Adult attention deficit hyperactivity disorder and other psychiatric symptoms in recreational polydrug users.

AIMS: Previous research has shown that recreational drug use is associated with more psychiatric symptoms and psychobiological distress. This study investigated whether symptoms of adult attention deficit hyperactivity disorder (ADHD) were also raised in polydrug users. METHODS: We assessed a non-clinical sample of 84 unpaid volunteers (mean age 27.5 years): n = 17 light-novice polydrug users; n = 29 moderate polydrug users; and n = 38 non-user controls (14 non-drug users, 24 alcohol/tobacco users). They completed the Symptom Checklist 90 (SCL-90) self-rating inventory for psychiatric symptoms, the Adult ADHD Self-report Scale symptom checklist for adult ADHD, and also the questions on positive moods and sociability. Saliva samples provided a neuroendocrine cortisol measure. RESULTS: Moderate polydrug users reported significantly higher adult ADHD symptoms and SCL-90 psychiatric symptoms and lower sociability than non-user controls and light polydrug users. Novice-light polydrug users did not differ from control groups on any measure. There were no significant group differences in cortisol. These findings are debated using the interactive diathesis-distress model. Psychoactive drugs can affect both mood and cognition. When taken regularly, the drug-induced psychobiological vacillation may exacerbate prior problems with mood stability and attentional-cognitive control. CONCLUSIONS: It is not polydrug usage per se, but rather their regular-repeated usage, that is associated with increased signs of psychiatric and attentional-hyperactivity distress.

Digit ratio (2D:4D), salivary testosterone, and handedness.

The length of the index finger relative to that of the ring finger, the 2D:4D ratio, has been taken to be a marker of the amount of testosterone (T) that was present in the foetal environment (Manning, Scutt, Wilson, & Lewis-Jones, 1998). It has also been suggested (Geschwind & Galaburda, 1987) that elevated levels of foetal T are associated with left-handedness and that adult levels of circulating T might relate to foetal levels (Jamison, Meier, & Campbell, 1993). We used multiple regression analyses to investigate whether there is any relationship between either left or right hand 2D:4D ratio and handedness. We also examined whether adult levels of salivary T (or cortisol, used as a control hormone) predict digit ratio and/or handedness. Although the 2D:4D ratio of neither the left nor the right hand was related to handedness, the difference between the digit ratios of the right and left hands, D(R-L), was a significant predictor of handedness and of the performance difference between the hands on a peg-moving task, supporting previous findings (Manning & Peters, 2009; Manning et al., 1998; Manning, Trivers, Thornhill, & Singh, 2000; Stoyanov, Marinov, & Pashalieva, 2009). Adult circulating T levels did not predict the digit ratio of the left or right hand; nor was there a significant relationship between concentrations of salivary T (or cortisol) and either hand preference or asymmetry in manual skill. We suggest that the association between D(R-L) and hand preference arises because D(R-L) is a correlate of sensitivity to T in the developing foetus.

The effects of GABA transporter inhibition on synaptophysin and synaptotagmin expression in diazepam tolerance.

BACKGROUND: In light of the differential interactions seen between benzodiazepine, GABA transporter (GAT) inhibition and drug tolerance, the locomotor effects of a GAT1-specific inhibitor (SKF89976A) following diazepam tolerance were analysed and compared with the concomitant expression of synaptic vesicle proteins implicated in synaptic plasticity. METHODS: Male PVG/OlaHsd rats were chronically dosed with diazepam to produce tolerance, and the expression of mRNA for synaptophysin and synaptotagmin were analysed in the hippocampus by means of in situ hybridisation. The action of the GAT inhibitor SKF89976A on the expression of these mRNAs, and on open field behaviour was subsequently observed. RESULTS: The results show an unexpected sedative effect of GAT-inhibition in diazepam-tolerant rats. The expression data show a significant effect of diazepam treatment on synaptophysin expression, which is reversible by SKF89976A treatment. CONCLUSIONS: The increased synaptophysin expression in the hippocampus of diazepam-tolerant rats may indicate a role for modulation of transmitter release, synaptic plasticity and learning in pharmacological tolerance. The reversibility of this effect following acute GAT inhibition suggests a complicated relationship between the benzodiazepine-binding site and other synaptic GABA-binding sites. Furthermore, the sedative behavioural effect of the GAT inhibitor in diazepam-tolerant rats is an unusual observation with implications for the treatment of drug-tolerant individuals.

Amygdala volume associated with alcohol abuse relapse and craving.

OBJECTIVE: Amygdala volume has been associated with drug craving in cocaine addicts, and amygdala volume reduction is observed in some alcohol-dependent subjects. This study sought an association in alcohol-dependent subjects between volumes of reward-related brain regions, alcohol craving, and the risk of relapse. METHOD: Besides alcohol craving, the authors assessed amygdala, hippocampus, and ventral striatum volumes in 51 alcohol-dependent subjects and 52 age- and education-matched healthy comparison subjects after detoxification. After imaging and clinical assessment, patients were followed for 6 months and alcohol intake was recorded. RESULTS: Alcohol-dependent subjects showed reduced amygdala, hippocampus, and ventral striatum volumes and reported stronger craving in relation to healthy comparison subjects. However, only amygdala volume and craving differentiated between subsequent relapsers and abstainers. A significant decrease of amygdala volume in alcohol-dependent subjects was associated with increased alcohol craving before imaging and an increased alcohol intake during the 6-month follow-up period. CONCLUSIONS: These findings suggest a relationship between amygdala volume reduction, alcohol craving, and prospective relapse into alcohol consumption.

Neurotrophic factor-related gene polymorphisms and adult attention deficit hyperactivity disorder (ADHD) score in a high-risk male population.

Adult attention deficit hyperactivity disorder (ADHD) is a widely under-reported but nevertheless common condition with a clear heritable component. Several genes have been proposed to play a role in the childhood onset of this neurodevelopmental disorder; however, association studies of persistence of ADHD into adulthood have rarely been performed. Neurotrophic factors (NTFs) are known to be involved in several aspects of neuronal development and neural plasticity in adults. They have also been linked, particularly through brain-derived neurotrophic factor (BDNF) interaction with dopamine transport, to the pathophysiology of ADHD. This study compares the genotypes of six different single nucleotide polymorphisms of genes within the neurotrophin system and their possible association with adult ADHD score in 143 high-risk male subjects referred to a forensic psychiatric unit. The genes included NTF3, NTRK2 (TrkB), NTRK3 (TrkC), BDNF, and p75(NTR). While none of the SNPs showed significant association with ADHD symptoms, one polymorphism within the exon of NTF3 (rs6332) showed a trend toward an association between the A-allele and increased scores using both the retrospective childhood analysis Wender-Utah Rating Scale (WURS-k) (P = 0.05) and the adult ADHD assessment Wender-Reimherr interview (P = 0.03). This SNP is a silent mutation which might be in linkage disequilibrium with a functional risk variant for ADHD. As the association was only suggestive, however, this finding needs replication in a larger study with higher power.

A functional serotonin transporter promoter gene polymorphism increases ADHD symptoms in delinquents: interaction with adverse childhood environment.

Although attention-deficit/hyperactivity disorder (ADHD) is highly heritable, environmental conditions play an important role in its manifestation during childhood development. Here, we report the results of an investigation on the interaction of adverse childhood environment with a functional polymorphism of the serotonin transporter promoter gene (5-HTTLPR) and its impact on ADHD psychopathology in young adult delinquents. Standardized instruments were used to assess childhood and current ADHD and adverse childhood environment in 184 male delinquents. Each subject was genotyped for 5-HTTLPR long (L) and small (S) alleles. Logistic regression analysis revealed independent effects of high childhood environmental adversity and the 5-HTTLPR LL-genotype on self-reported childhood ADHD and on persistent ADHD. In addition, a significant gene by environment interaction was found, indicating that carriers of at least one 5-HTTLPR short allele are more sensitive to childhood environment adversity than carriers of the LL-genotype. The results support prior findings of association between ADHD and 5-HTTLPR LL-genotype and adverse childhood environment, and they underline the need for further investigation of gene by environment interaction with respect to ADHD.

A polymorphism at the 3'-untranslated region of the CLOCK gene is associated with adult attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is frequently found in childhood and persists in about 50% of cases into adulthood. Several studies demonstrate a relationship between ADHD, circadian rhythmicity and sleeping disturbances in unmedicated ADHD patients. Since ADHD is a very complex disease with a high genetic load involving multiple genes of moderate effect, we hypothesized a link between adult ADHD and genes involved in the circadian timekeeping system. A 3'-UTR polymorphism of the circadian locomotor output cycles protein kaput (CLOCK) gene, rs1801260, has been linked to disturbed sleep patterns, although both the C-allele and more controversially the T-allele have been proposed as risk factors for different measures of evening preference. This study compared self-rating and interview based measures of ADHD psychopathology of 143 subjects with and without ADHD with their rs1801260 genotype to test the hypothesis that ADHD is linked to one of the alleles of the CLOCK polymorphism. The T > C single nucleotide polymorphism rs1801260 was genotyped in DNA isolated from blood samples. The associations between genotype and ADHD-scores were compared using non-parametric ANCOVA with post hoc pairwise comparisons. There was a strong, significant association (P < 0.001) between each of the adult ADHD assessments and the rs1801260 polymorphism with at least one T-mutation being the risk allele. This is the first study suggesting that a polymorphism of a gene within the circadian "clock" mechanism is a direct or linked contributing factor in adult ADHD.

Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment.

Aggressive behavior is influenced by variation in genes of the serotonergic circuitry and early-life experience alike. The present study aimed at investigating the contribution of polymorphisms shown to moderate transcription of two genes involved in serotonergic neurotransmission (serotonin transporter, 5HTT, and monoamine oxidase A, MAOA) to the development of violence and to test for gene-environment interactions relating to adverse childhood environment. A cohort of 184 adult male volunteers referred for forensic assessment participated in the study. Each individual was assigned to either a violent or a nonviolent group. Logistic regression was performed and the best-fitting model, with a predictive power of 74%, revealed independent effects of adverse childhood environment and MAOA genotype. High environmental adversity during childhood was associated significantly with violent behavior. Forty-five percent of violent, but only 30% of nonviolent individuals carried the low-activity, short MAOA allele. Most interestingly, an interaction effect between childhood environment and 5HTT genotype on violent behavior was found in that high adversity during childhood impacted only the later-life violence if the short promoter alleles were present. These findings indicate complex interactions between genetic variation of the serotonergic circuitry and environmental factors arguing against simplistic, mono-causal explanations of violent behavior.

Analysis of genetic variations of protein tyrosine kinase fyn and their association with alcohol dependence in two independent cohorts.

BACKGROUND: Decreased sensitivity to and increased tolerance for the effects of alcohol is a phenotype, which was shown to be associated with an increased risk for alcoholism in humans and was observed in protein tyrosine kinase (PTK) fyn knockout mice. METHODS: We performed an association study of genetic variations of PTK fyn in 430 alcohol-dependent patients and 365 unrelated control subjects from two independent samples. RESULTS: In a combined analysis, we found an association of alcohol dependence with the single nucleotide polymorphism (SNP) T137346C in the 5' untranslated region (UTR) of the gene. A relevant association could be excluded for the remaining two informative SNPs. Selection by phenotype showed that a high number of withdrawal symptoms, high amount of alcohol intake, and high maximum number of drinks compared with unrelated control subjects was associated with the SNP in the 5'-UTR region but not with the remaining SNPs. CONCLUSIONS: Our results indicate a possible association of alcohol dependence with a genotype of the SNP T137346C of the PTK fyn, with C being the risk allele.