A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

The benevolence hypothesis is supported, suggesting that blood donor motivation is partly selfish. Blood donation campaigns should focus on benevolent rather than purely altruistic messages.

Recent revisions of Gray's Reinforcement Sensitivity Theory (RST) have important implications for self-report measures of approach and avoidance behaviours and how Gray's model relates to other personality models. In this paper, we examine the revised RST by comparing Carver and White's (1994) original one-factor solution of the BIS scale with two alternative two-factor solutions separating BIS-Anxiety and FFFS-Fear. We also examine the relationships between Eysenck's PEN and revised RST factors. Two hundred and twelve participants completed Carver and White's BIS/BAS scales and Eysenck's Personality Questionnaire-Revised. Confirmatory factor analyses of the original BIS scale showed that the hypothesized two-factor model of BIS-Anxiety and FFFS-Fear was the best fit to these data. Associations between the revised RST and Eysenck's PEN were examined using path analysis. In line with theoretical predictions, Psychoticism was related to revised BIS-Anxiety and BAS, Neuroticism to revised BIS-Anxiety and FFFS- Thank you for organizing the review process and for you email of April 9 th 2008 giving us the opportunity to revise and resubmit the Manuscript. We would like to thank the three reviewers for the time and effort they put into their reviews. Their comments were very useful and allowed us to clarify the focus of the paper and strengthen the analyses. Detailed answers to the reviewers' comments are presented below. We have addressed all of the reviewers' concerns.First of all, we would like to thank you for your personal comments and reference for the recently released Corr & McNaughton chapter in Corr (2008). We have incorporated their invaluable discussion into our manuscript. For instance, you had pointed out that the first suggestion for the split of the BIS scale into specific anxiety and fear items was made by Corr & McNaughton (2008) and we have highlighted this in the paper (page 4, paragraph 3; page 5, paragraph 2).Moreover, a number of the reviewers' changes called for additional information and we have tried to make all of these changes while keeping the manuscript within the 5000 word limit for Personality and Individual Differences. For example, we have now included one additional model for the confirmatory factor analysis and the appropriate figures showing the two CFA models (e.g. page 9 and 10, Figure 2) as well as a descriptive table for the RST and PEN variables (page 11, Table 2). Throughout the text we have also clarified some arguments.Word count: 4908 Reviewer 1 General Comment: 'In this study the authors examine associations among Eysenck's PEN and indices relevant to Gray's RST, using Carver and White's (1994) BIS/BAS scales to index RST constructs. Noting important theoretical distinctions between Gray's early (1987) and revised (Gray & McNaughton,2000) theory (e.g., the reallocation of sensitivity to conditioned fear stimuli from the BIS to FFFS), the authors inspect the C&W BIS scale items and, on rational grounds, identify items more related to "fear" than to Response:We t...

The firing of mesolimbic dopamine neurons is important for druginduced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca 2+ -dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2 −/− mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2 −/− mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I A potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.I A current | neuroimaging genetic reward-anticipation preference T he reinforcing properties of addictive drugs are dependent on the activity of mesolimbic dopamine (DA) neurons in the ventral tegmental area (VTA) and their projections to the ventral striatum (VS) and prefrontal cortex (PFC) (1). Microdialysis studies using rodent models have shown that acute administration of addictive drugs, including alcohol, results in elevated DA levels in the VS (2). This effect results from local inhibition of DA reuptake, stimulation of its release, or an increase in firing rate of DA neurons in the VTA (3-5). PET studies have shown a similar effect in the VS of humans as evidenced by decreased competitive binding of a DA receptor antagonist [ 11 C] raclopride (6, 7). Illustrating the importance of DA signaling in the regulation of alcohol-induced reinforcement, rats are known to self-administer ethanol in the nucleus accumbens (8) and posterior VTA (9). These studies and other animal studies suggest that midbrain DA neurons are involved in the acquisition of primary alcohol reinforcement (review in ref. 1).Although the neurobiological and molecular mechanisms controlling DA neuron activity by different ...

Longitudinal and family-based research suggests that conduct disorder, substance misuse, and ADHD involve both unique forms of dysfunction as well as more specific dysfunctions unique to each condition. Using direct measures of brain function, this study also found evidence in both unique and disorder-specific perturbations.

This paper offers objective behavioral evidence that blood donors' charitable giving and blood donation, compared to non-blood donors, is more strongly motivated by warm glow. This provides additional support for the benevolence hypothesis of blood donation.

This paper presents the development of the Situational Triggers of Aggressive Responses (STAR) scale: a self-report instrument examining individual differences in the type of events and antecedents that make people feel aggressive. In Study 1 (N 5 145), participants recorded recently occurring incidents that had generated feelings of aggression in them and recorded their affect at the time of the event using the Positive and Negative Affectivity Scale. The results showed that aggression-triggering events provoked positive as well as negative affect in the sample. In Study 2 (N 5 849), a 23-item scale was generated based on the events recorded during Study 1. The scale comprised two sub-scales: Frustrations and Provocations, which showed good internal reliability and good factor congruency between male and female participants' factor structures. Studies 3 (N 5 241) and 4 (N 5 219) demonstrated the convergent reliability of the STAR scale with measures of trait aggression [Buss and Perry, 1992] and trait narcissism [Raskin and Terry, 1988] with self-concept clarity [Campbell, Trapnell, Heine et al., 1996]. Again, the STAR scale showed good internal reliability. There were no effects of sex on STAR scale scores across Studies 3 and 4. It is suggested, therefore, that sex differences may become more salient when examining aggressive behavior, rather than aggressive feelings.

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use.