Diminished Serotonergic Functioning in Hostile Children with ADHD: Tryptophan Depletion Increases Behavioural Inhibition

Department of Child and Adolescent Psychiatry and Psychotherapy, JW Goethe University of Frankfurt am Main, Frankfurt am Main, Germany.
Pharmacopsychiatry (Impact Factor: 1.85). 04/2008; 41(2):60-5. DOI: 10.1055/s-2007-1004593
Source: PubMed


Serotonergic (5-HT) functioning has been shown to account for a variety of behavioural characteristics, in particular aggressive and impulsive behaviour. This study explored the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of brain 5-HT synthesis on behavioural inhibition in passive avoidance learning assessed in a computerized go/no-go task.
22 male patients with an ICD-10 diagnosis of ADHD were administered RTD within an amino acid drink lacking tryptophan, the natural precursor of 5-HT, thus lowering the central nervous 5-HT synthesis rate in a placebo-controlled double-blind within-subject crossover-design. 4 hours after RTD/placebo intake the patients were subjected to a go/no-go task for assessment of behavioural inhibition.
Highly hostile aggressive patients showed increased inhibition errors under RTD compared to placebo. Low hostile aggressive patients showed lower rates of inhibition errors and thus better performance under RTD compared to placebo.
The data suggest that in ADHD levels of trait-aggressive characteristics influence the susceptibility to changed behavioural inhibition after an acute 5-HT dysfunction. The detected influence of 5-HT could also be relevant as regards behavioural inhibition being subject to a developmental change in 5-HT functioning.

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    • "In contrast, depleting central serotonin (e.g. by acute tryptophan depletion or a serotonin receptor antagonist M100907) increases premature responding (Fletcher et al., 2007; Robinson et al., 2008), impairs NoGo inhibition and right inferior frontal gyrus activation (Harrison et al., 1999; Rubia et al., 2005). In addition, several clinical disorders are associated with both impulsivity and reduction or deregulation of serotonin transmission , including Parkinson's disease, attention deficit hyperactivity disorder (Zepf et al., 2008), frontotemporal dementia (Huey et al., 2006), Tourette's syndrome (Haugbøl et al., 2007) and obsessive-compulsive disorder (Chamberlain et al., 2005). "
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    ABSTRACT: Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.
    Brain 02/2014; 137(4). DOI:10.1093/brain/awu032 · 9.20 Impact Factor
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    • "Our principal hypothesis was that chronic 5-HT 2A receptor availability, inferred from 18 F-altanserin steady-state binding measurements (BP P ), influences the effect of acute state manipulations on response inhibition. Such an interaction would explain some of the behavioral and imaging differences between healthy individuals (Del-Ben et al, 2005; Rubia et al, 2005; Evers et al, 2006; Lamar et al, 2009) and patients (LeMarquand et al, 1998; Zepf et al, 2008). We studied healthy subjects with 18 F-altanserin positron emission tomography (PET) and functional MRI sessions that differed only in 5-HT levels by (a) increased 5-HT neurotransmission by intravenous administration of the SSRI citalopram; (b) reduced brain 5-HT synthesis via acute dietary depletion of the 5-HT precursor tryptophan (ATD); (c) a control state without drug intervention. "
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    ABSTRACT: Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in 'NoGo' paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In twenty-four healthy adults, we used (18)F-altanserin positron emission tomography to assess cerebral 5-HT(2A) receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition, using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se, as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicating that the IFG is activated with inhibition in NoGo trials, rather than other aspects of invoked cognitive control. Activation of the left IFG during NoGo trials was greater with citalopram than acute tryptophan depletion. Moreover, to the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT(2A) receptor binding. Specifically, ATD produced a relatively larger NoGo response in the right IFG in subjects with low 5-HT(2A) BP(P) but reduced the NoGo response in those with high 5-HT(2A) BP(P). These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders.Neuropsychopharmacology accepted article preview online, 19 December 2012; doi:10.1038/npp.2012.264.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; 38(6). DOI:10.1038/npp.2012.264 · 7.05 Impact Factor
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    • "A modified mixture, ATD Moja-De, involves a body weight adapted administration of amino acids and lower concentration of methionine relative to conventional mixtures, which makes it less nauseating in humans. Its use has proven to be a safe and effective method of TRP depletion even in children and adolescents [9], [10], [11], [12], [13], [14], [15]. It has been shown that ATD Moja-De significantly lowers influx of TRP into the brain in humans [16], but its specific effect on brain 5-HT has not yet been established, which was the aim of this study. "
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    ABSTRACT: Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP-) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain-specific effect of ATD Moja-De on anxiety-like behavior.
    PLoS ONE 05/2012; 7(5):e35916. DOI:10.1371/journal.pone.0035916 · 3.23 Impact Factor
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