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https://www.readbyqxmd.com/read/29218782/therapy-development-in-huntington-disease-from-current-strategies-to-emerging-opportunities
#1
REVIEW
Audrey S Dickey, Albert R La Spada
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration...
December 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29194534/why-not-try-harder-computational-approach-to-motivation-deficits-in-neuro-psychiatric-diseases
#2
Mathias Pessiglione, Fabien Vinckier, Sébastien Bouret, Jean Daunizeau, Raphaël Le Bouc
Motivation deficits, such as apathy, are pervasive in both neurological and psychiatric diseases. Even when they are not the core symptom, they reduce quality of life, compromise functional outcome and increase the burden for caregivers. They are currently assessed with clinical scales that do not give any mechanistic insight susceptible to guide therapeutic intervention. Here, we present another approach that consists of phenotyping the behaviour of patients in motivation tests, using computational models...
November 29, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29189169/computer-aided-drug-design-applied-to-parkinson-targets
#3
Hamilton M Ishiki, Jose Maria Barbosa Filho, Marcelo S da Silva, Marcus T Scotti, Luciana Scotti
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Although the scientific community has performed great efforts in the study of PD, and from the most diverse points of view, the disease remains incurable. The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial dysfunction and inflammation are thought to play major roles in the etiology...
November 28, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/29164011/dat-s-awesome-hawai-i-s-first-dopamine-transporter-dat-nuclear-medicine-study
#4
Eric J Royston, Yang-En Kao, Kevin M Nakamura
Parkinsonian Syndromes are difficult to accurately diagnose and distinguish from other neurological processes such as essential tremor. Until now, physical exam and clinical presentation have been the gold standard for diagnosis (bradykinesia, tremor, rigidity, and postural instability).1 However, this leads to over- or under diagnosis and improper treatment due to variability in presentation and symptoms.1 A nuclear medicine study using I-123 Ioflupane (DaTSCAN) has been developed, which allows accurate differentiation of Parkinsonian Syndromes from other etiologies...
November 2017: Hawai'i Journal of Medicine & Public Health: a Journal of Asia Pacific Medicine & Public Health
https://www.readbyqxmd.com/read/29153928/enhancing-excitability-of-dopamine-neurons-promotes-motivational-behaviour-through-increased-action-initiation
#5
Linde Boekhoudt, Ellen C Wijbrans, Jodie H K Man, Mieneke C M Luijendijk, Johannes W de Jong, Geoffrey van der Plasse, Louk J M J Vanderschuren, Roger A H Adan
Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted...
November 16, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29149620/the-dopamine-d4-receptor-gene-birth-weight-maternal-depression-maternal-attention-and-the-prediction-of-disorganized-attachment-at-36-months-of-age-a-prospective-gene%C3%A3-environment-analysis
#6
Justin Graffi, Ellen Moss, Alexia Jolicoeur-Martineau, Gal Moss, Vanessa Lecompte, Katherine Pascuzzo, Vanessa Babineau, Cathryn Gordon-Green, Viara R Mileva-Seitz, Klaus Minde, Roberto Sassi, Meir Steiner, James L Kennedy, Helene Gaudreau, Robert Levitan, Michael J Meaney, Ashley Wazana
BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads...
November 14, 2017: Infant Behavior & Development
https://www.readbyqxmd.com/read/29105662/neural-correlates-of-impaired-reward-effort-integration-in-remitted-bulimia-nervosa
#7
Stefanie Verena Mueller, Yosuke Morishima, Simon Schwab, Roland Wiest, Andrea Federspiel, Gregor Hasler
The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa...
November 6, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29066971/the-sigma-2-receptor-selective-agonist-siramesine-lu-28-179-decreases-cocaine-reinforced-pavlovian-learning-and-alters-glutamatergic-and-dopaminergic-input-to-the-striatum
#8
Anna M Klawonn, Anna Nilsson, Carl F Rådberg, Sarah H Lindström, Mia Ericson, Björn Granseth, David Engblom, Michael Fritz
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29046641/buspirone-counteracts-mk-801-induced-schizophrenia-like-phenotypes-through-dopamine-d3-receptor-blockade
#9
Sebastiano Alfio Torrisi, Salvatore Salomone, Federica Geraci, Filippo Caraci, Claudio Bucolo, Filippo Drago, Gian Marco Leggio
Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29031913/chronic-pain-and-pain-processing-in-parkinson-s-disease
#10
REVIEW
Pierre J Blanchet, Christine Brefel-Courbon
Pain is experienced by the vast majority of patients living with Parkinson's disease. It is most often of nociceptive origin, but may also be ascribed to neuropathic (radicular or central) or miscellaneous sources. The recently validated King's Parkinson's Disease Pain Scale is based on 7 domains including musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, nocturnal pain, oro-facial pain, pain with discolouration/oedema/swelling, and radicular pain. The basal ganglia integrate incoming nociceptive information and contribute to coordinated motor responses in pain avoidance and nocifensive behaviors...
October 12, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29028556/buspirone-maintenance-does-not-alter-the-reinforcing-subjective-and-cardiovascular-effects-of-intranasal-methamphetamine
#11
Anna R Reynolds, Justin C Strickland, William W Stoops, Joshua A Lile, Craig R Rush
BACKGROUND: Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies...
December 1, 2017: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/28965318/the-drd2-taq1a-a1-allele-may-magnify-the-risk-of-alzheimer-s-in-aging-african-americans
#12
REVIEW
Kenneth Blum, Rajendra D Badgaiyan, Georgia M Dunston, David Baron, Edward J Modestino, Thomas McLaughlin, Bruce Steinberg, Mark S Gold, Marjorie C Gondré-Lewis
Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment...
September 30, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28950781/blockade-of-dopamine-d1-family-receptors-attenuates-the-mania-like-hyperactive-risk-preferring-and-high-motivation-behavioral-profile-of-mice-with-low-dopamine-transporter-levels
#13
Morgane Milienne-Petiot, Lucianne Groenink, Arpi Minassian, Jared W Young
BACKGROUND: Patients with bipolar disorder mania exhibit poor cognition, impulsivity, risk-taking, and goal-directed activity that negatively impact their quality of life. To date, existing treatments for bipolar disorder do not adequately remediate cognitive dysfunction. Reducing dopamine transporter expression recreates many bipolar disorder mania-relevant behaviors (i.e. hyperactivity and risk-taking). The current study investigated whether dopamine D1-family receptor blockade would attenuate the risk-taking, hypermotivation, and hyperactivity of dopamine transporter knockdown mice...
October 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28948979/effort-but-not-reward-sensitivity-is-altered-by-acute-sickness-induced-by-experimental-endotoxemia-in-humans
#14
Amelia Draper, Rebecca M Koch, Jos Wm van der Meer, M Apps, Peter Pickkers, Masud Husain, Marieke E van der Schaaf
Sickness behavior in humans is characterized by low mood and fatigue, which have been suggested to reflect changes in motivation involving reorganization of priorities. However, it is unclear which specific processes underlying motivation are altered. We tested whether bacterial endotoxin E. coli lipopolysaccharide (LPS) affected two dissociable constructs of motivational behavior, ie effort and reward sensitivity. After familiarization with 5 effort levels, participants made a series of accept/reject decisions on whether the stake offered (1, 4, 8, 12 or 15 apples)) was 'worth the effort' (10, 27...
September 26, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28930069/initial-elevations-in-glutamate-and-dopamine-neurotransmission-decline-with-age-as-does-exploratory-behavior-in-lrrk2-g2019s-knock-in-mice
#15
Mattia Volta, Dayne A Beccano-Kelly, Sarah A Paschall, Stefano Cataldi, Sarah E MacIsaac, Naila Kuhlmann, Chelsie A Kadgien, Igor Tatarnikov, Jesse Fox, Jaskaran Khinda, Emma Mitchell, Sabrina Bergeron, Heather Melrose, Matthew J Farrer, Austen J Milnerwood
LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28920936/dopamine-induces-soluble-%C3%AE-synuclein-oligomers-and-nigrostriatal-degeneration
#16
Danielle E Mor, Elpida Tsika, Joseph R Mazzulli, Neal S Gould, Hanna Kim, Malcolm J Daniels, Shachee Doshi, Preetika Gupta, Jennifer L Grossman, Victor X Tan, Robert G Kalb, Kim A Caldwell, Guy A Caldwell, John H Wolfe, Harry Ischiropoulos
Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice...
November 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28916140/an-integrative-interdisciplinary-perspective-on-social-dominance-hierarchies
#17
REVIEW
Chen Qu, Romain Ligneul, Jean-Baptiste Van der Henst, Jean-Claude Dreher
In the course of evolution, social dominance has been a strong force shaping the organization of social systems in many species. Individuals with a better ability to represent social dominance relationships and to adapt their behavior accordingly usually achieve better access to resources, hence providing benefits in terms of reproduction, health, and wellbeing. Understanding how and to what extent our brains are affected by social dominance requires interdisciplinary efforts. Here, we integrate findings from social neuroscience, evolutionary biology, and developmental psychology to highlight how social hierarchies are learned and represented in primates...
September 12, 2017: Trends in Cognitive Sciences
https://www.readbyqxmd.com/read/28915025/structural-evidence-for-the-dopamine-first-mechanism-of-norcoclaurine-synthase
#18
Benjamin R Lichman, Altin Sula, Thomas Pesnot, Helen C Hailes, John M Ward, Nicholas H Keep
Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocatalyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism-inspired ligand. The structure supports two key features of the NCS "dopamine-first" mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance...
October 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/28904554/plants-derived-neuroprotective-agents-cutting-the-cycle-of-cell-death-through-multiple-mechanisms
#19
REVIEW
Taiwo Olayemi Elufioye, Tomayo Ireti Berida, Solomon Habtemariam
Neuroprotection is the preservation of the structure and function of neurons from insults arising from cellular injuries induced by a variety of agents or neurodegenerative diseases (NDs). The various NDs including Alzheimer's, Parkinson's, and Huntington's diseases as well as amyotropic lateral sclerosis affect millions of people around the world with the main risk factor being advancing age. Each of these diseases affects specific neurons and/or regions in the brain and involves characteristic pathological and molecular features...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28866850/can-biomarkers-help-the-early-diagnosis-of-parkinson-s-disease
#20
REVIEW
Weidong Le, Jie Dong, Song Li, Amos D Korczyn
Parkinson's disease (PD) is a complex neurodegenerative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non-motor symptoms. In order to provide better early diagnosis and subsequent disease-modifying therapies for PD patients, there is an urgent need to identify sensitive and specific biomarkers. Biomarkers can be divided into four categories: clinical, imaging, biochemical, and genetic. Ideal biomarkers not only improve our understanding of PD pathogenesis and progression, but also provide benefits for early risk evaluation and clinical diagnosis of PD...
October 2017: Neuroscience Bulletin
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