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

Association analyses of candidate genes (VMAT2, DAT, BDNF) with personality and psychiatric diseases

Mit Hilfe von Assoziationsstudien wurde im Rahmen der vorliegenden Arbeit versucht, die Rolle verschiedener Kandidatengene (vesikulärer Monoamintransporter VMAT2, Dopamintransporter DAT, Brain Derived Neurotrophic Factor BDNF) bei Persönlichkeitsmerkmalen und psychiatrischen Erkrankungen näher zu beleuchten. C. Robert Cloninger postuliert in seiner biosozialen Persönlichkeitstheorie eine genetische Grundlage von Temperamentfaktoren, die im dopaminergen, serotoninergen und noradrenergen Transmittersystem zu finden sei. Im Rahmen der vorliegenden Arbeit wurde daher untersucht, ob Gene in Schlüsselpositionen monoaminerger Transmittersysteme - das Gen des vesikulären Monoamintransporters und des Dopamintransporters - die Ausprägung von Persönlichkeitsfaktoren beeinflussen. Außerdem wurde nach einer Assoziation von Genvarianten des vesikulären Monoamintransporters mit suizidalem Verhalten und der Panikstörung geforscht. Weiterhin flossen Ergebnisse zum Dopaminrezeptor D4 und zum Brain Derived Neurotrophic Factor ein. In dieser Arbeit konnte ein Zusammenwirken von Genvarianten des vesikulären Monoamintransporters und des Dopaminrezeptors D4 auf die Ausprägung der Persönlichkeitsdimension TPQ-Novelty Seeking (F2,244 = 3,851, p = 0,023) gezeigt werden. Auch ergab sich, dass die Gene des Dopamintransporters und des Brain Derived Neurotrophic Factors die Dimensionen TPQ-Harm Avoidance (F1,266 = 6,868, p = 0,009) und NEO-PI-R-Neurotizismus (F1,266 = 6,027, p = 0,015) modulieren. Letztgenannte Ergebnisse weisen deutlich darauf hin, dass mehrere Gene bei der Ausprägung von Persönlichkeitsdimensionen interagieren, die mit ängstlichem und depressivem Verhalten in Verbindung stehen. Da Persönlichkeitszüge die Entstehung von suizidalem Verhalten und die Entwicklung von Angsterkrankungen beeinflussen und weil diese Verhaltensabnormitäten entscheidend durch monoaminerge Prozesse modifiziert werden, wurde auch nach einer Assoziation von Varianten des vesikulären Monoamintransporters mit dem Suizid und der Panikstörung gesucht. In beiden Fällen fielen die Ergebnisse negativ aus. Eine mögliche Erklärung dafür ist, dass der vesikuläre Monoamintransporter ursächlich nicht in Zusammenhang mit suizidalem Verhalten und der Panikstörung steht. Möglicherweise spielt jedoch nur der hier untersuchte allelische Marker keine Rolle. Andere polymorphe Regionen dieses Gens könnten dagegen die Entwicklung solcher Verhaltensabnormitäten begünstigen. Auch können Einschränkungen, die durch das Studiendesign bedingt waren, für die hier beschriebenen Resultate verantwortlich sein. Die Bereitschaft zu suizidalem Verhalten wird - nach zahlreichen Studienergebnissen - ganz entscheidend von Prozessen im serotoninergen System geprägt. Bei der Ausbildung der Panikstörung wirken verschiedene monoaminerge Neurotransmitter, wie Noradrenalin, Dopamin und Serotonin zusammen. So scheint der vesikuläre Monoamintransporter, der zu all diesen Überträgerstoffen eine Affinität besitzt, nach wie vor in diesem Zusammenhang ein interessantes Kandidatengen. Zukünftig sind Untersuchungen in Form von familienbasierten Studien oder Zwillings-Adoptionsstudien nötig, um weiterführende Erkenntnisse zur genetischen Grundlage von suizidalem Verhalten und der Panikstörung zu gewinnen. TPQ: Tridimensional Personality Questionnaire; Cloninger, 1987 NEO-PI-R: NEO-Persönlichkeitsinventar, revidiert; Costa, McCrae, 1992In the present study we attempted to determine the role of vesicular monoamine transporter VMAT2, dopamine transporter DAT and brain derived neurotrophic factor BDNF in personality and psychiatric diseases. CR Cloninger discribes a heritability and neurobiological basis of personality traits in his biosocial theory of personality. Variation in personality dimensions seem to be strongly correlated with activity in central monoaminergic pathways as the dopaminergic, serotonergic and noradrenergic system. Therefore key enzymes of mentioned neurotransmitter systems were investigated for association with TPQ (tridimensional personality questionnaire; Cloninger, 1987) and NEO-PI-R (Costa, McCrae, 1992) personality traits. Furthermore polymorphisms of dopamine receptor D4 (DRD4) and BDNF were included. Via analyses of variance we found a significant effect of VMAT2 and DRD4 on TPQ-Novelty Seeking (F2,244 = 3,851, p = 0,023). In addition DAT and BDNF were associated with TPQ-Harm Avoidance (F1,266 = 6,868, p = 0,009) and NEO-PI-R-Neuroticism (F1,266 = 6,027, p = 0,015). The last-mentioned results support an interaction of several genes on anxiety- and depression-related traits. As personality influences suicidal behavior and development of anxiety disorders we investigated the importance of VMAT2 in these behavioral abnormalities. In our study we failed to report an association between VMAT2 and suicide or panic disorder. Several reasons may account for the failure. First, the sample may not have provided sufficient power to detect an association. Second, vesicular monoamine transporter might not influence suicidal behavior or anxiety disorders at all. It could also be that just a different polymorphism in the VMAT2 gene may play a crucial role. Finally, developmental factors and compensatory interactions with other biological mechanisms may account for the absence of a phenotypic effect of the investigated VMAT2 polymorphism. In the future additional family based and twin-/ adoption-studies will be necessary to further reveal the genetic basis of suicidal behavior and panic disorder

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins-as crucial moderators of neuroplasticity-impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = -2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η (2)  = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes