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1.
Substrate-induced conformational dynamics of the dopamine transporter.
Nielsen, AK, Möller, IR, Wang, Y, Rasmussen, SGF, Lindorff-Larsen, K, Rand, KD, Loland, CJ
Nature communications. 2019;(1):2714
Abstract
The dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-type Drosophila melanogaster dopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.
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2.
Enhancement in dopamine reduces generous behaviour in women.
Oroz Artigas, S, Liu, L, Strang, S, Burrasch, C, Hermsteiner, A, Münte, TF, Park, SQ
PloS one. 2019;(12):e0226893
Abstract
Generosity is a human behavior common in social contexts. However, humans are not equally generous to everyone alike. Instead, generosity decreases as a function of social distance, an effect called social discounting. Studies show that such social discounting effect depends on diverse factors including personality traits, cultures, stress or hormonal levels. Recently, the importance of the neurotransmitter dopamine in regulating social interactions has been highlighted. However, it remains unclear how exactly dopamine agonist administration modulates generous behavior as a function of social discounting. Here, we investigate the causal effect of dopamine agonist administration on social discounting in a pharmacological intervention study. We employ a randomized, double-blind, within-subject design to investigate the impact of the D2/D3 receptor agonist pramipexole on social discounting by keeping gender constant. We apply hyperbolic social discount model to the data and provide evidence that women under pramipexole become less generous in general, especially towards close others. Our results highlight the crucial role of dopamine in social decision making.
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3.
Dopamine Cytotoxicity on SH-SY5Y Cells: Involvement of α-Synuclein and Relevance in the Neurodegeneration of Sporadic Parkinson's Disease.
Ganguly, U, Ganguly, A, Sen, O, Ganguly, G, Cappai, R, Sahoo, A, Chakrabarti, S
Neurotoxicity research. 2019;(4):898-907
Abstract
The cytotoxicity of dopamine on cultured cells of neural origin has been used as a tool to explore the mechanisms of dopaminergic neurodegeneration in Parkinson's disease. In the current study, we have shown that dopamine induces a dose-dependent (10-40 μM) and time-dependent (up to 96 h) loss of cell viability associated with mitochondrial dysfunction and increased intra-cellular accumulation of α-synuclein in cultured SH-SY5Y cells. Dopamine-induced mitochondrial dysfunction and the loss of cell viability under our experimental conditions could be prevented by cyclosporine, a blocker of mitochondrial permeability transition pore, as well as the antioxidant N-acetylcysteine. Interestingly, the dopamine effects on cell viability and mitochondrial functions were significantly prevented by knocking down α-synuclein expression by specific siRNA. Our results suggest that dopamine cytotoxicity is mediated by α-synuclein acting on the mitochondria and impairing its bioenergetic functions.
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4.
Resting-state dynamics as a neuromarker of dopamine administration in healthy female adults.
Bellucci, G, Münte, TF, Park, SQ
Journal of psychopharmacology (Oxford, England). 2019;(8):955-964
Abstract
BACKGROUND Different neuromarkers of people's emotions, personality traits and behavioural performance have recently been identified. However, not much attention has been devoted to neuromarkers of neural responsiveness to drug administration. AIMS We investigated the predictive neuromarkers of acute dopamine (DA) administration. METHODS In a double-blind, within-subject study, we administrated a DA agonist (pramipexole) or placebo to 27 healthy female subjects. Using multivariate classification and prediction analyses, we examined whether dopaminergic modulations of task-free resting-state brain dynamics predict individual differences in pramipexole's modulation of facial attractiveness evaluations. RESULTS Our results demonstrate that pramipexole's effects on brain dynamics could be successfully discriminated from resting-state functional connectivity (accuracy: 78.9%; p < 0.0001). On the behavioural level, pramipexole increased facial attractiveness evaluations (t(39) = 4.44; p < 0.0001). In particular, pramipexole administration enhanced connectivity strength of the cinguloopercular network (t(23) = 3.29; p = 0.003) and increased brain signal variability in subcortical and prefrontal brain areas (t(13) = 3.05, p = 0.009). Importantly, multivariate predictive models reveal that pramipexole-dependent modulation of resting-state dynamics predicted the increase of facial attractiveness evaluations after pramipexole (connectivity strength: standardized mean squared error, smse = 0.65; p = 0.0007; brain signal variability: smse = 0.94, p = 0.015). CONCLUSION These results demonstrate that modulations of resting-state brain dynamics induced by a DA agonist predict drug-related effects on evaluation processes, providing a neuromarker of the neural responsiveness of specific brain networks to DA administration.
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5.
Presynaptic Striatal Dopaminergic Function in Atypical Parkinsonism: A Metaanalysis of Imaging Studies.
Kaasinen, V, Kankare, T, Joutsa, J, Vahlberg, T
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;(12):1757-1763
Abstract
Multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS) have signs and symptoms overlapping those of Parkinson disease (PD), complicating their clinical diagnosis. Although presynaptic dopaminergic brain imaging with PET and SPECT is clinically widely used for patients with suspected PD, the benefit of functional imaging in atypical parkinsonism syndromes remains unclear. We compared striatal presynaptic dopaminergic function in MSA parkinsonism variant (MSA-P), MSA cerebellar variant (MSA-C), PSP, CBS, and PD using combined quantitative data from all published studies. Methods: The PubMed database was searched from inception to August 2018 for the terms "dopamine" OR "dopaminergic" AND "PET" OR "SPECT" OR "SPET" and keywords related to PD, MSA, PSP, and CBS. In total, 1,711 publications were identified. PET or SPECT studies comparing patients with atypical parkinsonism to another diagnostic group (PD, MSA, PSP, or CBS) were included. Tracers for dopamine transporter (DAT), aromatic amino acid decarboxylase (AADC), or vesicular monoamine type 2 were investigated. Tracer binding data were extracted from the original articles. Heterogeneity of the data was examined using I2 statistics, and a random-effects model was used to summarize data. Hedges g was used as an estimator of effect size in group comparisons. Results are reported according to PRISMA guidelines. Results: Thirty-five studies (29 DAT, 6 AADC, no vesicular monoamine type 2 studies) with 356 MSA-P patients, 204 PSP patients, 79 CBS patients, and 62 MSA-C patients were included in the metaanalysis. Caudate nucleus and putamen DAT function was clearly lower in PSP than in PD (caudate: 34.1% difference, g = -1.08, 95% confidence interval [CI] = -1.52 to -0.64; putamen: 18.2%, g = -0.86, 95% CI = -1.50 to -0.21) and MSA-P (striatum: 31.4%, g = -0.70, 95% CI = -1.21 to -0.19) and was clearly lower in MSA-P than in MSA-C (striatum: 46.0%, g = 1.46, 95% CI = 0.23 to 2.68). Although not significant because of limited data, aromatic l-AADC results paralleled the DAT findings. Conclusion: Striatal presynaptic DAT function is clearly lower in PSP patients than in PD and MSA-P patients and is clearly lower in MSA-P patients than in MSA-C patients.
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6.
Neurochemical features of idiopathic restless legs syndrome.
Jiménez-Jiménez, FJ, Alonso-Navarro, H, García-Martín, E, Agúndez, JAG
Sleep medicine reviews. 2019;:70-87
Abstract
The most important traditional hypotheses of the pathogenesis of idiopathic restless legs syndrome (iRLS) involve dopaminergic dysfunction and iron deficiency. However, a possible role of other neurotransmitter or neuromodulators, mainly glutamate, gamma-hydroxybutyric acid (GABA), and adenosine have been suggested in recent reports. Moreover, iron deficiency in experimental models (which causes sensorimotor symptoms resembling those of RLS) is able to induce changes in dopaminergic, glutamatergic and adenosinergic neurotransmission, thus suggesting its crucial role in the pathogenesis of this disease. Relationship between iRLS and opiates, oxidative stress and nitric oxide, and with vitamin D deficiency has also been reported, although data regarding these variables should be considered as preliminary. In this review, we focus on studies relating to neurochemical findings in iRLS.
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Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.
Grillo, A, Chemi, G, Brogi, S, Brindisi, M, Relitti, N, Fezza, F, Fazio, D, Castelletti, L, Perdona, E, Wong, A, et al
European journal of medicinal chemistry. 2019;:111674
Abstract
Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.
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8.
Mean Diffusivity in the Dopaminergic System and Neural Differences Related to Dopaminergic System.
Takeuchi, H, Kawashima, R
Current neuropharmacology. 2018;(4):460-474
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Abstract
BACKGROUND The mean diffusivity (MD) parameter obtained by diffusion tensor imaging provides a measure of how freely water molecules move in brain tissue. Greater tissue density conferred by closely arrayed cellular structures is assumed to lower MD by inhibiting the free diffusion of water molecules. METHODS In this paper, we review studies showing MD variation among regions of the brain dopaminergic system (MDDS), especially subcortical structures such as the putamen, caudate nucleus, and globus pallidus, in different conditions with known associations to dopaminergic system function or dysfunction. The methodologies and background related to MD and MDDS are also discussed. RESULTS Past studies indicate that MDDS is sensitive to pathological derangement of dopaminergic activity, neural changes caused by cognitive and pharmacological interventions that are known to affect the dopaminergic system, and individual character traits related to dopaminergic function. CONCLUSION These results suggest that MDDS can be one useful tool to tap the neural differences related to the dopaminergic system.
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9.
THE RESTLESS LEGS SYNDROME (REVIEW).
Japaridze, G, Kasradze, S, Maisuradze, L, Popp, R, Wetter, T
Georgian medical news. 2018;(285):74-81
Abstract
The restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common sleep related neurological disorder with prevalence between 1 and 10%, increasing with age. Women are more frequently affected than men. RLS is characterized by an urge to move the legs accompanied by uncomfortable and unpleasant sensations in the legs, worsening of complaints during periods of rest, improvement by movement and an increase of symptoms in the evening or at night. In addition, affected patients may also suffer from severe sleep disorders and negative effects on daily activities. There is often a history of RLS among first-degree relatives, especially with the primary form. Among other, comorbidities or causal factors are iron deficiency, terminal renal insufficiency, pregnancy, polyneuropathy, or psychotropic drugs. The etiology of primary (idiopathic) RLS has not been clarified yet; however, genetic factors and dysfunctional dopaminergic neurotransmission as well as alterations of central iron metabolism play an important role. In addition to non-pharmacological treatment such as lifestyle modifications or behavioral strategies, levodopa, dopamine agonists, or anticonvulsants are effective. Opioids may be used in otherwise refractory forms. In the case of secondary or comorbid RLS, treatment of the underlying disease is necessary.
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Dopamine-Related Genotypes and Physical Activity Change During an Intervention: The Lifestyle Interventions and Independence for Elders Study.
Rosso, AL, Metti, AL, Glynn, NW, Boudreau, RM, Rejeski, WJ, Bohnen, N, Chen, H, Johannsen, NM, King, AC, Manini, TM, et al
Journal of the American Geriatrics Society. 2018;(6):1172-1179
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Abstract
OBJECTIVES To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. DESIGN Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). SETTING Multicenter study, 8 U.S. PARTICIPANTS Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). INTERVENTIONS Structured PA versus health education (HE) for an average of 2.6 years. MEASUREMENTS Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. RESULTS White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. CONCLUSION Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01072500.