Roessner V, Sagvolden T, Dasbanerjee T, Middleton FA, Faraone SV, Walaas SI et al. Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type. Neuroscience 167: 1183-1191
Department of Child and Adolescent Psychiatry, University of Goettingen, Germany.Neuroscience (Impact Factor: 3.36). 03/2010; 167(4):1183-91. DOI: 10.1016/j.neuroscience.2010.02.073
The spontaneously hypertensive rat (SHR/NCrl) is a validated model of attention-deficit/hyperactivity disorder (ADHD) combined subtype, whereas a recently identified substrain of the Wistar Kyoto rat (WKY/NCrl) is a model of ADHD inattentive subtype. In this study, we first examined the expression of genes involved in dopamine signaling and metabolism in the dorsal striatum and ventral mesencephalon of these two rat strains, as well as three reference control strains (WKY/NHsd, WK/HanTac, and SD/NTac) using quantitative real time RT-PCR. Next, striatal dopamine transporter (DAT) density was determined by ligand binding assay in the two ADHD-like strains at different developmental stages and after methylphenidate treatment. In adult rats, the mRNA expression of DAT and tyrosine hydroxylase was elevated in SHR/NCrl and WKY/NCrl rats compared to control strains, with differences between SHR/NCrl and WKY/NCrl rats also evident. During normal development, changes of striatal DAT densities occurred in both strains with lower densities in WKY/NCrl compared to SHR/NCrl after day 25. Two-weeks methylphenidate treatment during different developmental stages was associated with decreased striatal DAT density in both rat strains compared to the non-treated rats with more pronounced effects followed prepubertal treatment. These results suggest differences in the pathophysiology of the combined versus the predominantly inattentive animal model of ADHD. Finally, treatment with methylphenidate might reduce elevated DAT levels more effectively in the combined subtype especially when applied before puberty.
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- "DAT1, encoded by the solute carrier family 6 member 3 (SLC6A3), regulates neurotransmission by terminating dopamine signaling at the synapse through high-affinity reuptake of dopamine into presynaptic terminals (Bannon et al., 2001). SLC6A3 has been associated with a number of disorders including attention deficit hyperactivity disorder (ADHD; Asherson et al., 2007; Brookes et al., 2008; Roessner et al., 2010). The 3ʹ untranslated region of the SLC6A3 contains a 40 bp variable number of tandem repeat (VNTR) polymorphism (rs28363170). "
ABSTRACT: A review of recent research in visual masking and TMS-masking to be published in 2014. The preliminary eBook version of this volume can be obtained from http://store.elsevier.com/Visual-Masking/Talis-Bachmann/isbn-9780128003831/
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- "We described a new rat model for the inattentive subtype of ADHD (WKY/NCrl, from Charles River, Germany) [Sagvolden et al., 2008], which shows impaired sustained attention, but normal activity level and impulsiveness. Both rat models show increased dopamine transporter (DAT) activity [Roessner et al., 2010]. We subsequently found increased SLC9A9 expression in hippocampus (WKY/NCrl rats) and prefrontal cortex (SHR/ NCrl) rats. "
ABSTRACT: Medications for attention deficit hyperactivity disorder (ADHD) are only partially effective. Ideally, new treatment targets would derive from a known pathophysiology. Such data are not available for ADHD. We combine evidence for new etiologic pathways with bioinformatics data to assess the possibility that existing drugs might be repositioning for treating ADHD. We use this approach to determine if prior data implicating the sodium/hydrogen exchanger 9 gene (SLC9A9) in ADHD implicate sodium/hydrogen exchange (NHE) inhibitors as potential treatments. We assessed the potential for repositioning by assessing the similarity of drug-protein binding profiles between NHE inhibitors and drugs known to treat ADHD using the Drug Repositioning and Adverse Reaction via Chemical-Protein Interactome server. NHE9 shows a high degree of amino acid similarity between NHE inhibitor sensitive NHEs in the region of the NHE inhibitor recognition site defined for NHE1. We found high correlations in drug-protein binding profiles among most ADHD drugs. The drug-protein binding profiles of some NHE inhibitors were highly correlated with ADHD drugs whereas the profiles for a control set of nonsteroidal anti-inflammatory drugs (NSAIDs) were not. Further experimental work should evaluate if NHE inhibitors are suitable for treating ADHD. © 2013 Wiley Periodicals, Inc.
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- "Elevated DAT density has been observed in untreated children and adults with ADHD (Spencer et al. 2005; Krause 2008; Weiss et al. 2003) and also in adolescent SHR (Roessner et al. 2010). The ability of methylphenidate to reduce high DAT density in SHR (Roessner et al. 2010; Simchon et al. 2010) as well as in Fig. 4 Inhibition of dopamine (DA) or norepinephrine (NE) uptake by oroxylin A, methylphenidate or atomoxetine. Cells were incubated with uptake buffer containing [ 3 H]DA or [ 3 H]NE and DA (a) or NE (b) uptake was measured for 5 min after treatment with oroxylin A, methylphenidate or atomoxetine for 30 min 138 S. Y. Yoon et al. individuals with ADHD (Vles et al. 2003) has been considered as a potential mechanism underlying the beneficial effects of this drug. "
ABSTRACT: Oroxylin A, a major flavonoid in Scutellaria baicalensis, has been shown to alleviate attention-deficit/hyperactivity disorder (ADHD)-like behaviors in the Spontaneously Hypertensive rat (SHR) model of ADHD. As part of our continuing effort to discover effective ADHD drug candidates, we synthesized a number of oroxylin A derivatives and characterized their biological activities. Among all oroxylin A analogues, compound 7-7 (5,7-dihydroxy-6-methoxy-4'-phenoxyflavone) showed the most remarkable inhibition of dopamine reuptake alike methylphenidate, a dopamine transporter (DAT) blocker and typical drug for ADHD, and oroxylin A. It did not influence norepinephrine reuptake unlike atomoxetine, a selective norepinephrine inhibitor. Moreover, compound 7-7 reduced hyperactivity, sustained inattention and impulsivity in the SHR as measured by the open field, Y-maze and electro-foot shock aversive water drinking tests, respectively. Most drugs that enhance brain dopamine levels (e.g. DAT blockers like cocaine and methylphenidate) produce behavioral effects like those of stimulants causing them to be abused. However, the repeated treatment of compound 7-7 failed to elicit locomotor sensitization in rats, and neither produced conditioned place preference response nor maintained self-administration behavior. Altogether, the present study suggests the promising therapeutic value of compound 7-7as an ADHD drug. Furthermore, compound 7-7 may be considered as an alternative therapy to psychostimulant ADHD treatments (e.g. amphetamine and methylphenidate) for which use has been deemed controversial due to their abuse liability.