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.

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 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.

Tetrahydroisoquinoline derivatives: a new perspective on monoaminergic dysfunction in children with ADHD?

BACKGROUND: The dopamine-derived tetrahydroisoquinolines (TIQ) synthesized endogeneously from aldehydes and catecholamines have shown to modulate neurotransmission, central metabolism and motor activity. Converging evidence has implicated abnormalities of the dopamine metabolism to the pathophysiology of Attention-Deficit/Hyperactivity Disorder (ADHD). Therefore, four TIQ derivatives involved in central dopamine metabolism (salsolinol, N-methyl-salsolinol, norsalsolinol, N-methyl-norsalsolinol) have been analyzed for the first time in children and adolescents with ADHD and healthy controls. METHODS: 42 children and adolescents with ADHD and 24 controls from three sites participated in this pilot study. Free and bound amounts of salsolinol, N-methyl-salsolinol, norsalsolinol, N-methyl-norsalsolinol have been analyzed in urine. RESULTS: In the ADHD group, free and total amounts of the four TIQ derivatives in urine were significantly higher compared to urine levels of healthy controls. For N-methyl-salsolinolfree, most of the ADHD patients were identified correctly with a sensitivity of 92.5% (specificity 94.4%). CONCLUSION: Urine levels of salsolinol, N-methyl-salsolinol, norsalsolinol and N-methyl-norsalsolinol are elevated in children and adolescents with ADHD and point to a new perspective on catecholaminergic dysfunction in ADHD. However, replication and extension of this pilot study would progress this innovative and promising field.

Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits.

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus--in interaction with other gene variants--influences anxiety- and depression-related personality traits.