bluuebunny/crossref_metadata_2025 huggingface dataset:
Cocaine and cardiovascular toxicity
Authors: SCHINDLER CHARLES
Published: August 2003

Over the past 10 years a great deal has been learned about the cardiovascular effects of cocaine. In particular, the acute effects of cocaine have been studied extensively. Upon acute administration cocaine increases blood pressure and heart rate, primarily through an action on the sympathetic nervous system. Cocaine also suppresses the baroreflex response and vagal tone, further contributing to its effects on heart rate. At the same time cocaine is increasing the work‐load on the heart it induces coronary artery vasoconstriction, potentially leading to cardiac ischemia. At higher doses cocaine can depress ventricular function and slow electrical conduction in the heart. Both these effects appear to be mediated by cocaine's local anesthetic action. The effects of cocaine mediated by the sympathetic nervous system are greatly reduced in anesthetized animals. Further, when cocaine is administered repeatedly over a short period of time, acute tolerance can develop to the sympathomimetic effects of cocaine. In contrast, the effects of cocaine mediated by its local anesthetic action do not appear blunted by anesthesia or susceptible to acute tolerance. With chronic administration, higher doses appear to induce tolerance while lower doses may induce sensitization to cocaine's sympathomimetic effects. Cocaine also induces a variety of pathological changes in the heart, including myocardial contraction band necrosis and ventricular hypertrophy. These effects of cocaine on the heart can all contribute to potentially lethal cardiovascular events. In addition to the effects of cocaine alone, the metabolites of cocaine may also contribute to cocaine's cardiovascular toxicity, and both licit and illicit drugs used in combination with cocaine might potentially alter its cardiovascular effects.
Functional coupling of a μ opioid receptor to G proteins and adenylyl cyclase: modulation by chronic morphine treatment
Authors: CHEN YAN , LIU JIAN , YU LEI
Published: August 2003

A cloned μ opioid receptor was used to study its coupling to signal transduction pathways and its involvement in morphine‐induced opioid dependence in stably transfected Chinese hamster ovary (CHO) cells. Membrane binding assays with a μ‐selective agonist [3 H]DAMGO showed that one cell line expresses a high level of μ opioid receptors with a B max of ∼ 630 fmol/mg membrane protein and a K d of 0.47 nM for DAMGO. Stimulation of the transfected cells with DAMGO led to an increase in the low K m GTPase activity, indicative of activation of guanine nucleotide regulatory proteins (G proteins), and this effect was blocked by the opioid antagonist naloxone. In addition, binding of the μ opioid receptor to DAMGO was affected by GTP and nonhydrolizable GTP analogs, Gp(NH)pp and GTP‐γ‐S. These results suggest a functional coupling between the μ opioid receptor and G proteins. Furthermore, DAMGO treatment of the cells produced a dose‐dependent inhibition of the intracellular cyclic adenosine monophosphate (cAMP) level, with an EC 50 value of approximately 30 nM. Chronic treatment of the cells with morphine not only elevated the basal and forskolin‐stimulated cAMP levels after morphine withdrawal, but also increased the extent of the DAMGO‐induced reduction of intracellular cAMP levels. The whole cell binding assay with [3 H]DAMGO, on the other hand, did not detect receptor down‐regulation after chronic morphine treatment. These results suggest that chronic morphine treatment may trigger a compensatory mechanism in cellular signaling pathways to offset the inhibitory input from the μ receptor without down‐regulation of the surface receptor number, and that withdrawal of chronic inhibition leads to elevated activities of adenylyl cyclase to provide a basis for system sensitization.
Alcohol and glucose metabolism in skeletal muscles in the rat
Authors: XU DAN , DHILLON AMARDEEP , DAVEY CHRISTOPHER , FOURNIER PAUL , PALMER T. NORMAN
Published: August 2003

Ethanol is known to cause an acute and profound insulin resistance in man and the rat primarily via effects on glucose utilization. This paper examines the nature of these inhibitory effects on whole‐body glucose utilization using the euglycaemic hyperinsulinaemic clamp in the conscious unrestrained rat. We confirm that ethanol infusion causes an acute insulin resistance, the rate of glucose infusion required to maintain euglycaemia (GIR) being decreased markedly by ethanol. To ensure that the GIR is a measure of whole‐body glucose disposal, glucose turnover and hepatic glycogen levels were measured. These studies showed that ethanol totally suppressed hepatic glucose production. The reduction in GIR is associated with marked decreases in glucose uptake and glycogen synthesis in most skeletal muscles. In oxidative but not in non‐oxidative muscles, the activation of glycogen synthase in response to insulin was decreased by ethanol, suggesting that a defect in glycogen synthase activation may be responsible for the decrease in glycogen synthesis. The basis of the inhibitory effects of ethanol on insulin‐stimulated glucose metabolism in muscle is unknown, but may involve membrane‐associated impairments in insulin signalling and/or the glucose transport system.
Characterization of contractile and non‐contractile protein synthesis in the stomach, small and large intestine and caecum of the rat, and response to acute ethanol dosage
Authors: MARWAY JASPAUL , BONNER ADRIAN , PREEDY VICTOR
Published: August 2003

An investigation was made into the relative composition and synthesis rates of smooth muscle contractile proteins in vivo in different regions of the rat gastrointestinal tract. There was considerable homogeneity in the composition of sarcoplasmic proteins in the small bowel (i.e. 54‐58 mg/g) but considerable variability in the large bowel, i.e. highest in the caecum (97 mg/g) and lowest in the colon (21 mg/g). The myofibrillary protein concentration was constant throughout the gastrointestinal tract, i.e. 20‐34 mg/g. Stromal fractions varied from 6 to 39 mg/g and was highest in the cardiac region of the stomach and lowest in the duodenum. Fractional rates of protein synthesis were measured with a flooding dose of L‐[4‐3 H]phenylalanine. In control rats synthesis rates in sarcoplasmic protein fractions were relatively much higher (43‐107%/day) than myofibrillar (27‐52%/day) or stromal (6‐26%/day) proteins. Fractional rates of stromal protein synthesis showed the greatest variability while myofibrillar synthesis rates the least, throughout the alimentary tract. Jejunal seromuscular layer myofibrillar proteins had the highest synthesis rates (49%/day). In response to acute ethanol injection, protein synthesis in all jejunal fractions fell by 20‐30%. Contractile and non‐contractile proteins from the cardiac region of the stomach, duodenal seromuscular layer and large bowel seromuscular layer were insensitive to ethanol administration. Protein synthesis of sarcoplasmic proteins from the antrum, ileum seromuscular layer and myofibrillar proteins from the ileum seromuscular layer and caecum were also significantly depressed as a result of ethanol treatment.
β‐Carbolines in chronic alcoholics following trauma
Authors: SPIES CLAUDIA , ROMMELSPACHER HANS , WINKLER THOMAS , MÜLLER CHRISTIAN , BRUMMER GLENDA , FUNK THOMAS , BERGER GERD , FELL MICHAEL , BLUM SUSANNE , SPECHT MARTIN , HANNEMANN LUTZ , SCHAFFARTZIK WALTER
Published: August 2003

In our society every second polytraumatized patient is a chronic alcoholic. A patient's alcohol‐related history is often unavailable and laboratory markers are not sensitive or specific enough to detect alcohol‐dependent patients who are at risk of developing alcohol withdrawal syndrome (AWS) during their post‐traumatic intensive care unit (ICU) stay. Previously, it has been found that plasma levels of norharman are elevated in chronic alcoholics. We investigated whether β‐carbolines, i.e. harman and norharman levels, could identify chronic alcoholics following trauma and whether possible changes during ICU stay could serve as a predictor of deterioration of clinical status. Sixty polytraumatized patients were transferred to the ICU following admission to the emergency room and subsequent surgery. Chronic alcoholics were included only if they met the DSM‐III‐R and ICD‐10 criteria for alcohol dependence or chronic alcohol abuse/harmful use and their daily ethanol intake was ≥ 60 g. Harman and norharman levels were assayed on admission and on days 2, 4, 7 and 14 in the ICU. Harman and norharman levels were determined by high pressure liquid chromatography. Elevated norharman levels were found in chronic alcoholics (n = 35) on admission to the hospital and remained significantly elevated during their ICU stay. The area under the curves (AUC) showed that norharman was comparable to carbohydrate‐deficient transferrin (CDT) and superior to conventional laboratory markers in detecting chronic alcoholics. Seventeen chronic alcoholics developed AWS; 16 of these patients experienced hallucinations or delirium. Norharman levels were significantly increased on days 2 and 4 in the ICU in patients who developed AWS compared with those who did not. An increase in norharman levels preceded hallucinations or delirium with a median period of approximately 3 days. The findings that elevated norharman levels are found in chronic alcoholics, that the AUC was in the range of CDT on admission and that norharman levels remained elevated during the ICU stay, support the view that norharman is a specific marker for alcoholism in traumatized patients. Since norharman levels increased prior to the onset of hallucinations and delirium it seems reasonable to investigate further the potential role of norharman as a possible substance which triggers AWS.
Pharmacokinetic and pharmacodynamic interactions in an outpatient maintenance therapy of intravenous heroin users with levomethadone
Authors: SCHALL ULRICH , PRIES ELLEN , KATTA TALEB , KLÖPPEL ACHIM , GASTPAR MARKUS
Published: August 2003

The plasma levels of 42 patients on a levomethadone maintenance treatment programme for intravenous heroin users were measured before and, respectively, 1, 2 or 4 hours after oral routine administration and related to the individual additional drug usage (detected by urine drug screening), liver function, side‐effects and withdrawal symptoms. In general, accelerated levomethadone metabolism induced by additional misuse of benzodiazepines, barbiturates and opiates resulted in significantly lower plasma levels of the substitute. In particular, high γ‐glutamyltransferase activity was related to benzodiazepine consumption. On the other hand, an impaired liver function reflected by increased β‐globulins resulted in an insufficient body clearance and drug accumulation. Major side effects, such as sweating, were not related to plasma levels whereas withdrawal symptoms like diarrhoea or “feeling cold” correlate with lower plasma concentrations. It is concluded that polydrug misuse in the methadone maintenance therapy creates a vicious circle of enzyme induction, thus increasing “instrumental drug utilization”. However, underestimated maintenance dosage may lead to additional drug consumption resulting, finally, in therapeutic failure.
Book and Media Reviews
Authors: COOK CHRIS
Published: August 2003

Books review in this article:

In addition to book reviews, which seem to be a popular feature of contemporary scientific and medical journals, Addiction Biology will also include “media” reviews of other materials relevant to its readers. These media will include primarily videos and computer software, but we will also consider audio tapes, compact discs and other materials where relevant. Suggestions for suitable materials to be reviewed are welcomed.

Neurochemistry of Drug Dependence SUSAN WONNACOTT & GEORGE G. LUNT (Eds)

Animal Experimentation and the Future of Medical Research J. H. BOTTING (Ed.)

Advances in Protein Phosphatases, Volumes 7 (1993) & 8 (1994)

The Biochemical Basis of Biology. 3. Manipulating DNA E. J. WOOD
Current state of knowledge about the mechanisms of alcohol tolerance
Authors: KALANT HAROLD
Published: August 2003

Far from being a simple homeostatic response to the presence of ethanol in the brain, tolerance is now recognized as a complex process which can develop within various time frames (acute, rapid, chronic) and in which the drug interacts with various environmental and cognitive factors, including associative and operant learning. A major question is whether the acute form is an innate adaptive response, which is converted into the rapid and chronic forms by the action of these external influences. So far, all behavioral and neuropharmacological manipulations that alter chronic tolerance also modify rapid and acute tolerance in similar ways. These include lesions of serotonergic forebrain projections, blockade of NMDA‐type glutamate receptors and calcium “L” channels, central or peripheral injection of vasopressin and blockade of vasopressin V1 receptors. Cytochemical and immunofluorescence studies, combined with use of retrograde tracers, indicate the existence of a septohippocampal circuit which may mediate the interactions of these diverse elements in the production and maintenance of tolerance. There is limited evidence that development of tolerance leads to increased consumption of ethanol in experimental animals, but the clinical significance of these findings remains to be proven.
Metabolic effects of alcohol on skeletal muscle
Authors: XU DAN , DHILLON AMARDEEP , PALMER T. NORMAN
Published: August 2003

The purpose of this review is to summarize our current understanding of the acute and chronic interactions between alcohol and nutrient metabolism in skeletal muscle. Insulin is well known to play an important regulatory role in nutrient, especially glucose, uptake and utilization in skeletal muscle. Several studies have shown that alcohol can acutely reduce the normal metabolic responses of skeletal muscle to the action of insulin. The most obvious of these is an acute impairment in glucose metabolism associated with alcohol consumption. While the exact mechanism(s) underlying this acute insulin resistance is presently unclear, several possible factors are discussed in this review. In contrast to these short‐term effects, the effects of alcohol on skeletal muscle insulin sensitivity in chronic alcohol abusers are not as well established. Chronic alcohol abuse is known to be associated with skeletal myopathies, believed to result from alcohol induced abnormalities in muscle protein synthesis. Finally, the alcohol‐mediated impairments of many aspects of skeletal muscle metabolism are discussed in relation to the insulin resistance associated broad spectrum of common lifestyle‐related disorders, including non‐insulin dependent diabetes mellitus and obesity, the consequences of which may be important to the pathogenesis of alcohol‐related diseases.
Transfected cells for study of alcohol actions on GABAA receptors
Authors: HARRIS R. ADRON
Published: August 2003

The ability to transfect and express foreign genes in cultured cells and Xenopus oocytes has contributed immensely to our knowledge of drug‐receptor interactions and signal transduction following receptor activation. These techniques are now being used to study acute and chronic effects of ethanol on neurotransmitter receptors and cellular signaling. This article reviews the use of transfected cells to study ethanol actions on the GABAA receptor.
Oral and dental health in the alcohol misuser
Authors: GELBIER STANLEY , HARRIS COLIN
Published: August 2003

This review explores the relationship between oral and dental health and disease in substance misusers. Although it focuses on oral cancer, we also examine the relationship of misuse with dental caries and periodontal diseases. It is difficult to separate out the inter‐related aetiological factors such as the use of alcohol and tobacco (smoked and chewed). They probably act in a synergistic manner.
The acute and chronic effects of alcohol upon cardiac nucleotide status
Authors: PATEL V. B. , SALISBURY J. R. , RODRIGUES L. M. , GRIFFITHS J. R. , RICHARDSON P. J. , PREEDY V. R.
Published: August 2003

The aim of the investigation was to ascertain the biochemical and morphological basis for the functional impairments in the heart due to alcohol. In chronic studies rats were fed a nutritionally complete liquid diet containing 35% of total calories as ethanol, controls were pair‐fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. In acute studies rats were injected with ethanol at a dose of 75 mmol/kg body weight. Pre‐treatment of acute ethanol‐dosed rats with cyanamide (ALDH inhibitor) was designed to raise acetaldehyde levels. In chronic studies ventricular adenine nucleotides, ATP, ADP and AMP; NAD+, ATP ratios and the energy charge showed no alteration after 6 weeks of alcohol feeding. Light and electron microscopy sections indicated very little structural damage to muscle fibres and organelles (especially the mitochondria) in both atria and ventricles. Ventricular fibre diameters, throughout the different ranges, showed no significant differences between chronically alcohol and control‐fed rats. In acute studies an increase in ventricular AMP levels (μ moles/g wet weight) occurred following cyanamide and cyanamide + ethanol treatment (+57%, p < 0.025 and +76%, p <0.01, respectively), but not as a consequence of ethanol alone. Cyanamide+ethanol caused marked elevation in ADP levels (+28%, p < 0.05) and again ethanol was without effect. ATP and GTP levels were not altered by any of the acute treatments. The energy charge was slightly reduced in both cyanamide and cyanamide+ethanol groups (− 8%, p < 0.01 and − 7%, p < 0.05, respectively), but not by ethanol alone. In conclusion, chronic alcohol appears to have minimal effects upon cardiac nucleotides which suggest that possible adaptive mechanisms are induced during the 6‐week period and that alternative pathways other than defects in adenine nucleotide concentrations are involved in the pathogenesis of AHMD. The acute study suggests that the heart is resilient to toxic levels of alcohol and acetaldehyde in terms of ATP and GTP levels, despite the elevated AMP, ADP and GDP levels.
Children with Fetal Alcohol Syndrome in North Dakota: a case control study utilizing birth certificate data
Authors: BURD LARRY , MARTSOLF JOHN , KLUG MARILYN
Published: August 2003

A retrospective case control study utilizing birth certificate data in a population of children with Fetal Alcohol Syndrome (FAS) or Fetal Alcohol Effect (FAE) and controls in North Dakota was completed. Using the North Dakota FAS registry, 97 cases of FAS and FAE aged birth‐18 years of age were identified. The North Dakota Department of Vital Records then searched for the child's birth certificates. For each case child, four controls were selected from the birth records. The controls were of the same race, sex, month and county of birth as the cases. Birth certificates for 68 children were identified, 44 with FAS and 24 with FAE. When compared with the FAE group, the FAS group had lower birth weights and mothers who began prenatal care later in pregnancy. The FAS/FAE group combined had mothers who were older, were more likely to be unmarried, had less weight gain during pregnancy, started prenatal care later in pregnancy and had fewer prenatal visits compared to controls. The FAS/FAE children had lower birth weights and higher rates of sibling deaths. The use of birth certificate data is a useful data source to compare maternal, paternal and prenatal characteristics for a population of children with FAS/FAE.
Studies on the sensitivity to alcohol and alcohol dependence*
Authors: MONTEIRO MARISTELA
Published: August 2003

The role of genetic and environmental factors in the development of alcohol dependence is beginning to be investigated in Brazil. This paper reviews recent studies on genetic aspects of alcohol use and alcohol dependence, with emphasis on those carried out in Brazilian populations. Most findings replicated studies in developed countries, while some indicate new possible venues for investigation in the future. They underscore the need for a cross‐cultural and interethnic approach to biomedical aspects of alcohol use and dependence.
A study of hepatobiliary function in chronic heroin smokers
Authors: BANERJEE DHRITI , SARKAR NIRMAL KUMAR
Published: August 2003

The controversy over the relationship between heroin addiction and hepatocellular dysfunction was examined by assay of serum activities of aspartate and alanine aminotransferases, total protein, albumin and globulin in 48 chronic heroin smokers and 33 controls. Biliary secretion in the addicts was compared to controls by assay of serum bilirubin and its conjugated and unconjugated fractions. Serum aminotransferases, total protein, albumin and globulin did not differ significantly between the addict and the control groups (p < 0.05), whereas total bilirubin and its conjugated fraction were significantly higher in the addicts (p < 0.02). The results indicate that chronic abuse of heroin by smoking affects biliary secretion but exercises little influence over hepatocellular function.
Book and Media Reviews
Authors: COOK CHRIS
Published: August 2003

Books review in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CD's, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for review, but especially software and other media of specific relevance to the addictions.

Alcohol and the Heart in Perspective. Sensible Drinking Limits Reaffirmed Report of a joint working group

Alcohol: Guidelines on Sensible Drinking

Towards a Molecular Basis of Alcohol Use and Abuse B. JANSSON, H. JÖRNVALL, U. RYDBERG, L. TERENIUS & B. L. VALLEE (Eds)

Treatment Approaches for Alcohol and Drug Dependence: An Introductory Guide T. J. JARVIS, J. TEBBUTT & R. P. MATTICK

Buprenorphine: Combatting Drug Abuse with a Unique Opioid ALAN COWAN & JOHN W. LEWIS (Eds)

Brain Imaging of Nicotine and Tobacco Smoking E. F. DOMINO (Ed.)

Medications Development for the Treatment of Pregnant Addicts and their Infants C. N. CHIANG & L. P. FINNEGAN (Eds)

Discovery of Novel Opioid Mechanisms R. S. RAPAKA & H. SORER (Eds)

Diagnosis and Severity of Drug Abuse and Drug Dependence J. D. BLAINE, A. MACNEILL HORTON & L. H. TOWLE (Eds)

Problems of Drug Dependence 1994 Proceedings of the 56th Annual Scientific Meeting, Vols. 1 & 2

Epidemiology of Inhalant Abuse: An Inter‐national Perspective

An Introduction to Recombinant DNA in Medicine 2nd Edition ALAN E. H. EMERY & SUE MALCOLM

Cell and Molecular Biology D. RICKWOOD & D. PATEL

Understanding Genetics: A Molecular Approach N. V. ROTHWELL

Gel Electrophoresis of Nucleic Acids—A Practical Approach 2nd Edition D. RICKWOOD & B. D. HANES (Eds)

Guide to Libraries and Information Sources in Medicine and Health Care Compiled by PETER DALE

Reference Manager Special Edition: The Bibliographic Solution
Quantitative trait locus gene mapping: a new method for locating alcohol response genes
Authors: CRABBE JOHN
Published: August 2003

Alcoholism is a multigenic trait with important non‐genetic determinants. Studies with genetic animal models of susceptibility to several of alcohol's effects suggest that several genes contributing modest effects on susceptibility (Quantitative Trait Loci, or QTLs) are important. A new technique of QTL gene mapping has allowed the identification of the location in mouse genome of several such QTLs. The method is described, and the locations of QTLs affecting the acute alcohol withdrawal reaction are described as an example of the method. Verification of these QTLs in ancillary studies is described and the strengths, limitations, and future directions to be pursued are discussed. QTL mapping is a promising method for identifying genes in rodents with the hope of directly extrapolating the results to the human genome. This review is based on a paper presented at the First International Congress of the Latin American Society for Biomedical Research on Alcoholism, Santiago, Chile, November 1994.
Are tobacco and alcohol use related to Alzheimer's disease? A critical assessment of the evidence and its implications
Authors: TYAS SUZANNE
Published: August 2003

Elucidation of the association of tobacco and alcohol use with Alzheimer's disease (AD) may advance etiological hypotheses and provide a theoretical basis for treatment. There is currently no cure or effective treatment for AD, and no cause has been established. Pharmacological evidence supports a plausible biological mechanism for the involvement of tobacco use: nicotine compensates for some of the cholinergic deficits observed in AD. Epidemiological evidence, however, is inconsistent, although recent meta‐analyses also support a protective effect. Although smoking per se is certainly not advocated, further investigation of a potential protective effect of nicotine on AD is warranted. Pharmacological studies implicate alcohol use as a possible risk factor for AD; the epidemiological studies are again inconclusive. Alcohol consumption is associated with daily smoking and smokers are, in turn, more likely to consume alcohol. Since tobacco use may decrease the risk of developing AD and alcohol use may increase it, it is important to consider these two substances together: the effect of one may negate the other. This literature review critically evaluates the evidence for an association of tobacco and alcohol use with AD and identifies key issues for further research.
Ethanol dosage regimes in studies of ethanol toxicity: influence of nutrition and surgical interventions
Authors: PREEDY VICTOR , MCINTOSH ANDREW , BONNER ADRIAN , PETERS TIMOTHY
Published: August 2003

In this review we consider some of the practical facets of acute and chronic drug regimes. In particular, we illustrate our arguments with specific reference to alcohol and draw attention to methodological constraints that might alter biochemical or physiological processes. These includes the imposition of nutritional abnormalities and surgical procedures. These two areas are highlighted because there is evidence to show that they have marked influences on metabolic parameters, exemplified by tissue protein synthesis. In general, there is no controversy as to methods for acute studies with alcohol, although some reports have failed to investigate whether intravenous, intragastric or intraperitoneal regimes more accurately mimic the clinical situation. With regard to chronic feeding regimes, evidence is provided to support the argument that, currently, the most appropriate feeding protocol ensures that both control and treated groups receive identical amounts of nutrients albeit with differences in the calories apportioned to ethanol, which is substituted by isocaloric glucose or other carbohydrates in controls. However, there are still other methods being employed: these are subject to misinterpretation as the principle of ensuring that control and ethanol‐fed rats receive identical amounts of nutrients, is ignored. In this review we also draw attention to the fact that surgical procedures, which are often employed to facilitate the measurement of body parameters (for example, implantation of cannulae), themselves alter tissue metabolism. The importance of this relates to the concept of metabolic superimposition, which implicates interacting responses when two or more stresses (i.e. surgery and drug administration) are superimposed.
Brain regional pharmacology of GABA A receptors in alcohol‐preferring AA and alcohol‐avoiding ANA rats
Authors: WONG GARRY , OVASKA TIMO , KORPI ESA
Published: August 2003

Compounds interacting with the GABA A receptor system modulate voluntary alcohol consumption in alcohol‐preferring AA (Alko, Alcohol) rats. Therefore, we compared the central GABA A receptor pharmacology of the AA rats to that of their counterpart, alcohol‐avoiding ANA (Alko, Non‐Alcohol) rats with receptor autoradiography. Total flumazenil‐sensitive [3 H]Ro 15‐4513 binding to the benzodiazepine site of GABA A receptor was slightly lower in the hippocampus, striate cortex and lateral hypothalamus of the AA than ANA rats. The proportions of zolpidem‐ and diazepam‐sensitive components were similar in both rat lines. Basal picrotoxin‐sensitive [35 S]TBPS binding to the convulsant site of GABA A receptor was similar in most regions between the rat lines, but the up‐modulation of the binding by 10 μ M diazepam in the hippocampal, amygdaloid and entorhinal cortical areas was greater in the AA than ANA rats. These results do not reveal any general genetic defect in the GABA A receptors of AA or ANA rats, but the regional profile of the ligand binding differences between the lines, especially in the coupling of the benzodiazepine and chloride channel sites, suggests receptor subtype‐specific changes in brain regions implicated in behavioural reward and anxiolysis.
Performance in the cross‐maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior
Authors: SALIMOV R. M. , MCBRIDE W. J. , SINCLAIR J. D. , LUMENG L. , LI T.‐K.
Published: August 2003

Alcohol naive rats from lines genetically selected for high and low alcohol drinking and founded on either Wistar (P/NP lines) and distinct heterogeneous stocks (AA/ANA and replicate HAD/LAD lines) were tested in the explorative cross‐maze and the inescapable slip funnel. Rats of the low alcohol‐consuming ANA, NP, LAD1 and LAD2 lines all exhibited a shorter latency before initiating exploration of the maze than did their high alcohol‐consuming counterparts (66, 51, 33 and 51% of the values for AA, P, HAD1 and HAD2 lines, respectively). Significant line differences were also found with the slip funnel test (AA > ANA for time in a sprawling posture; P > NP but HAD1 < LAD1 and HAD2 < LAD2 for time escaping), but the directions of line differences were not consistently related to those in alcohol drinking.
No association between D3 dopamine receptor (DRD3) alleles and cocaine dependence
Authors: FREIMER MARTIN , KRANZLER HENRY , SATEL SALLY , LACOBELLE JAMES , SKIPSEY KITZIA , CHARNEY DENNIS , GELERNTER JOEL
Published: August 2003

Cocaine is thought to act in the brain primarily by blocking dopamine re‐uptake. The dopamine D3 receptor (genetic locus DRD3) is localized to brain regions that have been implicated in the reinforcing effects of a number of substances of abuse, including cocaine. The DRD3 coding region contains a polymorphism identifiable as a polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP). This polymorphism leads to an amino acid substitution at position 9 in the extracellular N‐terminus of the D3 dopamine receptor. We examined alleles of the DRD3 gene in cocaine dependence using a genetic association strategy in samples of 62 white and 62 black cocaine‐dependent individuals. Comparisons were made with local (Connecticut) control subjects for both groups, and with a larger sample of literature controls (for the white subjects) and a contrast group of schizophrenic patients (for the black subjects). No association was found between cocaine dependence and DRD3 alleles in either group (Bonferroni corrected). There was a significant difference in allele frequency between whites and blacks. These results are consistent with no role for genetic variation of the D3 dopamine receptor in susceptibility to cocaine dependence.
Ethanol acutely impairs glycogen repletion in skeletal muscle following high intensity short duration exercise in the rat
Authors: PETERS TIMOTHY , NIKOLOVSKI SASHA , RAJA GHAZALA , PALMER T. NORMAN , FOURNIER PAUL
Published: August 2003

Ethanol is recognized to affect adversely carbohydrate metabolism in skeletal muscle. This paper seeks to establish whether ethanol acutely impairs glycogen repletion during recovery from high intensity short duration exercise in the rat. High intensity exercise caused the massive mobilization of glycogen stores in muscles rich in type IIa and IIb fibres and marked increases in plasma and muscle lactate levels. During the 30‐minute recovery period, there was substantial glycogen repletion in these muscles in both the ethanol‐treated and control rats. Ethanol, however, was associated with reduced glycogen resynthesis in both the tibialis anterior (by 22%) and red gastrocnemius (by 31%) muscles but not in the white gastrocnemius muscle. This reduction in post‐exercise glycogen deposition was accompanied by decreased lactate disposal and elevated plasma glucose levels. These effects of ethanol on glycogen repletion may involve interactions with hepatic gluconeogenesis, glucose uptake and utilization in muscle, muscle glycogen synthesis and lactate glyconeogenesis. The ethanol‐mediated impairment in post‐exercise glycogen repletion may have important implications for the pathogenesis of chronic alcoholic skeletal myopathy.
Cardiovascular risk factors in young drug addicts
Authors: BERG JOHN , HØSTMARK ARNE
Published: August 2003

Since the type of life‐style often encountered in drug addicts is purported to influence their risk of cardiovascular disease, it seemed of interest to carry out a descriptive study on risk factors in young addicts. Twenty‐four young intravenous drug addicts, mean age 29 years and mean body mass index (BMI) 22.5 (kg/m−2), were compared with 24 healthy people matched for age, gender and BMI. Both groups responded to a questionnaire on life‐style risk factors. In addition, fasting blood samples were investigated for several coronary risk factors. Drug addicts had smoked more cigarettes (17 vs. 3 cigarettes/day) for a longer time period (15 vs. 5 years) than control subjects. They also had higher serum activities of liver enzymes related to alcohol abuse than controls. Level of physical activity and indicators of dietary intake of fruit, vegetables and salt were not significantly different between the groups. Blood lipid values, total cholesterol (5.1 vs. 5.6 mmol/l), and HDL‐cholesterol (1.2 mmol/l), apolipoproteins, and an atherogenic index reflecting the balance between the atherogenic low density lipoproteins (LDL) and the antiatherogenic fraction (HDL), as well as the smoking‐related factors fibrinogen and TBARS, were all similar in both groups. The study indicates that the prevalence of many known cardiovascular risk factors was similar in drug addicts and matched controls.
Interaction of mazindol with alcohol in mice
Authors: GEVAERD MONIQUE , TAKAHASHI REINALDO
Published: August 2003

Combined anorectic‐alcohol misuse is a prevalent problem in Brazil. In order to understand better the interactive effects of ethanol (EtOH) and mazindol (MZ), we examined the effects of EtOH (1.2 g/kg) and MZ (5.0 mg/kg) given alone or in combination, on mouse behaviour. The results indicate that EtOH plus MZ induces a significantly greater increase in locomotor activity of mice than either constituent alone. However, no such interactive effect was detected in the place preference and in the plus‐maze test of anxiety. MZ given alone was found to increase the locomotor activity and to possess rewarding effects as measured in the place preference conditioning. At the dose selected, EtOH alone showed anxiolytic and rewarding effects. These results provide some evidence of increased behavioural effects in mice due to combinations of EtOH and MZ. These findings suggest that a major determinant of combined anorectic‐alcohol misuse may be the increased stimulating effects produced by such combination.
Book and Media Reviews
Authors: COOK CHRIS
Published: August 2003

Books review in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for review, but especially software and other media of specific relevance to the addictions.

Enzymology and Molecular Biology of Carbonyl Metabolism 5 H. WIENER, R. S. HOLMES & BENDICHT WERMUTH (Eds)

Neurotransmitter Release and its Modulation: Biochemical Mechanisms, Physiological Function and Clinical Relevance D. A. POWIS & S. J. BUNN (Eds)

Health Update No. 2—Smoking R. WALTERS & H. WENT

Atlas of Clinical Gastroenterology, 2nd edn J. J. MISIEWICZ, A. FORBES, A. B. PRICE, P. J. SHORVON, D. R. TRIGER & G. N. J. TYTGAT

Addiction Psychiatry: Current Diagnosis and Treatment N. S. MILLER

Clinical Handbook of Psychotropic Drugs—5th revised edn KALYNA Z. BEZCHLIBNYK‐BUTLER & J. JOEL JEFFRIES

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Genetic Analysis: Principles, Scope and Objectives J. R. S. FINCHAM

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Nucleic Acid Hybridization—Essential data P. M. GILMARTIN

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Current Awareness in Biological Sciences
Alcoholism and the dopaminergic system: a review
Authors: NOBLE ERNEST
Published: August 2003

Alcohol as well as other substances of abuse are reinforcing substances which manifest their effects through activation of the mesolimbic dopaminergic reward pathways of the brain. In animal genetic models of alcoholism, reduced dopamine levels and D2 dopamine receptor (DRD2) numbers have been found in the brains of alcohol‐preferring animals. Dopamine receptor agonists reduce alcohol consumption, whereas antagonists, in general, show the opposite effect. Moreover, quantitative trait loci studies in animals suggest the DRD2 gene and the region proximate to this locus is a chromosomal “hot spot” for alcohol‐related behaviors. Human studies provide additional support for connection between alcohol dependence and CNS dopaminergic function. In endocrinological studies, using dopamine receptor agonists, reduced dopaminergic activity has been found in more severe and more genetic types of alcoholics. Brain imaging studies are similarly revealing a diminished dopaminergic tone in alcoholics. Treatment of alcoholics with dopamine receptor agonists shows reduced alcohol consumption and improvements in other outcome measures. Molecular genetic studies in humans have identified an association of the Al allele of the DRD2 gene with alcoholism. Moreover, a diminished central dopaminergic function has been found in DRD2 A1 allele subjects using pharmacological, electrophysiological and neuropsychological studies. Further, treatment of alcoholics with a dopamine receptor agonist showed more salutary effects on alcoholics who carry than those who do not carry the DRD2 A1 allele. The A1 allele has also been associated with substance use disorders other than alcoholism, including and cocaine and nicotine dependence and polysubstance abuse. The emerging evidence suggests that the DRD2 is a reinforcement or reward gene. It could represent one of the most prominent single‐gene determinants of susceptibility to severe substance abuse. However, the environment and other genes, when combined, still play the larger role.
Alcohol dehydrogenases and aldehyde dehydrogenases among inbred strains of mice: multiplicity, development, genetic studies and metabolic roles
Authors: ROUT UJJWAL , HOLMES ROGER
Published: August 2003

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for the metabolism of alcohols and aldehydes in the body. Both exist as a family of isozymes in mammals, and have been extensively studied in animal models, particularly among inbred strains of mice. Mouse ADH exists as at least three major classes, which are predominantly localized in liver (classes I and III), and in stomach/cornea (class IV). Mouse ALDH exhibits extensive multiplicity, several forms of which have been characterized, including ALDH1 (liver cytoplasmic/class 1 isozyme); ALDH2 (liver mitochondrial/class 2.); ALDH3 (stomach cytosolic/class 3); ALDH4 (liver microsomal/class 3); and ALDH5 (testis cytosolic/class 3). Biochemical, genetic and molecular genetic analyses have been performed on several of these enzymes, including studies on variant forms of ADH and ALDH. Distinct metabolic roles are proposed, based upon their tissue and subcellular distribution characteristics and the biochemical properties for these enzymes.
Pathogenesis of alcoholic hepatic steatosis
Authors: SIMPSON K. J.
Published: August 2003

Chronic alcohol misuse is the most common cause of hepatic steatosis. The accumulation of lipid is reversible with abstinence, but some workers have suggested that the severity of hepatic steatosis predicts the progression with time to alcoholic cirrhosis. Triacylglycerol is the major accumulating lipid and subcellular fractionation and electron microscopy studies have shown accumulation of lipid droplets within the golgi fraction. This is consistent with the reports in both experimental animals and man of reduced hepatic secretion of very low density lipoprotein triacylglycerol which may be secondary to acetaldehyde‐induced disruption of the cytoskeletal elements. In addition, hepatic production of triacylglycerol increases, but most studies in animal models suggest that increased triacylglycerol synthesis becomes less important as hepatic lipid accumulates.
The effects of acute administration of ethanol on jejunal protein synthesis and circulating insulin‐like growth factor (IGF)‐1 and IGF binding proteins in ad libitum fed and nutritionally restricted rats
Authors: MIELL JOHN , MARWAY JASPAUL , JONES JENNY , PREEDY VICTOR
Published: August 2003

The effects of acute ethanol administration (75 mmol/kg body weight) to male Wistar rats (either ad libitum fed or nutritionally restricted) on fractional rates of protein synthesis in the jejunum was assessed together with the changes in IGF‐1 and IGF binding protein concentrations. Acute administration of ethanol resulted in significant decreases in fractional rates of protein synthesis in the whole jejunum and jejunal seromuscular layers of both the ad libitum fed and nutritionally restricted animals. The synthesis rate per unit RNA (k RNA, mg protein/day/mg RNA) in whole jejunum was reduced by 29% and 24% in the nutritionally restricted and ad libitum fed animals, respectively. Mean IGF‐1 levels were lower in the nutritionally restricted group (871 ± 36.9 μ g/l) than the ad libitum animals (960 ± 27.3 μ g/l) although this did not reach significance. In contrast, administration of alcohol to both groups markedly reduced circulating IGF‐1 levels (ad libitum : 518 ± 19.8 μ g/l, nutritionally restricted: 417 ± 33.7 μ g/l). Furthermore, ethanol treatment resulted in a three‐fold increase in the intensity of a 30 kDa IGF binding protein (IGFBP) in the ad libitum fed animals and a fourfold increase in both 30 and 32 kDa IGFBP bands in the nutritionally restricted group as visualized by Western ligand blotting. Decreases in levels of IGF‐1 allied with increased circulating small molecular weight IGFBPs may contribute to the reduction in fractional rates of protein synthesis in the gastrointestinal tract of ethanol‐treated rats.
Acetaldehyde metabolism by liver mitochondrial ALDH from UChA and UChB rats: effect of inhibitors
Authors: TAMPIER LUTSKE , SÁNCHEZ ELIANA , ELENA MARÍA
Published: August 2003

We have observed that blood acetaldehyde (AcH) levels after an ethanol dose were significantly higher in disulfiram‐pre‐treated UChA (low ethanol consumer) than in UChB (high ethanol consumer) rats. In order to explore these results further, we studied the effect of disulfiram (300 mg/kg i.p.) and chlorpropamide (80) mg/kg i.p.) pre‐treatment on blood AcH levels after oral ethanol (60 mmol/kg) and on AcH metabolism by liver mitochondrial aldehyde(s) dehydrogenase(s) from UChA and UChB rats. AcH metabolism by liver mitochondrial aldehyde dehydrogenase (ALDH) was studied by following AcH disappearance rate and the formation of NADH at 340 nm in the incubation medium. The results showed that chlorpropamide, like disulfiram, produced a higher blood AcH level consistent with a greater inhibition of the low‐Km mitochondrial ALDH in the UChA rats than in the UChB rats. These drugs did not inhibit the high Km mitochondrial ALDH. Kinetic studies of mitochondrial ALDH show that low‐Km mitochondrial ALDH from UChB rats exhibits a higher affinity for NAD than UChA rats. This observation could explain the different inhibition of ALDH by both drugs, assuming that the inhibitors reduce NAD availability, the rate limiting step in the mitochondrial ALDH oxidation.
Salivary glands in alcoholism: a histologic and sialographic study
Authors: SMITH PATRICIO , RAMIREZ JULIO , ROMO RAFAEL , ESGUEP ALFREDO
Published: August 2003

A qualitative and quantitative histological analysis of minor salivary glands was carried out in 60 alcoholics (20 alcoholics with liver damage, 20 without liver damage, 20 young alcoholics) and 20 matched control patients. A sialographic study was carried out in the same 60 alcoholic patients and in 40 non‐alcoholic control individuals. Minor salivary gland biopsies were obtained and samples were processed for light microscopy. A quantitative morphometrical assessment was carried out by counting the number of acinar cells with a squared grid eye‐piece. Both experimental and control samples presented very similar results demonstrating that, at least in this study, minor salivary glands do not develop hypertrophic, atrophic or hyperplastic changes. We detected a statistical difference between adult alcoholics without liver damage and adult alcoholics with liver damage. A diffuse mononuclear inflammatory cell infiltrate was distributed through the stroma or concentrated around the salivary ducts in both experimental and control samples. Acinar degeneration and hyperaemia were common changes observed in both experimental and control samples. Sialographic images from alcoholics demonstrated a similar morphology when compared with control patients, perhaps a reduction in secondary ducts diameter was observed in alcoholic patients. From this study we may conclude that minor salivary glands are scarcely affected by alcoholism, even when this disease has progressed to liver damage. Based on a presentation to the Latin‐American Society for Biomedical Research on Alcoholism (LASBRA), November 1994 at Santiago, Chile