Dopaminergic polymorphisms in Tourette syndrome: Association with the DAT gene (<i>SLC6A3</i>)

Yoon, Dustin Y.; Rippel, Christopher A.; Kobets, Andrew J.; Morris, Cynthia Taft; Lee, Jennifer E.; Williams, Phillip N.; Bridges, Dana; Vandenbergh, David J.; Shugart, Yin Yao; Singer, Harvey S.

doi:10.1002/ajmg.b.30466

Cited by 66 publications

(30 citation statements)

References 49 publications

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“…The explanation would be that due to dopamine agonists, repetitive behaviors would be more reinforced by rewarding outcomes than impeded by punishing consequences. In contrast, the case for an overactive dopamine transmission in TS has not reached general agreement (28)(29)(30), despite supporting evidence from both genetic and neuroimaging studies (31)(32)(33)(34). That TS patients mirrored PD patients would further support the idea of underlying dopaminergic hyperactivity.…”

Section: Discussionmentioning

confidence: 96%

Pharmacological modulation of subliminal learning in Parkinson's and Tourette's syndromes

Palminteri

Lebreton

Worbe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

144

128

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Theories of instrumental learning aim to elucidate the mechanisms that integrate success and failure to improve future decisions. One computational solution consists of updating the value of choices in proportion to reward prediction errors, which are potentially encoded in dopamine signals. Accordingly, drugs that modulate dopamine transmission were shown to impact instrumental learning performance. However, whether these drugs act on conscious or subconscious learning processes remains unclear. To address this issue, we examined the effects of dopamine-related medications in a subliminal instrumental learning paradigm. To assess generality of dopamine implication, we tested both dopamine enhancers in Parkinson's disease (PD) and dopamine blockers in Tourette's syndrome (TS). During the task, patients had to learn from monetary outcomes the expected value of a risky choice. The different outcomes (rewards and punishments) were announced by visual cues, which were masked such that patients could not consciously perceive them. Boosting dopamine transmission in PD patients improved reward learning but worsened punishment avoidance. Conversely, blocking dopamine transmission in TS patients favored punishment avoidance but impaired reward seeking. These results thus extend previous findings in PD to subliminal situations and to another pathological condition, TS. More generally, they suggest that pharmacological manipulation of dopamine transmission can subconsciously drive us to either get more rewards or avoid more punishments.dopamine ͉ instrumental learning ͉ subliminal perception ͉ reward ͉ punishment H ow we learn from success and failure is a long-standing question in neuroscience. Instrumental learning theories explain how outcomes can be used to modify the value of choices, such that better decisions are made in the future. A basic learning mechanism consists of updating the value of the chosen option according to a reward prediction error, which is the difference between the actual and the expected reward (1, 2). This learning rule, using prediction error as a teaching signal, has provided a good account of instrumental learning in a variety of species including both human and nonhuman primates (3, 4). Single-cell recordings in monkeys suggest that reward prediction errors are encoded by the phasic discharge of dopamine neurons (5, 6). In humans, dopamine-related drugs have been shown to bias prediction error encoding in the striatum to modulate reward-based learning (7). One of these drugs, levodopa (a metabolic precursor of dopamine), is used to alleviate motor symptoms in idiopathic Parkinson's disease (PD), which is primarily caused by degeneration of nigral dopamine neurons. PD patients were shown to learn better from positive feedback when on levodopa and from negative feedback when off levodopa (8, 9). This double dissociation lead Frank and colleagues to propose a computational model of fronto-striatal circuits where dopamine bursts (encoding positive prediction errors) reinforce approach pathways,...

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Section: Discussionmentioning

confidence: 96%

Pharmacological modulation of subliminal learning in Parkinson's and Tourette's syndromes

Palminteri

Lebreton

Worbe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

144

128

View full text Add to dashboard Cite

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“…Similarly, candidate gene studies have failed to yield consistent results for specific susceptibility genes. Much attention has been paid to dopaminergic candidates, and there is evidence of a significant association between TS and a dopamine transporter polymorphism (DAT1 Ddel) (Yoon et al, 2007b). Several recent candidate genes have included: a heterozygous loss of function mutation in L-histidine decarboxylase, which encodes the rate limiting enzyme in histamine biosynthesis (Ercan-Sencicek et al, 2010); functional variations of the SLITRK1 gene, with homology to a known axon guidance molecule (Scharf et al, 2008); and DLGAP3, a postsynaptic scaffolding protein highly expressed in striatal glutamatergic synapses (Crane et al, 2011).…”

Section: Etiologymentioning

confidence: 99%

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Felling¹,

Singer²

2011

J. Neurosci.

203

116

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Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ϳ5-7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.In the 1880's, Georges Gilles de la Tourette published a two-part article in which he emphasized differences between tics and chorea. Although many of the descriptions about the disorder, which now bears his name [Tourette syndrome (TS)], have been revised, his belief that tics are a neurological movement disorder and not a psychiatric condition persists to the present (Goetz and Klawans, 1982). Nevertheless, despite multiple advances and widespread acceptance of TS being a biological disorder, the precise etiology and underlying pathophysiological mechanisms remain unknown. The goals of the present review are to briefly describe the clinical phenomenology of TS and related tic disorders, to review current information on genetic and neurobiological mechanisms, and to identify areas in need of further investigation.

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“…A total of 170 controls were matched with 170 obese individuals on age and gender by the Match utility (Van Casteren and Davis 2007) and analyzed for ten TaqMan SNP genotyping assays (ABI, Foster City, USA) selected from the marker set used by Yoon et al (2007) to estimate population structure . All TaqMan assays were run as 5 l reactions in 384-well format on a LightCycler 480 using a standard protocol.…”

Section: Analysis Of Population Stratiwcationmentioning

confidence: 99%

Association of SIRT1 gene variation with visceral obesity

et al. 2008

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The sirtuin SIRT1 is an important regulator of energy metabolism through its impact on glucose and lipid metabolism and therefore we tested the hypothesis that genetic variation in SIRT1 may have an effect on adiposity in a Belgian case/control association study. This study included 1,068 obese patients (BMI > or = 30 kg/m(2)) from the outpatient obesity clinic and 313 lean controls (BMI between 18.5 and 25 kg/m(2)). Anthropometrics were assessed by classical methods and visceral (VFA), subcutaneous (SFA) and total abdominal (TFA) fat areas were determined by a CT scan. The extent of linkage disequilibrium in SIRT1 allowed us to reduce the number of SNPs to two, sufficient to cover the entire gene. The two tagSNPs (rs7069102 and rs3818292) were analyzed by LightSNiP assays in all subjects. Rs3818292 genotypes were similarly distributed in cases and controls, whereas rs7069102 was different for the additive (P = 0.007) and dominant (P = 0.01) model. The variant C-allele of rs7069102 reduced obesity risk with an OR of 0.74 (P = 0.025; 95% CI 0.57-0.96) under a dominant model. In obese male subjects, this variant allele was associated with increased waist circumference (P = 0.04), WHR (P = 0.02), TFA (P = 0.03) and VFA (P = 0.005) (dominant model; adjusted for age and BMI). Rs3818292 was related to VFA (P = 0.005; adjusted for age and BMI) in obese males while in obese women, no significant associations were detected. Our data suggest that genetic variation in SIRT1 increases the risk for obesity, and that SIRT1 genotype correlates with visceral obesity parameters in obese men.

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Dopaminergic polymorphisms in Tourette syndrome: Association with the DAT gene (SLC6A3)

Cited by 66 publications

References 49 publications

Pharmacological modulation of subliminal learning in Parkinson's and Tourette's syndromes

Pharmacological modulation of subliminal learning in Parkinson's and Tourette's syndromes

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Association of SIRT1 gene variation with visceral obesity

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