Effects of dopamine receptor D4 variation on alcohol and tobacco use and on novelty seeking: Multivariate linkage and association analysis

The dopamine D4 receptor gene contains a polymorphic sequence consisting of a variable number of 48-base-pair (bp) repeats, and there have been a number of reports that this polymorphism is associated with variation in novelty seeking or in substance abuse and addictive behaviors. In this study we have assessed the linkage and association of DRD4 genotype with novelty seeking, alcohol use, and smoking in a sample of 377 dizygotic twin pairs and 15 single twins recruited from the Australian Twin Registry (ATR). We found no evidence of linkage or association of the DRD4 locus with any of the phenotypes. We made use of repeated measures for some phenotypes to increase power by multivariate genetic analysis, but allelic effects were still non-significant. Specifically, it has been suggested that the DRD4 7-repeat allele is associated with increased novelty seeking in males but we found no evidence for this, despite considerable power to do so. We conclude that DRD4 variation does not have an effect on use of alcohol and the problems that arise from it, on smoking, or on novelty seeking behavior. (C) 2003 Wiley-Liss, Inc.

Drug use patterns and mental health of regular amphetamine users during a reported 'heroin drought'

Aims The present study extends the findings of a pilot study conducted among regular amphetamine users in Newcastle, NSW, in 1998. It compares key features between current participants in a state capital city (Brisbane) and a regional city (Newcastle) and between the 1998 and current Newcastle sample. Design Cross-sectional survey. Setting Brisbane and Newcastle, Australia. Participants The survey was conducted among 214 regular amphetamine users within the context of a randomized controlled trial of brief interventions for amphetamine use. Measurements Demographic characteristics, past and present alcohol and other drug use and mental health, treatment, amphetamine-related harms and severity of dependence. Findings The main findings were as follows: (i) the rate of mental health problems was high among regular amphetamine users and these problems commonly emerged after commencement of regular amphetamine use; (ii) there were regional differences in drug use with greater accessibility to a wider range of drugs in a state capital city and greater levels of injecting risk-taking behaviour outside the capital city environment; and (iii) there was a significant increase in level of amphetamine use and percentage of alcohol users, a trend for a higher level of amphetamine dependence and a significant reduction in the percentage of people using heroin and benzodiazepines among the 2002 Newcastle cohort compared to the 1998 cohort. Conclusions Further longitudinal research is needed to elucidate transitions from one drug type to another and from recreational to injecting and regular use and the relationship between drug use and mental health in prospective studies among users. Implications Intervention research should evaluate the effectiveness of interventions aimed at: preventing transition to injecting and regular use of amphetamines; toward reducing levels of depression among amphetamine users and interventions among people with severe psychopathology and personality disorders; and toward reducing the prevalence of tobacco dependence among amphetamine users.

A transdisciplinary approach to adolescent forensic mental health

Objective: To examine new strategies which may be implemented to address the significant mental health and substance abuse problems of young people within the juvenile justice system. Method: Wide-ranging literature review of mental health problems within the juvenile justice population is given, illustrating the high prevalence of mental health problems within this cohort of young people. Reference is made to the differing demographics and agendas of the American justice system compared to that found in Australia. Results: It is suggested that new initiatives stemming from quality Australian studies are required in order to facilitate reform within adolescent forensic mental health. Psychiatrists need to be at the forefront of innovative policy delivery within the juvenile justice system. Conclusions: A transdisciplinary approach is required to meet the changing needs of young people within the juvenile justice system. Such a system of care recognizes that these young people and their families have multiple needs that cross traditional boundaries and a collaborative approach across agencies is essential at both the policy and practical level. Psychiatrists have an important role to play in the development of these services. A systemic process to address such needs is offered.

The application of proteomics to the human alcoholic brain

Alcoholism results in changes in the human brain that reinforce the cycle of craving and dependency, and these changes are manifest in the pattern of expression of proteins in key cells and brain areas. Described here is a proteomics-based approach aimed at determining the identity of proteins in the superior frontal cortex (SFC) of the human brain that show different levels of expression in autopsy samples taken from healthy and long-term alcohol abuse subjects. Soluble protein fractions constituting pooled samples combined from SFC biopsies of four well-characterized chronic alcoholics (mean consumption > 80 g ethanol/day throughout adulthood) and four matched controls (< 20 g/day) were generated. Two-dimensional electrophoresis was performed in triplicate on alcoholic and control samples and the resultant protein profiles analyzed for differential expression. Overall, 182 proteins differed by the criterion of twofold or more between case and control samples. Of these, 139 showed significantly lower expression in alcoholics, 35 showed significantly higher expression, and 8 were new or had disappeared. To date, 63 proteins have been identified using MALDI-MS and MS-MS. The finding that the expression level of differentially expressed proteins is preponderantly lower in the alcoholic brain is supported by recent results from parallel studies using microarray mRNA transcript.

Genes and gene expression in the brain of the alcoholic

Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABA(A) receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-D-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor subunit mRNA expression, and GABB2 and DRD2B genotypes with p subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence. (C) 2004 Elsevier Ltd. All rights reserved

Gene expression in profiling in individual cases reveals consistent transcriptional changes in alcoholic human brain

Chronic alcohol exposure induces lasting behavioral changes, tolerance, and dependence. This results, at least partially, from neural adaptations at a cellular level. Previous genome-wide gene expression studies using pooled human brain samples showed that alcohol abuse causes widespread changes in the pattern of gene expression in the frontal and motor cortices of human brain. Because these studies used pooled samples, they could not determine variability between different individuals. In the present study, we profiled gene expression levels of 14 postmortem human brains (seven controls and seven alcoholic cases) using cDNA microarrays (46 448 clones per array). Both frontal cortex and motor cortex brain regions were studied. The list of genes differentially expressed confirms and extends previous studies of alcohol responsive genes. Genes identified as differentially expressed in two brain regions fell generally into similar functional groups, including metabolism, immune response, cell survival, cell communication, signal transduction and energy production. Importantly, hierarchical clustering of differentially expressed genes accurately distinguished between control and alcoholic cases, particularly in the frontal cortex.

Reasons for cannabis use in men with and without psychosis

Psychoses are relatively low prevalence disorders that have a disproportionately negative impact on individuals and society. Cannabis use is one factor that can exacerbate the negative consequences associated with psychotic disorders. Relatively few studies have examined the effects or reasons for using cannabis self-reported by individuals with psychosis. The present study is the first known to compare directly such factors in individuals with and without psychosis, within a single study. At baseline and follow-up participants with psychosis most commonly reported using cannabis for positive mood alteration (36% and 42%), coping with negative affect (27% and 29%) and for social activity reasons (38% and 29%). The control group most commonly reported using cannabis for relaxation (34% and 43%) and social activity reasons (49% and 51%). Participants with psychosis were less likely to report relaxation as the most important effect after use ( 27%) or expect it at follow-up ( 49%) compared to the control group (53% and 70%). In both groups, addiction and positive affect enhancement were the composite variable scores correlated most consistently with concurrent amount and frequency of use.

GABAA receptor beta subunit mRNA expression in the human alcoholic brain

A competitive RT-PCR assay was used to quantify the expression of the GABA(A) receptor beta(1), beta(2) and beta(3) isoform mRNA transcripts in the superior frontal cortex and motor cortex of 21 control and 22 alcoholic cases. A single set of primers was designed that permitted amplification of all three transcripts and the internal standard simultaneously; differentiation of the individual transcripts was achieved by restriction enzyme digestion. Construction of a standard curve, using the internal standard and a concentration range of beta(2) cRNA-enabled quantitation of mRNA expression levels. No significant difference in mRNA expression was found between the control and alcoholic case groups in either the superior frontal or motor cortex for the beta(2) or beta(3) isoforms. A significant interaction was found between isoform and area, although, the two case groups did not partition on this measure. The interaction was due to a significant difference between superior frontal and motor cortex for the beta(3) isoform; this regional comparison was not significant for beta(2) mRNA. Age at death and post-mortem delay (PMD) had no significant effect on beta mRNA expression in either case group in either region. A beta(1) signal could not be detected in the RT-PCR assay. (C) 2004 Elsevier Ltd. All rights reserved.

General practitioners' role in preventive medicine: scenario analysis using alcohol as a case study

The purpose of this analysis is threefold: first, to extract from the literature, current levels of GP detection of at-risk drinking by their patients, rates at which general practitioners (GPs) offer an intervention; and the effectiveness of these interventions; secondly, to develop a model based on this literature to be used in conjunction with scenario analysis; and thirdly, to consider the cost implications of current efforts and various scenarios. This study deals specifically with Australian general practice. A two-step procedure is used in the scenario analysis, which involves identifying opportunities for detection, intervention, effectiveness and assigning probabilities to outcomes. The results suggest that increasing rates of GP intervention achieves greatest benefit and return on resource use. For every 5% point increase in the rate of GP intervention, an additional 26 754 at-risk drinkers modify their drinking behaviour at a cost of $231.45 per patient. This compares with a cost per patient modifying drinking behaviour of $232.60 and $208.31 for every 5% point increase in the rates of detection and effectiveness, respectively. The knowledge, skill and attitude of practitioners toward drinking are significant, and they can be the prime motivators in persuading their patients to modify drinking behaviour.

Smoking behaviour among Indigenous secondary school students in North Queensland

This study investigated smoking behaviour among Indigenous youth. A sample of schools (n = 12) in north Queensland with large proportions of Indigenous students was selected. Details about the prevalence of smoking behaviour in both Indigenous and non-Indigenous students ( n = 883) were gathered. Data were also collected on the cultural, social, and psychological factors associated with cigarette smoking for Indigenous and non-Indigenous students. This survey indicated smoking rates for Indigenous and non-Indigenous students were 24% and 30%, respectively. The study found similarities between both groups regarding where they obtained their cigarettes ( friends) and their reasons for not smoking ( their parents and health). Results of this survey challenge the belief that Indigenous youth are significantly different in their smoking patterns and behaviours compared to non-Indigenous secondary school students in rural regions. It indicated the potential importance of school communities in promoting non-smoking behaviours among Indigenous students even in the face of strong normative pressures from elsewhere in the community. This survey can be used to monitor smoking prevalence among Indigenous secondary students in north Queensland, help guide the development of culturally appropriate school curriculum resources and contribute to the overall evaluation of smoking prevention and smoking cessation programs which are developed for Indigenous secondary school students.

Genetic study of alcoholism and novel gene expression in the alcoholic brain

Alcohol dependence may result from neuroadaptation involving alteration of gene expression after long-term alcohol exposure. The systematic study of gene expression profiles of the human alcoholic brain was initiated using the method of polymerase chain reaction (PCR)-differential display and was followed by DNA microarray. To date, more than 100 alcohol-responsive genes have been identified from the frontal cortex, motor cortex and nucleus accumbens of the human brain. These genes have a wide range of functions in the brain and indicate diverse actions of alcohol on neuronal function. This review discusses the current information on the genetic basis of alcoholism and the induction and characterization of these alcohol-responsive genes.

Web-based screening and brief intervention for hazardous drinking: a double-blind randomized controlled trial

Background Strong evidence exists for the efficacy of screening and brief intervention for reducing hazardous drinking. However, problems have been highlighted with respect to its implementation in health-care systems, not least of which is a reluctance of some doctors to discuss alcohol proactively with their patients. Aims To determine the efficacy of a novel web-based screening and brief intervention (e-SBI) to reduce hazardous drinking. Design A double-blind randomized controlled trial. Setting A university student health service. Participants A total of 16 7 students (17-26 years) were recruited in the reception area and completed a 3-minute web-based screen including the Alcohol Use Disorder Identifiation Test (AUDIT) questionnaire. Of these, 112 tested positive, and 104 (52 females) who consented to follow-up were included in the trial. Measurements Drinking frequency, typical occasion quantity, total volume, heavy episode frequency (females > 80 g ethanol, males > 120 g ethanol), number of personal problems, an academic problems score. Intervention Participants were randomized to 10-15 minutes of web-based assessment and personalized feedback on their drinking (intervention, n = 5 1) or to a leaflet-only control group (n = 5 3). Findings Mean baseline AUDIT scores for control and intervention groups were 16.6 (SD = 6.0) and 16.6 (SD = 5.7). At 6 weeks, participants receiving e-SBI reported significantly lower total consumption (geometric mean ratio = 0.74; 9 5 % confidence interval: 0.56-0.96), lower heavy episode frequency (0.63; 0.42-0.92) and fewer personal problems (0.70; 0.54-0.91). At 6 months personal problems remained lower (0.76; 0.60-0.97), although consumption did not differ significantly. At 6 months, academic problems were lower in the intervention group relative to controls (0.72; 0.51-1.02). Conclusions e-SBI reduced hazardous drinking among university students, to an extent similar to that found for practitioner-delivered brief interventions in the general population. e-SBI offers promise as a strategy to reduce alcohol-related harm in a way that is non-intrusive, appealing to the target group, and capable of being incorporated into primary care. Research is required to replicate the findings, to determine the duration of intervention effects, and to investigate the mechanisms by which the intervention operates.