Genetic and Environmental Influences on Ethanol Consumption: Perspectives From Preclinical Research (original) (raw)
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Genetic and early environmental contributions to alcohol's aversive and physiological effects
Pharmacology Biochemistry and Behavior, 2008
Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ; however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood.
Genetic Basis of Idiosyncratic Responses to Alcoholism
European Journal of Clinical and Biomedical Sciences
Aim: The scientific viewpoint of genetic polymorphisms associated with risk of alcoholism and its adverse individual behavioural reactions is the main focus of this review. A complex syndrome like alcoholism and its idiosyncrasy may not be entirely understood on the basis of pathophysiological concept of neurotransmission alone. While neuropharmacology explains the mechanism behind molecular basis of alcoholism, the variation in alcohol induced abnormal neurotransmission due to presence or absence of different gene variants or isoenzymes of a particular gene on the other hand is a strong indication of genetic predisposition to alcoholism. In this article the term alcohol is used as a generic name for ethanol, which is the main subject of this discussion. Conclusion: The concomitant untoward intrinsic toxicity associated with alcoholism that makes it a potential trigger to a myriad of abnormal behavioural reactions in not only dose dependent pattern but with strong genetic disposition arises majorly due to different modes and levels of genetic variation in metabolic enzymes.
Genetics of alcoholism: Role of the endogenous opioid system
Metabolic Brain Disease, 1994
At the present time alcoholism is recognized as a metabolic disease exhibiting the clinical features of craving for alcohol, loss of control over drinking, tolerance and physical dependence on alcohol, while both epidemiological and experimental studies have demonstrated that genetic factors may be important in determining whether an individual has a high or low vulnerability to develop alcoholism. Evidence also indicates that alcoholism is not characterized by a single gene single allele inheritance. Instead it seems that multiple genes and environmental factors interact to increase or decrease an individual's vulnerability to become an alcoholic. Current research is aimed at investigating whether certain behavioral, physiological and biochemical markers are highly associated with the incidence of alcoholism. Among the biochemical markers currently under investigation is the endogenous opioid system and its implication in mediating the reinforcing effects of ethanol. It is the objective of this manuscript to review current research on: (a) the interactions of ethanol with the endogenous opioid system at the molecular level; (b) the existence of genetically determined differences in the response of the endogenous opioid system to ethanol between subjects at high and low risk for excessive ethanol consumption, as well as between lines of animals showing preference or aversion for ethanol solutions; (c) the decrease of alcohol consumption following pretreatment with opioid antagonists; and (d) the possible use of specific opioid receptor antagonists together with behavioral therapy to modify drinking behavior, to control craving and to prevent relapse.
The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks
Genome Biology, 2012
Alcohol abuse and alcoholism are significant global public health problems. In the USA, alcoholism affects approximately 14 million people at a healthcare cost of $184 billion per year. Excessive alcohol consumption is associated with violent crime, aggression and increased risk of accidents, injury and death. The term 'alcoholism' was first coined by Magnus Huss to describe the persis tence of drinking despite adverse health effects. The Diagnostic and Statistical Manual of Mental Disorders classifies alcoholism as an addictive disorder [1]. It is a complex disorder affected by genetic, epigenetic and environ mental etiologic factors. High levels of alcohol intake are associated with im pair ment of multiple organs, including brain, liver, pancreas and the immune system. The first stage of liver damage following chronic alcohol consumption is the develop ment of fatty liver, which may be followed by inflamma tion, apoptosis, fibrosis and cirrhosis. Alcohol and its metabolite acetaldehyde are carcinogens, and excessive alcohol consumption is associated with increased risk for mouth and oropharyngeal cancer, breast cancer and liver cancer. The risk of upper gastrointestinal cancer is increased by a missense variant in the gene encoding aldehyde dehydrogenase (ALDH), which is found in some
Molecular Biology of Alcohol Dependence, a Complex Polygenic Disorder
Clinical Chemistry and Laboratory Medicine, 2000
Alcohol dependence, and the medical conditions which arise from prolonged excessive alcohol use, have no single cause. Like other complex diseases, they result from a combination of social, personal and genetic contributions; but within any society genetic variation has a substantial influence on individual risk. The genes presently known to affect alcohol dependence produce variation in alcohol metabolism; other genes which affect personality or susceptibility to intoxication are likely to be significant but so far reproducible evidence is scanty. Designs which include related subjects have advantages for the study of complex diseases, because any association effects can be placed in the context of overall heritability and because linkage analysis can also be included. Examples of our studies of alcohol metabolism, consumption and dependence are presented.
Frontiers in Behavioral Neuroscience, 2022
Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.
Ontogeny of ethanol intake in alcohol preferring (P) and alcohol nonpreferring (NP) rats
Developmental Psychobiology, 2011
There is a scarcity of research on ethanol affinity in alcohol-preferring (P) rats before weaning and it is unknown if neonate P rats exhibit ethanol intake preferences comparable to those observed in adult P rats. This study examined ethanol intake in alcohol-preferring and non-preferring (NP) rats 3 hours after birth (Experiment 1, surrogate nipple test), at postnatal days (PD) 8, 12 and 18 (Experiment 2, consumption off the floor procedure) and at adolescence (Experiment 3, two-bottle choice test at PD32). The high-preference genotype was readily expressed three hours after birth. P neonates drank twice as much ethanol as their NP counterparts. This heightened ethanol preference transiently reversed at P8, reemerged as weaning approached (P18) and was fully expressed during adolescence. These results help clarify the ontogeny of genetic predisposition for ethanol. Genetic predisposition for higher ethanol intake in P than in NP rats seems to be present immediately following birth.
Complex genetics of interactions of alcohol and CNS function and behavior
Alcoholism-clinical and Experimental Research, 2005
This work summarizes the proceedings of a symposium at the 2004 RSA Meeting in Vancouver, Canada. The organizers were R. W. Williams and D. B. Matthews; the Chair was M. F. Miles. The presentations were (1) WebQTL: A resource for analysis of gene expression variation and the genetic dissection of alcohol related phenotypes, by E. J. Chesler, (2) The marriage of microarray and qtl analyses: what's to gain, by J. K. Belknap, (3) Use of WebQTL to identify QTLs associated with footshock stress and ethanol related behaviors, by D. B. Matthews, (4) A high throughput strategy for the detection of quantitative trait genes, by R. J. Hitzemann, and (5) The use of gene arrays in conjunction with transgenic and selected animals to understand anxiety in alcoholism, by. B. Tabakoff.