Dopamine transporter density in schizophrenic subjects with and without tardive dyskinesia

Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Schizophrenia Research (Impact Factor: 3.92). 01/2005; 71(2-3):371-5. DOI: 10.1016/j.schres.2004.03.015
Source: PubMed


Striatal dopamine transporter (DAT) binding potential (BP) was compared between schizophrenic subjects with and without tardive dyskinesia and controls. Although the groups were not statistically different in striatal BP, tardive subjects had apparently lower DAT density than non-tardive schizophrenic subjects. Significant and trend-level inverse correlations were found between DAT BP in the striatum, and especially the severity of negative symptom scores, but also cognitive, and depression/anxiety scores on the PANSS.

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Available from: Anantha Shekhar, Jan 07, 2014
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    • "B. The transporter sites in dopamine neuron terminals were not reduced in five schizophrenia patients who had been on long-term antipsychotics for years, but who did not have tardive dyskinesia (Yoder et al., 2004). C. The transporter sites in dopamine neuron terminals were reduced by 31% in five schizophrenia patients who had been on long-term antipsychotics for years (Yoder et al.) and who had tardive dyskinesia (Yoder et al., 2004). et al. (2012) found that the proportion of schizophrenia patients with drug-induced parkinsonism with a normal density of dopamine transporters progressively fell from 16 out of 21 patients (or 76%, at ages 41–50) down to 3 out of 12 patients (or 25%) for patients in their seventies, a fall of approximately 50% over 30 years or at least 15% per decade (Fig. 2C). "
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    ABSTRACT: The in vivo labeling and brain imaging of dopamine transporters measures the density of dopamine neuron terminals in the human caudate/putamen. A review of such studies shows that the long-term use of antipsychotics had no major effect on the density of the dopamine terminals in individuals who had no tardive dyskinesia, but had reduced the density in those patients with tardive dyskinesia. In addition, the normal loss of dopamine terminals in healthy individuals was approximately 5% per decade. However, this rate of cell loss was apparently increased by approximately three-fold, to about 15% per decade, in schizophrenia patients using antipsychotics on a long-term basis, as measured by the in vivo imaging of the dopamine transporters in the dopamine neuron terminals. While an apparent reduction in dopamine transporters may result from reduced expression of the transporters secondary to antipsychotic treatment, the seemingly increased loss rate is consistent with the accumulation of antipsychotics in the neuromelanin of the substantia nigra, subsequent injury to the dopamine-containing neurons, and the development of extrapyramidal motor disturbances such as tardive dyskinesia or Parkinson's disease.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2013; 44. DOI:10.1016/j.pnpbp.2013.02.011 · 3.69 Impact Factor
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    • "Prior post-mortem studies of SLC6A3 mRNA or protein levels using similarly sized samples have not consistently detected reduction among cases [Hirai et al., 1988; Seeman and Niznik, 1990; Hitri et al., 1995; Akil et al., 1999; Dean and Hussain, 2001]. Brain imaging studies have also yielded mixed results [Laakso and Hietala, 2000; Laruelle et al., 2000; Sjoholm et al., 2004; Yang et al., 2004; Yoder et al., 2004; Schmitt et al., 2006; Prata et al., 2009], though some investigators have replicated reduced SLC6A3 binding in the striatum among drug na€ ıve, first episode patients [Mateos et al., 2005, 2007]. The variable results suggest that case–control differences in SLC6A3 transcription or translation, if present are modest. "
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    ABSTRACT: The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2010; 153B(8):1434-47. DOI:10.1002/ajmg.b.31125 · 3.42 Impact Factor
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