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Krause J. SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder. Expert Rev Neurother 8: 611-625

Expert Review of Neurotherapeutics (Impact Factor: 2.83). 05/2008; 8(4):611-25. DOI: 10.1586/14737175.8.4.611
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ABSTRACT Abnormalities of frontostriatal circuits, which are modulated by dopamine, have been found by brain imaging studies in patients with attention-deficit/hyperactivity disorder (ADHD). With special radiolabeled ligands selective imaging of the dopamine transporter (DAT), which has a key function in dopamine metabolism, can be performed by SPECT and PET. Most of the studies showed a higher DAT availability in untreated patients with ADHD compared with controls. The relationship between DAT availability and a polymorphism of DAT1 gene in patients with ADHD is not clear and the results are controversial. It has been shown that methylphenidate lowers DAT availability very effectively in normal people and in patients with ADHD. First results seem to indicate that nonresponders to methylphenidate among ADHD patients have a low primary DAT availability, whereas patients with a good response to the drug have high DAT. Nicotine seems to lower DAT availability such as stimulant medication; this may explain the high percentage of smokers among patients with ADHD. Zinc is a DAT inhibitor and seems to have a positive therapeutic effect on ADHD symptoms. This article reviews the function and structure of the DAT, the results of DAT imaging with SPECT and PET, the relations between DAT availability and the DAT1 gene polymorphism, the influence of stimulants on DAT and the significance of DAT for therapeutic response, nicotine, zinc and psychotic symptoms in patients with ADHD.

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    • "Pathophysiologically, ADHD is mainly ascribed to dopamin(DA)ergic dysfunctions in mesocorticolimbic regions (for review see Del Campo et al. 2011). In vivo imaging studies have shown that ADHD patients display an increased availability of striatal DA transporters (DAT), while D2 receptor binding as well as DA synthesis and release in the majority of investigations have been unaltered (for reviews see Krause 2008; Nikolaus et al. 2009). The pivotal role of DAT binding sites is supported by the therapeutic efficacy of DAT inhibitors, such as methylphenidate (for review see Volkow et al. 2005). "
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    ABSTRACT: Intranasal application of dopamine (IN-DA) has been shown to increase motor activity and to release DA in the ventral (VS) and dorsal striatum (DS) of rats. The aim of the present study was to assess the effects of IN-DA treatment on parameters of DA and excitatory amino acid (EAA) function in prepuberal rats of the Naples high-excitability (NHE) line, an animal model for attention-deficit hyperactivity disorder (ADHD) and normal random bred (NRB) controls. NHE and NRB rats were daily administered IN-DA (0.075, 0.15, 0.30 mg/kg) or vehicle for 15 days from postnatal days 28-42 and subsequently tested in the Làt maze and in the Eight-arm radial Olton maze. Soluble and membrane-trapped L-glutamate (L-Glu) and L-aspartate (L-Asp) levels as well as NMDAR1 subunit protein levels were determined after sacrifice in IN-DA- and vehicle-treated NHE and NRB rats in prefrontal cortex (PFc), DS and VS. Moreover, DA transporter (DAT) protein and tyrosine hydroxylase (TH) levels were assessed in PFc, DS, VS and mesencephalon (MES) and in ventral tegmental area (VTA) and substantia nigra, respectively. In NHE rats, IN-DA (0.30 mg/kg) decreased horizontal activity and increased nonselective attention relative to vehicle, whereas the lower dose (0.15 mg/kg) increased selective spatial attention. In NHE rats, basal levels of soluble EAAs were reduced in PFc and DS relative to NRB controls, while membrane-trapped EAAs were elevated in VS. Moreover, basal NMDAR1 subunit protein levels were increased in PFc, DS and VS relative to NRB controls. In addition, DAT protein levels were elevated in PFc and VS relative to NRB controls. IN-DA led to a number of changes of EAA, NMDAR1 subunit protein, TH and DAT protein levels in PFc, DS, VS, MES and VTA, in both NHE and NRB rats with significant differences between lines. Our findings indicate that the NHE rat model of ADHD may be characterized by (1) prefrontal and striatal DAT hyperfunction, indicative of DA hyperactivty, and (2) prefrontal and striatal NMDA receptor hyperfunction indicative of net EAA hyperactivty. IN-DA had ameliorative effects on activity level, attention, and working memory, which are likely to be associated with DA action at inhibitory D2 autoreceptors, leading to a reduction in striatal DA hyperactivity and, possibly, DA action on striatal EAA levels, resulting in a decrease of striatal EAA hyperfunction (with persistence of prefrontal EAA hyperfunction). Previous studies on IN-DA treatment in rodents have indicated antidepressant, anxiolytic and anti-parkinsonian effects in relation to enhanced central DAergic activity. Our present results strengthen the prospects of potential therapeutic applications of intranasal DA by indicating an enhancement of selective attention and working memory in a deficit model.
    Amino Acids 05/2014; 46(9). DOI:10.1007/s00726-014-1753-8 · 3.65 Impact Factor
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    • "In-vivo imaging studies have reported inconsistent findings regarding DAT availability in ADHD patients compared to healthy controls (van Dyck et al., 2002; Fusar-Poli et al., 2012; Hesse et al., 2009; Krause, 2008), but MPH treatment in ADHD patients without comorbid SUD has generally resulted in significant blockage of striatal DATs (Krause et al., 2000; Volkow et al., 1998). So far, only one imaging study examined the effect of MPH in adolescent ADHD patients with cannabis or cannabis/cocaine dependence (Szobot et al., 2008b). "
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    ABSTRACT: Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [123I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients.
    European Neuropsychopharmacology 06/2013; · 5.40 Impact Factor
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    • "In-vivo imaging studies have reported inconsistent findings regarding DAT availability in ADHD patients compared to healthy controls (van Dyck et al., 2002; Fusar-Poli et al., 2012; Hesse et al., 2009; Krause, 2008), but MPH treatment in ADHD patients without comorbid SUD has generally resulted in significant blockage of striatal DATs (Krause et al., 2000; Volkow et al., 1998). So far, only one imaging study examined the effect of MPH in adolescent ADHD patients with cannabis or cannabis/cocaine dependence (Szobot et al., 2008b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [(123)I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients. This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 05/2013; 23(12). DOI:10.1016/j.euroneuro.2013.05.002 · 5.40 Impact Factor
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