Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Genetics of alcoholism: role of the endogenous opioid system. 807 60

This article reviews recent efforts in developing laboratory animal models for the study of alcoholism and abnormal alcohol-seeking behavior. Through selective breeding, stable lines of rats that reliably exhibit high and low voluntary alcohol consumption have been raised. The high preference animals self-administer ethanol by free-choice drinking, and operantly for intragastric infusion, in amounts that produce intoxication. With chronic free-choice drinking, the preferring rats develop tolerance and physical dependence. Low to moderate concentrations (50-150 mg%) of ethanol are reinforcing to the preferring rat, as evidenced by intracranial self-administration studies. Compared with nonpreferring animals, they are less affected and develop tolerance more quickly to the sedative-hypnotic effects of ethanol. Neurochemical, -anatomical and -pharmacological studies indicate innate differences between the alcohol-preferring and -nonpreferring lines in the brain limbic structures. Depending on the animal model under study, a change in the main dopaminergic pathway and/or the serotonergic, opioid, and GABAergic systems that regulate this pathway may underlie the vulnerability to the abnormal alcohol-seeking behavior in these pharmacogenetic animal models of alcoholism.
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PMID:Pharmacogenetic models of alcoholism. 861 63

The alcohol dependence syndrome includes the presence of alcohol tolerance, physical dependence and an inability to control one's alcohol intake. Studies are reviewed that implicate the mesolimbic dopaminergic systems, and the gamma-aminobutyric acid-A (GABAA) and N-methyl-D-aspartate (NMDA) receptors as mediators of various aspects of the alcohol dependence syndrome. It is suggested that alcohol-induced changes in the GABAA receptor may play a role in certain aspects of tolerance to alcohol and in altered abilities of an individual to terminate alcohol intake. Chronic alcohol-induced increases in the activity of NMDA receptors may contribute to the withdrawal signs that are the defining feature of physical dependence on alcohol. It is hypothesized that decreased mesolimbic dopaminergic function, which occurs during alcohol withdrawal, may be involved in the compulsion to initiate and maintain alcohol drinking, another aspect of the alcohol dependence syndrome. Furthermore, evidence is presented that this decreased dopaminergic function could occur secondarily to the increase in NMDA receptor function, such that the alcohol-induced increase in NMDA receptor function could underlie both the overt withdrawal signs and the compulsion to drink alcohol in the alcohol-dependent individual.
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PMID:Alcohol dependence: a commentary on mechanisms. 887 79

Gamma-hydroxybutyrate (GHB) is a compound found in mammalian brain which meets many criteria of a neurotransmitter. GHB has been investigated as a tool for inducing absence (petit mal) seizures, for use as an anesthetic, and for treatment of narcolepsy, alcohol dependence and opiate dependence. Since 1990 GHB has been abused in the United States for euphoric, sedative and anabolic effects. Coma and seizures have been reported following abuse of GHB, but dependence liability has received little attention. The neuropharmacology, potential therapeutic uses and acute adverse effects of GHB are reviewed, followed by a case series of eight people using GHB. Adverse effects of GHB may include prolonged abuse, seizure activity and a withdrawal syndrome. This withdrawal syndrome includes insomnia, anxiety and tremor; withdrawal symptoms resolve in 3-12 days. GHB has the potential to cause a significant incidence of abuse and adverse effects. Prolonged use of high doses may lead to a withdrawal syndrome, which resolves without sequelae. Educational efforts should address the narrow therapeutic index, possible physical dependence and dangers of combining GHB with other drugs of abuse.
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PMID:Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. 937 74

Animal studies have shown that chronic ethanol consumption produces physical dependence upon ethanol and alters gamma-aminobutyric acid-A (GABA(A)) receptor subunit gene expression in brain. Although extensive investigation has been conducted in animal models, relatively little work has been performed directly on human alcoholic brain tissue to determine if there are alterations in GABA(A) receptor gene expression. In this study, GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and peptide expression in postmortem frontal cortex from human alcoholics (n = 15) and age- and sex-matched controls (n = 13) were measured by quantitative, competitive reverse transcription polymerase chain reaction and Western blot analysis. GABA(A) receptor beta3 subunit mRNA expression was 35% greater (p < 0.05) in alcoholics, compared with nonalcoholic controls. We found no significant difference in alpha1 and alpha4 subunit mRNA levels between groups. However, there was a trend toward greater (21%) alpha1 subunit mRNA expression. There was no difference in alpha1, alpha4, or beta2/3 subunit peptide levels in frontal cortex between controls and alcoholics. Neither the age of the subjects nor the postmortem interval correlated with mRNA or peptide levels. Blood ethanol content also did not correlate with mRNA or peptide expression in alcoholic samples. These data suggest that GABA(A) receptor adaptations, resulting from prolonged alcohol consumption in human alcoholics, may differ from animal models of alcohol dependence. These differences may be related to the longevity of alcohol exposure in human alcoholics, as well as variability in the dependence/withdrawal state of the human subjects. Therefore, further studies in human postmortem brain tissue are warranted.
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PMID:GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and protein expression in the frontal cortex of human alcoholics. 966 Mar 6

Prolonged and excessive intake of alcoholic beverages can lead to addiction, increased tolerance and physical dependence as in the case of other drugs. It is the cause of many deaths due to cirrhosis, cancer and accidents. It favours numerous symptoms and disorders that can be reversible on withdrawal of alcohol. Alcohol is not toxic. Taken in regular and moderate fashion (20 to 30 g of alcohol per day), alcoholic beverages play a psychosocial role that gives a certain pleasure. In addition, many concordant epidemiologic studies support the notion that overall morbidity and mortality are significantly less than in those who abstain. The benefit is particularly evident in mortality due to cardiovascular events, but also in senile dementia and osteoporosis. However, there are no data confirming a cause and effect relationship. Despite this potentially favourable role, it cannot be recommended to suggest the use of alcohol to those who abstain, given the possibility that some might subsequently develop alcohol dependence.
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PMID:[Beneficial and deleterious effects of alcoholic beverages]. 1031 84

This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.
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PMID:Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. 1034 15

The aim of the present study was to examine the influence of ifenprodil (a non-competitive NMDA receptor antagonist which also blocks 5-HT3 receptors and alpha1-adrenoceptors) on the effects of ethanol in the mouse in vivo and to elucidate the role of various receptors in these actions. The ethanol (4 g/kg i.p.)-induced sleeping time was shortened by ifenprodil 1 mg/kg but was not affected by ifenprodil 0.3 mg/kg, the 5-HT3 receptor antagonist ondansetron 0.03 mg/kg and the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) 0.01 mg/kg. Ifenprodil 10 mg/kg mimicked the alpha1-adrenoceptor antagonist prazosin 1 mg/kg in that it prolonged the hypnotic response to ethanol (no additive effect when both drugs were given in combination); this is compatible with an involvement of alpha1-adrenoceptors in this effect of ifenprodil. Chronic exposure to ethanol (7%) induced physical dependence. The severity of ethanol withdrawal was suppressed by ifenprodil 1 and 10 mg/kg. In conclusion, ifenprodil influences ethanol-related changes in mouse behaviour and may prove to be useful in the treatment of alcoholism.
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PMID:Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration. 1044 20

The purpose of the present study was to evaluate two polymorphisms near the D2 receptor gene (TaqI A RFLP and C microsatellite) and a VNTR for D4. A nonparametric linkage (NPL) technique, SIBPAL, was used to test for the presence or absence of linkage in 54 multiplex alcoholic families. These families had been ascertained through two alcoholic proband siblings in order to increase the density of alcoholic cases within these pedigrees. Phenotypic definitions of alcoholism were manipulated in an effort to determine the impact of severity (signs of physical dependence, early age of onset, presence of antisocial personality disorder) on the likelihood of finding positive evidence for linkage. A regression analysis that simultaneously evaluated the allele sharing identical by descent for Feighner criteria alcoholism in affected, unaffected, and discordant sib pairs (SIBPAL) for two D2 polymorphisms and the D4 polymorphism gave no evidence for linkage. Phenotypes associated with greater alcoholism severity (presence of physical dependence symptoms, earlier onset, or comorbid antisocial personality disorder) revealed some evidence for linkage. The presence of one or more physical dependence symptoms in combination with Feighner criteria alcoholism provided some evidence favoring linkage (TaqI A and D4). Alcoholics with an earlier onset of alcoholism showed some evidence for linkage especially when the presence of physical dependence was required (e. g., morning drinking, wanted to stop drinking but could not, binges or benders, and evidence of withdrawal symptoms). Finally, alcoholics with antisocial personality disorder differed significantly in their allele sharing from nonalcoholics for both D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:676-685, 1999.
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PMID:Linkage studies of D2 and D4 receptor genes and alcoholism. 1058 89

The main objective in alcoholism therapy is to achieve and maintain abstinence and to prevent relapse. Pharmacotherapy may be necessary in treating persons who are not helped by group or psychosocial support alone. Among the substances experimented with in the past few years, gamma-hydroxybutyric acid has been effective in preventing alcohol withdrawal syndrome and in inducing a reduction in craving and an increase in the abstinence rate in treated alcoholics, in view of the alcohol-mimicking effects of the drug on the central nervous system. However, a possible development of craving for the drug and the risk of abuse and physical dependence have been reported in subjects who used gamma-hydroxybutyric acid for different reasons, including alcoholism therapy. The present review updates the existing differences in drug abuse behavior, side effects, and poisoning in the use of gamma-hydroxybutyric acid in a treatment alcoholism program and in self nonclinical illicit use.
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PMID:Gamma-hydroxybutyric acid efficacy, potential abuse, and dependence in the treatment of alcohol addiction. 1086 62


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