Brophy 1 , Samy Suissa 1 ,2 & … Christel Renoux 1 ,2 ,3 CNS Drugs volume 29 , pages 985–998 (2015 )Cite this article 551 Accesses 27 Citations Metrics details Abstract Background Dopamine agonists (DAs) are commonly used in the therapy of Parkinson’s disease (PD). However, several observational studies have suggested a putative association between DAs and specific cardiac adverse events. Objectives The aim of this study was to systematically review and summarize the available epidemiologic evidence on the association between use of ergot- and non-ergot-derived DAs and the risk of valvular heart disease, specifically cardiac valve regurgitation (CVR) and heart failure (HF) in patients with PD.

Mice overexpressing human G2019S or R1441C/G mutations through BAC technology did not show overt dopaminergic neurodegeneration [39 , 40 , 53 ] but reduced striatal DA content or basal extracellular levels in vivo when compared to non-transgenic wild-type controls [4 , 53 ]. Consistently, the K+ -evoked DA release was reduced in striatal slices from BAC hG2019S mice [40 ]. In mice where hG29019S [13 , 64 ] or hR1441C [88 ] overexpression in SNc was achieved through the CMV/PDGF promoter, an 18–50% reduction in the number of nigral DA cells was observed at old ages (16–21 months). In these mice, no changes of in vivo DA content was observed [64 ], although the K+ -evoked DA release from striatal slices was reduced [88 ]. Conditional expression of hG2019S [41 ] or hR1441C [83 ] in SNc also did not cause nigral DA neuron loss; only a mild reduction in the density of TH terminals was observed in 16-month-old mice [41 ]. In these mice, hG2019S overexpression caused a reduction of DA content and release from striatal slices [41 ]. Lack of nigro-striatal degeneration [37 , 74 , 93 ] or changes in DA content [37 , 93 ] were also confirmed in transgenic rats overexpressing hG2019S or hR1441C mutations. In vitro, a reduction of the K+ -evoked DA release in BAC overexpressing rats was found [74 ]. Finally, no overt neurodegeneration [29 , 82 , 92 ] or changes in striatal DA content [29 , 82 ] were observed in G2019S or R1441C knock-in (KI) mice, although in vivo microdialysis revealed a 60% reduction in both spontaneous and amphetamine-induced DA release in 12-month-old G2019S KI mice [92 ]. In a previous longitudinal study, we reported that G2019S KI mice had enhanced motor behavior compared to both WT mice and mice carrying the D1994S kinase-dead mutation [43 ]. In this follow-up study, we sought to investigate the mechanisms underlying such phenotype, and in particular, whether G2019S LRRK2 is associated with dysregulation of nigro-striatal DA transmission.

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The negative symptoms and cognitive impairments that often characterize schizophrenia are attributed to reduced dopamine signaling, or hypo dopaminergia, in the mesocortical dopamine system, which involves dorsolateral prefrontal cortex (DLPFC) and other cortical and extrastriatal subcortical areas (Davis et al., 1991, Slifstein et al., 2015, Weinberger, 1987, Weinstein et al., 2016). Evidence supporting a role for mesolimbic hyper dopaminergia in psychosis has come from in vivo microdialysis studies in freely-moving rats showing a preferential increase of extracellular dopamine in the ventral striatum following administration of dopamine agonists (Carboni et al., 1989, Robinson et al., 1988). Both post-mortem and in vivo positron emission tomography (PET) studies have reported evidence of increased density of dopamine receptors, particularly D2 receptors, in the striatum of treatment-naive and medicated schizophrenia patients (Howes et al., 2012, Lee and Seeman, 1980, Owen et al., 1978, Wong et al., 1986), although these increases may be partly driven by antipsychotic medication (for a discussion see (Howes et al., 2015)). Evidence supporting a role for mesocortical hypo dopaminergia in negative symptoms and cognitive deficits has come from studies showing that schizophrenia patients perform poorly on cognitive tasks subserved by the DLPFC, and which are thought to depend on D1 receptor signaling (Barch and Ceaser, 2012, Goldman-Rakic, 1995, Sawaguchi and Goldman-Rakic, 1994). Patients with established schizophrenia often show reduced prefrontal glucose metabolism and task-related activation, and administration of dopamine agonists can reverse this effect (Daniel et al., 1989, Daniel et al., 1991). PET studies of D1 receptor availability in prefrontal cortex have been inconsistent, with some reporting reduced receptor density while others have found increased density (Abi-Dargham, 2003, Abi-Dargham et al., 2002, Okubo et al., 1997). This inconsistency may be driven by a lack of binding specificity for some of the tracers used in this research (e.g., (Catafau et al., 2010)). Where the focus of early models of dopamine dysfunction in psychosis was on diffusely projecting dopaminergic systems such as the mesolimbic and mesocortical pathways, recent work has attempted to more precisely delineate the specific neural circuits that mediate dopamine dysregulation. Later work showed that the [18 F]-DOPA elevations in the ARMS group were specific to individuals who later developed psychosis (Howes et al., 2011b). Smaller elevations have been found in the sensorimotor division of the striatum of ARMS individuals, and these appear to increase longitudinally during the transition to psychosis (Egerton et al., 2013, Howes et al., 2011a). Increased [18 F]-DOPA has also been found in the substantia nigra of patients with established schizophrenia, a result that is consistent with post-mortem evidence that patients show elevated nigral levels of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (Howes et al., 2013). Collectively, these results form part of a growing body of evidence indicating that striatal dopamine synthesis and release are consistently elevated in patients, particularly those experiencing acute psychotic symptoms (Abi-Dargham et al., 2009, Fusar-Poli and Meyer-Lindenberg, 2013, Laruelle et al., 1999, Mizrahi et al., 2012, Pogarell et al., 2012), and suggest that striatal hyper dopaminergia may be primarily associated with abnormalities of presynaptic, rather than postsynaptic, function (Howes et al., 2012). Some studies have identified relatively smaller dopaminergic changes in the ventral striatum of patients (Kegeles et al., 2010), but reports have been less consistent than those for the dorsal subregion.

Biol Blood Marrow Transplant. 2018;24:2517–22. Article CAS Google Scholar Takahashi S, Ooi J, Tomonari A, Konuma T, Tsukada N, Oiwa-Monna M, et al. Biol Blood Marrow Transplant. 2017;23:1932–8. Article CAS Google Scholar Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, et al.

A frequent intron8 5/6-repeat (rs3836790) inserted into reporter gene constructs was found to affect expression in vitro , which is further modulated by cellular signaling including cocaine stimulation,29 , 30 with the 6-repeat allele identified as a risk factor in cocaine abuse.29 We have shown that the intron8 5-repeat is associated with reduced DAT mRNA levels in human substantia nigra; however, exon9 rs6347 is in high LD with the 5/6-repeat, and therefore, cannot be excluded as a contributor to altered expression.24 Moreover, the 3′-UTR SNP rs27072 (MAF ∼ 18%) affects DAT mRNA expression and translation, the latter regulated by the overall DAT mRNA level—a mechanism that may involve microRNA regulation and translational control.24 No evidence was obtained for a regulatory role of the 3′-UTR 9/10 repeat (rs28363170),24 frequently used in clinical association studies with variable results.28 , 32 In an analysis of both DAT and DRD2 polymorphisms, Kazantseva et al. 34 found that each was associated with personality traits, but their study was not guided by molecular genetic evidence in the selection of variants and failed to address gene–gene interactions. Table 4 Two-variant DAT haplotype frequency distributions, by race Full size table If one ignores phasing of the 2-variant haplotype and only considers the number of minor alleles for each African American, the OR for cocaine related death is 11.6 comparing three or more minor alleles with less than three alleles (P =0.006, exact logistic regression). Comparing instead three or more minor alleles with less than two, we obtain an OR of 2.25 (exact P =0.086). This result indicates that the intron8 5-repeat and rs27072 T alleles must be in phase on the same haplotype to convey strong risk (22-haplotype). Effects of DRD2 and DAT variants on DAT protein expression in ventral putamen Striatal dopamine transporter B max values were obtained from previous [3 H] WIN 35 428 experiments.35 , 41 DAT B max levels increased substantially in cocaine abusers (49 pmol g−1 tissue in cases versus 10 pmol g−1 in controls; two-sided unequal variance t -test, P =1.5e-09) (Figure 1b , Supplementary Table 6A ). Owing to the large B max differences between cocaine abusers and controls, genotype models were formed separately within each subgroup, also coinciding with a prior hypothesis that effects would differ.