for regulation of this gene. Then a novel protein factor was identified that specifically binds to methylated but not unmethylated C3 in prodynorphin. Thus selective demethylation of specific cytosine in the prodynorphin gene is associated with alcoholism, prodynorphin expression may be regulated through DNA methylation at this site, and a novel DNA-binding factor may have a role in this regulation.
Clinical implications
In summary, current research proposes a novel pathophysiological mechanism and understanding of cognitive deficit in human alcoholics:
- At the molecular level, the mechanism may be based on epigenetic dysregulations in the expression of genes of the endogenous opioid systems. These dysregulations are critical determinants that mediate effects of chronic alcohol consumption on learning and memory in animal models and probably in human alcoholics.
- In the clinical perspective, a new concept is emerging that proposes the prodynorphin and kappa-opioid receptor system (PDYN/KOR) as target for pharmacotherapy of cognitive impairment associated with alcoholism. This concept may be generalised to other learning and memory disorders. Indeed, previous studies have revealed a new role of dynorphin opioid peptides in
- regulation of cognitive behaviour in animal models, and
- pathogenesis of Alzheimer´s disease by inducing neurodegeneration or cognitive impairment (Kuzmin et al., 2006; Nguyen et al., 2005; Yakovleva et al., 2007).
- These findings may also explain several neurocognitive aspects of clinical actions of the anti-alcohol drug naltrexone. By binding to the kappa-opioid receptor (KOR) as a non-selective antagonist, naltrexone may affect cognitive performance and thus contribute to cognitive control of alcohol drinking behaviour and alcohol dependence.
- Future studies will focus on KOR-antagonists as learning and memory improving drugs, and further evaluate molecular, epigenetic and neurobiological mechanisms involved in the dysregulation of the prodynorphin and kappa-opioid receptor system (PDYN/KOR) in human alcoholics, investigating its role in cognitive impairment and alcohol dependence.
- Furthermore, it will be assessed whether PDYN-polymorphisms are associated with cognitive impairment in human alcoholics, which will help to determine the vulnerability of individual persons to this disease.
These findings are paving the groundwork for new therapeutic interventions with kappa-opioid receptor (KOR)-antagonistic drugs to improve alcohol-induced cognitive impairment in patients with alcohol dependence.
Acknowledgments: This work was supported by grant from AFA Forsäkring.
References
- Kuzmin A., Madjid N., Terenius L., Ogren S.O. and Bakalkin G. Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 2006;31:1928-1937
- Nguyen X.V., Masse J., Kumar A., Vijitruth R., Kulik C., Liu M., Choi D.Y., Foster T.C., Usynin I., Bakalkin G. and Bing G. Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance. Behav Brain Res. 2005;161:254-262
- Yakovleva T., Marinova Z., Kuzmin A., Seidah N.G., Haroutunian V., Terenius L. and Bakalkin G. Dysregulation of dynorphins in Alzheimer disease. Neurobiol. Aging 2007;28:1700-1708
Correspondence:
Professor Georgy Bakalkin, Ph.D.
Division of Biological Research on Drug Dependence,
Department of Pharmaceutical Biosciences,
Uppsala University
E-mail: georgy.bakalkin@farmbio.uu.se