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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-salsolinol , most free 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. ally, ADHD is regarded as a multifactorial disorder caused Background Attention-Deficit/Hyperactivity Disorder (ADHD) is a by many interacting and/or additive risk factors . There common worldwide disorder characterized by inatten- is equivocal evidence from genetic, imaging and medica- tion, impulsivity, and hyperactivity. Despite a large tion studies in humans as well as in animal models of amount of research its etiology still remains unclear. Actu- ADHD that dopamine and noradrenaline metabolism are Page 1 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:64 http://www.behavioralandbrainfunctions.com/content/3/1/64 affected [1,2]. Current models of ADHD propose a hypo- TIQ are found at low concentrations in postmortem brain functioning of e.g. three interacting dopamine systems , cerebrospinal fluid  and urine  of adults : (1) the mesolimbic dopamine system primarily asso- without any neuropsychiatric disorder. In human brain ciated with altered reinforcement of novel behavior and the highest concentration of the TIQ derivative salsolinol deficient extinction of previously reinforced behavior, (2) and its metabolites have been detected in the basal ganglia the mesocortical dopamine system associated with defi-  – an area implicated in the etiology of ADHD . cient attention and poor behavioral organization and (3) Thus in ADHD deviations of TIQ levels might indicate dis- the nigrostriatal dopamine system impairing motor func- turbances of dopamine and noradrenaline metabolism. tions and causing poor nondeclarative habit learning. But In the human brain, two TIQ derivatives salsolinol and the detailed mechanisms underlying these metabolic norsalsolinol are suggested to be synthesized from impairments are still unknown . Previous studies in dopamine by both a non-enzymatic formation via a ADHD found only a limited relationship of plasma and Pictet-Spengler reaction and an enzymatic synthesis via a urine levels of dopamine metabolites to the activity of salsolinol synthase ; their N-methyl derivatives were central dopamine metabolism as well as small effects of formed subsequently enzymatically by N-methyltrans- stimulant medication on urinary dopamine metabolites ferase  (Fig. 1). . Accordingly, studies on the levels of dopamine metabolites in the cerebrospinal fluid have been per- Because TIQ occur physiologically not only from their in formed, but yielded also mixed results of limited value [6- vivo formation but also from ingestion of various foods 9]. [21,22], they seem to be worth to be investigated also in the light of the ongoing debate concerning nutritional In this context the dopamine-derived tetrahydroisoquino- influences on ADHD symptomatology [23,24]. lines (TIQ) including salsolinol and norsalsolinol deriva- tives are of high interest  because of their role as an Because there are still different hypotheses on hyper- and acute modulator of dopamine and noradrenaline neuro- hypodopamine deviances in central metabolism in transmission (see  for a review). TIQ affect receptor ADHD  and TIQ have never been examined in ADHD, status, enzyme activity of the catecholamine biosynthesis there is no directed hypothesis in our pilot study, i.e. it is as well as mitochondrial metabolism. Furthermore, exog- unclear if the four TIQ derivatives under investigation are enously administered TIQ are known to produce changes normal or enhanced versus reduced in the urine of chil- of motor activity in rodents [12-14]. dren and adolescents with ADHD compared to healthy Physiological metabolism Figure 1 of TIQ derivatives Physiological metabolism of TIQ derivatives. Page 2 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:64 http://www.behavioralandbrainfunctions.com/content/3/1/64 controls. Thus, the study also serves to generate a hypoth- Statistics esis for further testing in larger samples. Statistical evaluations were conducted using the Statistical Package for the Social Sciences (SPSS, version 12.0). Val- ues were expressed in nM ± SEM as indicated . We per- Methods Subjects formed analyses of variance (ANOVA) to compare the 42 children and adolescents with ADHD (mean age 12.1, concentrations of the TIQ derivatives among the groups SD 3.2 years) and 24 healthy controls (mean age 23.8, SD followed by analyses of covariance (ANCOVA) with age, 17.0 years) from three sites (Departments of Child and medication (yes/no), and co-existing psychiatric prob- Adolescent Psychiatry of the Universities of Goettingen lems (yes/no) as covariates to control for these possible and Wuerzburg, Department of Clinical Neurology of the confounders. University of Vienna) were enrolled. All patients were referred and fulfilled DSMIV-TR  criteria for ADHD. Results 18 patients were on stimulant medication at the day of In the ADHD group (n = 42), free and total concentrations urine sampling. 16 patients suffered from one or more co- of all measured TIQ derivatives were increased in urine existing psychiatric problems such as conduct disorder (n samples compared to those of healthy controls (n = 24) = 13), learning disorders (n = 4), tic disorders (n = 2) and (ANOVA, Table 1). In contrast, of the conjugated TIQ others (n = 5). forms only the concentration of norsalsolinol was bound significantly different between the groups. Controls were recruited from hospital staff, their children and a school class near Goettingen. All controls were Since the ADHD group and the healthy controls differed screened by an expert child and adolescent psychiatrist for in age (F = 18.99, df = 1,64, p < .001), and since the con- absence of psychiatric disorders and reported no medica- trol group itself was heterogeneous in age (children: n = tion before and during study participation. 13, mean age 10.5 SD 3.9 years; adults: n = 11, mean age 36.7 SD 11.3 years; F = 62.01, df = 1,22, p < .001), we sub- Urine was collected over 12 hours starting at 7 p.m.. Study sequently performed an ANCOVA with the covariate 'age'. participants were not allowed to consume food or bever- Additionally, because of differences in the ADHD group ages rich in TIQ derivatives (cheese, chocolate, fresh and in medication status (24 without versus 18 with) and co- dried banana, soya sauce, beer, Port and white wine) for existing psychiatric problems (26 without versus 16 with) 48 hours before urine samples were obtained . two further covariates were included. There were signifi- cant effects of the covariates 'medication status' (F = The pilot study was approved by the ethics committees of 11.53, df = 1, p < .001) and 'additional psychiatric diag- each participating sites. Informed consent was obtained noses' (F = 7.80, df = 1, p < .01) only for N-methyl-sal- from the children and their parents. This study was con- solinol . However, the same results as obtained using free ducted in accordance with the Helsinki Declaration. ANOVA were found for all measured TIQ derivatives free (ANCOVA, Table 1). In addition to the TIQ derivatives, free Urine analyses also the concentrations of norsalsolinol , norsalsolinol- total The 12 h urine samples were collected in the presence of and N-methyl-norsalsolinol remained increased bound total 50 mg semicarbazide and 50 mg Na EDTA. All aliquot in ADHD. samples collected were stored at -40°C and subsequently measured by a two-step chromatography. Urine samples To determine the predictive quality (ADHD yes/no) of were analyzed at least three times for all conditions, firstly elevated TIQ levels (elevated yes/no) sensitivity and spe- processed by affinity chromatography, and then TIQ cificity were calculated. For the definition of an elevated derivatives were quantified by high performance liquid TIQ level an arbitrary limit was set by the mean of the free chromatography with electrochemical detection (HPLC/ concentration of the control group for each TIQ derivative ECD) as previously described [17,27]. Under our experi- plus one SEM. Specificity is the proportion of true nega- mental conditions, free and total concentrations of TIQ tives (no diagnosis of ADHD and no elevated TIQ level) compounds could be measured. As described earlier , of all negative cases (no diagnosis of ADHD = all controls) dihydroxylated TIQ derivatives are in part bound to sulfo- in the population; sensitivity is the proportion of true pos- or gluco-residues which can be deconjugated by incuba- itives (diagnosis of ADHD and elevated TIQ level) of all tion with arylsulfatases and β-glucuronidases. Since con- positive cases (all ADHD patients) in the population (sen- jugated derivatives can not be detected directly, in our sitivity/specificity (%): N-methyl-salsolinol : 92.5/94.4; free study individual bound amounts were calculated by TIQ- norsalsolinol : 87.8/80.0; N-methyl-norsalsolinol : free free = TIQ -TIQ . 69.0/93.5; salsolinol : 55.5/95.2). bound total free free Page 3 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:64 http://www.behavioralandbrainfunctions.com/content/3/1/64 Table 1: Urine levels of tetrahydroisoquinoline (TIQ) derivatives of children and adolescents with ADHD and healthy controls in nmol. a) TIQ Derivative ADHD controls ANOVA ANCOVA N concentration mean (SEM) N concentration mean (SEM) F F Salsolinol Free 36 8.44 (2.04) 24 0.06 (0.1) 11.17*** 5.87** ns Total 38 19.34 (5.0) 24 2.79 (1.9) 6.57* 2.82 ns ns Bound 23 20.1 (7.2) 3 22.3 (11.0) 0.01 0.01 cal N-methyl-Salsolinol Free 39 71.13 (8.6) 19 14.54 (4.0) 19.76*** 10.31** ns Total 39 129.01 (17.8) 21 53.51 (6.9) 9.22** 3.12 ns ns Bound 37 59.0 (16.2) 19 32.0 (6.7) 1.61 0.23 cal Norsalsolinol Free 41 553.30 (68.0) 24 121.50 (21.7) 22.64*** 25.73*** Total 42 1107.89 (123.7) 22 253.09 (53.37) 23.63*** 29.84*** Bound 39 599.4 (68.3) 17 195.1 (53.9) 13.58*** 20.78*** cal N-methyl- Norsalsolinol Free 42 9.06 (1.6) 24 0.94 (0.7) 77.07*** 12.28*** Total 42 33.76 (7.1) 24 10.64 (4.3) 5.38* 6.56* ns ns 38 27.3 (6.5) 13 17.9 (6.0) 0.63 1.88 Bound cal a) covariates: age, medication (yes/no), co-existing psychiatric problems (yes/no); no effect of covariates except 'medication status' (F = 11.53; df = 1; p < .001) and 'co-existing psychiatric problems' (F = 7.80; df = 1; p < .01) for N-methyl-salsolinol free * p < 0.5; ** p < 0.01;*** p < 0.001; ns = not significant To exclude possibly confounding effects of age, medica- = 727.93 SEM 102.37 nmol; controls: n = 10, mean = tion and comorbidity not only statistically by including 94.70 SEM = 21.54 nmol; F = 17.72, df = 1,29; p < 0.001) covariates but also by strict in- and exclusion criteria of and N-Methyl-norsalsolinol (ADHD: n = 21, mean = free both groups, we analyzed in a second step the data of 21 11.93 SEM 2.90 nmol; controls: n = 12, mean = 0.44 SEM children and adolescents with ADHD compared to 19 = 0.26 nmol; F = 8.79, df = 1,31; p < 0.01). Analogously, healthy controls under the age of 18 years. There were no the absence of group differences remained for N-methyl- differences in age (ADHD: n = 21, mean age 11.8 SD 3.5 salsolinol (ADHD: n = 18, mean = 52.88 SEM 9.02 bound years; controls: n = 12, mean age 9.5 SD 3.2 years; F = nmol; controls: n = 11, mean = 36.55 SEM = 9.31 nmol; F 3.50, df = 1,32, p > .05) and in the ADHD group there = 1.43, df = 1,27; p = 0.243), N-Methyl-norsalsolinol bound were no patients with medication and comorbidity. The (ADHD: n = 18, mean = 30.52 SEM 13.46 nmol; controls: group differences in TIQ levels remained as calculated by n = 8, mean = 4.75 SEM = 1.68 nmol; F = 1.37, df = 1,24; (ADHD: (ADHD: n = 10, mean = 8.54 the ANOVA in the whole sample for salsolinol p = .25). For salsolinol free bound n = 16, mean = 5.64 SEM 2.02; controls: n = 12, mean = SEM 2.41 nmol; controls: n = 1, mean = 2.67) no group 0.11 SEM = 0.11; F = 5.56, df = 1,26; p < 0.05), salsolinol- comparison could be performed because in the control (ADHD: n = 19, mean = 10.81 SEM 2.17 nmol; con- group only for one child its concentration could be calcu- total trols: n = 12, mean = 0.22 SEM = 0.22 nmol; F = 14.78, df lated successfully. For N-Methyl-norsalsolinol the sig- total = 1,29; p < .001), N-methyl-salsolinol (ADHD: n = 18, nificant difference between both groups including all free mean = 66.28 SEM 8.27 nmol; controls: n = 10, mean = patients changed to a trend (ADHD: n = 21, mean = 38.10 10.50 SEM = 1.71 nmol; F = 24.54, df = 1,26; p < 0.001), SEM 13.88 nmol; controls: n = 12, mean = 4.81 SEM = N-methyl-salsolinol (ADHD: n = 20, mean = 116.52 1.51 nmol; F = 3.23, df = 1,31; p = .08). total SEM 13.03 nmol; controls: n = 11, mean = 46.09 SEM = 9.11 nmol; F = 13.85, df = 1,29; p < 0.001), norsal- Discussion solinol (ADHD: n = 21, mean = 688.73 SEM 122.37 Comparisons of urine concentrations of TIQ derivatives free nmol; controls: n = 12, mean = 66.26 SEM = 14.64 nmol; between children and adolescents with ADHD and F = 14.52, df = 1,31; p < 0.001), norsalsolinol (ADHD: healthy controls revealed higher concentrations of sal- total n = 21, mean = 1416.67 SEM 211.09 nmol; controls: n = solinol , N-methyl-salsolinol , norsalsolinol , and free free free 11, mean = 150.89 SEM = 28.09 nmol; F = 18.45, df = N-methyl-norsalsolinol in ADHD patients even when free 1,30; p < 0.001), norsalsolinol (ADHD: n = 21, mean considering three covariates (age, medication status, co- bound Page 4 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:64 http://www.behavioralandbrainfunctions.com/content/3/1/64 existing psychiatric problems) or when subjects with these venting elevated levels of non-conjugated TIQ deriva- free confounders were excluded. N-methyl-salsolinol tives in urine . In addition, oral TIQ ingestion seems free showed the highest sensitivity (92.5%) and specificity unlikely to lead to a simultaneous increase of all four TIQ (94.4%) of the four TIQ derivatives. derivatives in the ADHD group since on the contrary exog- enous origin would lead to individual amount profiles of Although Moser et al  demonstrated a correlation the different TIQ derivatives. Nevertheless, nutritional between salsolinol levels in urine and CSF and a time influences on ADHD symptomatology [23,24] can not be course study of N-methyl-norsalsolinol in CSF indicated a completely ruled out because there may be an ADHD spe- parallel decline of TIQ derivatives on both sides of the cific profile of changes in TIQ metabolism for each TIQ blood-brain barrier [17,31] the evidence for a reliable cor- derivative as an addition of the different TIQ sources. relation between TIQ levels in urine and the central nerv- ous system remains limited. However, analyses of urine Independently of considerations of causality, the sensitiv- levels seem to be methodologically and ethically justified ity and specificity of TIQ urine levels, especially that for N- as the first step to investigate TIQ in children with ADHD, methyl-salsolinol, which is much better than that of other because in studies analyzing other dopamine metabolites neurobiological procedures  needs confirmation and in the CSF, the lack of a control group  due to ethical differentiation by studies including the analyses of other considerations  limited the significance of the find- dopamine metabolites as well as including patients with ings and they were not superior to the results of plasma or other disorders of dopamine dysfunction (e.g. tic disor- urine analyses. Nevertheless, increased central dopamine ders, schizophrenia). Additionally, a further study with concentrations might cause increased concentrations of larger sample size should differentiate between ADHD salsolinol and norsalsolinol in urine resulting also in subtypes. Since hyperactivity was found after injection of increased urine concentrations of N-methyl-salsolinol TIQ in rodents [12-14], in ADHD there might be the and N-methyl-norsalsolinol. This would support the strongest correlation between the core symptom hyperac- "hyperdopamine hypothesis" of ADHD which is in con- tivity and TIQ derivatives as well as the highest urine lev- trast to the majority of findings indicating hypodopamine els in the predominantly hyperactive-impulsive subtype. neurotransmission in ADHD [3,5] although some authors combined both hypotheses to a comprehensive and more Conclusion complex model . In conclusion, urine levels of salsolinol, N-methyl-salsoli- nol, norsalsolinol and N-methyl-norsalsolinol are ele- Interestingly, in the present study there is no hint for an vated in children and adolescents with ADHD and point effect of the therapy with the psychostimulant methylphe- to a new perspective on catecholaminergic dysfunction in nidate on TIQ levels, although the increase of the endog- ADHD. Replication of the findings in a larger sample of enously produced synaptic dopamine concentration children and adolescents with ADHD focusing on sub- through inhibition of the dopamine transporter (DAT), types and including a control group of children with other which takes up the dopamine into the presynaptic neu- movement related catecholaminergic disorders would rons , might have led to higher concentrations of sal- progress this innovative and promising field of research. solinol and norsalsolinol . free free Abbreviations Attention-Deficit/Hyperactivity Disorder (ADHD), Tet- In any case, concluding an exclusive relationship between increased central dopamine metabolism and elevated rahydroisoquinolines (TIQ), analyses of variance urine concentrations of TIQ derivatives might be an over- (ANOVA), analyses of covariance (ANCOVA). simplified view because the found elevation of TIQ levels in ADHD could result not only from primary central but Competing interests also from peripheral synthesis . The author(s) declare that they have no competing inter- ests. Because ingestion of TIQ influences their levels in urine [21,22], participants of our study were not allowed to con- Authors' contributions sume food or beverages rich in TIQ derivatives for 48 VR contributed to the conception and design of the study hours before urine samples were obtained  and so var- and was primarily responsible for the interpretation of the iations of exogenous TIQ or precursor intake might play a data and writing of the manuscript. SW contributed to the minor role for the group differences found. Moreover, the study design and data acquisition. FR contributed to the elevated levels of the non-conjugated TIQ derivatives in study design and data acquisition. RH contributed to the free urine give evidence for endogenous synthesis rather than study design and data acquisition. AR contributed to the oral ingestion, because ingested TIQ derivatives will be design of the study and revision of the final manuscript. free rapidly inactivated by gluco- or sulfo-conjugation pre- MG contributed to the conception and design of the study Page 5 of 6 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:64 http://www.behavioralandbrainfunctions.com/content/3/1/64 17. Scholz J, Klingemann I, Moser A: Increased systemic levels of nor- and the interpretation of the data and writing of the man- salsolinol derivatives are induced by levodopa treatment and uscript. AM contributed to the conception and design of do not represent biological markers of Parkinson's disease. J the study, to the analyses and the interpretation of the Neurol Neurosurg Psychiatry 2004, 75(4):634-636. 18. Musshoff F, Schmidt P, Dettmeyer R, Priemer F, Wittig H, Madea B: data and writing of the manuscript. All authors have read A systematic regional study of dopamine and dopamine- and accepted the final manuscript. derived salsolinol and norsalsolinol levels in human brain areas. Forensic Sci Int 1999, 105(1):1-11. 19. Naoi M, Maruyama W, Dostert P, Kohda K, Kaiya T: A novel Acknowledgements enzyme enantio-selectively synthesizes (R)salsolinol, a pre- We acknowledge the help and support with statistics of Andreas Becker cursor of a dopaminergic neurotoxin, N-methyl(R)salsolinol. and Björn Albrecht at the University of Goettingen. Finally we express our Neurosci Lett 1996, 212(3):183-186. 20. Naoi M, Maruyama W, Matsubara K, Hashizume Y: A neutral N- gratitude to all the staff and patients at all three centers that supported this methyltransferase activity in the striatum determines the work. level of an endogenous MPP+-like neurotoxin, 1,2-dimethyl- 6,7-dihydroxyisoquinolinium ion, in the substantia nigra of References human brains. Neurosci Lett 1997, 235(1-2):81-84. 21. 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Behavioral and Brain Functions – Springer Journals
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