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Extending Corticostriatal Systems.
Deutch AY
(2016) JAMA Psychiatry 73: 871-2
MeSH Terms: Animals, Cerebral Cortex, Corpus Striatum, Humans, Neural Pathways
Added April 6, 2017
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1 Members
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5 MeSH Terms
Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine.
Smith CT, Dang LC, Cowan RL, Kessler RM, Zald DH
(2016) Neuropharmacology 108: 394-402
MeSH Terms: Administration, Oral, Adolescent, Adult, Central Nervous System Stimulants, Corpus Striatum, Dextroamphetamine, Dopamine, Humans, Male, Positron-Emission Tomography, Prefrontal Cortex, Receptors, Dopamine D2, Signal Transduction, Young Adult
Show Abstract · Added February 9, 2017
Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Differential CaMKII regulation by voltage-gated calcium channels in the striatum.
Pasek JG, Wang X, Colbran RJ
(2015) Mol Cell Neurosci 68: 234-43
MeSH Terms: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Animals, Calcium, Calcium Channel Agonists, Calcium Channel Blockers, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Chelating Agents, Corpus Striatum, Egtazic Acid, Enzyme Inhibitors, Gene Expression Regulation, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Pyrroles, Receptors, Glutamate, Signal Transduction, Spider Venoms
Show Abstract · Added February 15, 2016
Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.
Copyright © 2015 Elsevier Inc. All rights reserved.
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20 MeSH Terms
GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson's disease via its RGS homology domain.
Ahmed MR, Bychkov E, Li L, Gurevich VV, Gurevich EV
(2015) Sci Rep 5: 10920
MeSH Terms: Animals, Behavior, Animal, Corpus Striatum, Disease Models, Animal, Dyskinesias, G-Protein-Coupled Receptor Kinase 3, Gene Expression, Gene Knockdown Techniques, Levodopa, Parkinson Disease, Protein Interaction Domains and Motifs, RGS Proteins, RNA Interference, RNA, Small Interfering, Rats, Signal Transduction
Show Abstract · Added February 15, 2016
Degeneration of dopaminergic neurons causes Parkinson's disease. Dopamine replacement therapy with L-DOPA is the best available treatment. However, patients develop L-DOPA-induced dyskinesia (LID). In the hemiparkinsonian rat, chronic L-DOPA increases rotations and abnormal involuntary movements modeling LID, via supersensitive dopamine receptors. Dopamine receptors are controlled by G protein-coupled receptor kinases (GRKs). Here we demonstrate that LID is attenuated by overexpression of GRK3 in the striatum, whereas knockdown of GRK3 by microRNA exacerbated it. Kinase-dead GRK3 and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK3 with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK3, kinase-dead GRK3, and RH inhibited accumulation of ∆FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK3 knockdown exacerbated ∆FosB accumulation. Our findings reveal a novel mechanism of GRK3 control of the dopamine receptor signaling and the role of Gq in LID.
0 Communities
1 Members
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16 MeSH Terms
Comparative diffusion tractography of corticostriatal motor pathways reveals differences between humans and macaques.
Neggers SF, Zandbelt BB, Schall MS, Schall JD
(2015) J Neurophysiol 113: 2164-72
MeSH Terms: Adult, Animals, Brain Mapping, Cerebral Cortex, Corpus Striatum, Diffusion Tensor Imaging, Efferent Pathways, Female, Humans, Macaca radiata, Male, Species Specificity, Young Adult
Show Abstract · Added February 12, 2015
The primate corticobasal ganglia circuits are understood to be segregated into parallel anatomically and functionally distinct loops. Anatomical and physiological studies in macaque monkeys are summarized as showing that an oculomotor loop begins with projections from the frontal eye fields (FEF) to the caudate nucleus, and a motor loop begins with projections from the primary motor cortex (M1) to the putamen. However, recent functional and structural neuroimaging studies of the human corticostriatal system report evidence inconsistent with this organization. To obtain conclusive evidence, we directly compared the pattern of connectivity between cortical motor areas and the striatum in humans and macaques in vivo using probabilistic diffusion tractography. In macaques we found that FEF is connected with the head of the caudate and anterior putamen, and M1 is connected with more posterior sections of the caudate and putamen, corroborating neuroanatomical tract tracing findings. However, in humans FEF and M1 are connected to largely overlapping portions of posterior putamen and only a small portion of the caudate. These results demonstrate that the corticobasal connectivity for the oculomotor and primary motor loop is not entirely segregated for primates at a macroscopic level and that the description of the anatomical connectivity of corticostriatal motor systems in humans does not parallel that of macaques, perhaps because of an expansion of prefrontal projections to striatum in humans.
Copyright © 2015 the American Physiological Society.
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1 Members
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13 MeSH Terms
Evidence against dopamine D1/D2 receptor heteromers.
Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D, Mészáros J, Urizar E, Sibley DR, Kellendonk C, Sonntag KC, Graham DL, Colbran RJ, Stanwood GD, Javitch JA
(2015) Mol Psychiatry 20: 1373-85
MeSH Terms: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, Animals, Corpus Striatum, Dopamine Agonists, Dopamine Antagonists, GTP-Binding Protein alpha Subunits, Gq-G11, Grooming, HEK293 Cells, Humans, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Motor Activity, Nucleus Accumbens, Phosphorylation, Protein Multimerization, Protein Structure, Tertiary, Receptors, Dopamine D1, Receptors, Dopamine D2
Show Abstract · Added January 20, 2015
Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.
0 Communities
2 Members
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22 MeSH Terms
A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease.
Tidball AM, Bryan MR, Uhouse MA, Kumar KK, Aboud AA, Feist JE, Ess KC, Neely MD, Aschner M, Bowman AB
(2015) Hum Mol Genet 24: 1929-44
MeSH Terms: Amino Acid Motifs, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Corpus Striatum, DNA Damage, Disease Models, Animal, Female, Humans, Huntington Disease, Male, Manganese, Mice, Neural Stem Cells, Phosphorylation, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added February 3, 2015
The essential micronutrient manganese is enriched in brain, especially in the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models. We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreased manganese-dependent phosphorylation of p53. Likewise, analysis of ATM autophosphorylation and additional ATM kinase targets, H2AX and CHK2, support a role for ATM in the activation of p53 by manganese and that a defect in this process occurs in HD. Furthermore, the deficit in Mn-dependent activation of ATM kinase in HD neuroprogenitors was highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalize manganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
1 Communities
3 Members
0 Resources
17 MeSH Terms
The initiation of synaptic 2-AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium.
Shonesy BC, Winder DG, Patel S, Colbran RJ
(2015) Neuropharmacology 91: 57-62
MeSH Terms: Animals, Arachidonic Acids, Calcium Signaling, Corpus Striatum, Diglycerides, Endocannabinoids, Glycerides, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Neurons, Synapses
Show Abstract · Added January 20, 2015
On-demand postsynaptic synthesis and release of endocannabinoid lipids and subsequent binding to presynaptic CB1 receptors (CB1Rs) mediates short and long-term depression (LTD) of excitatory transmission in many brain regions. However, mechanisms involved in the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) by diacylglycerol lipase α (DGLα) are poorly understood. Since Gq-coupled receptor activation can stimulate production of a major DGL substrate 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) by PLCβ, we sought to determine if 2-AG biosynthesis was limited only by a lack of substrate availability, or if other pathways, such as Ca(2+) signaling, also need to be simultaneously engaged. To address this question, we loaded medium spiny neurons of the dorsolateral striatum with SAG while monitoring excitatory synaptic inputs. SAG-loading had no significant effect on evoked excitatory synaptic currents when cells were voltage-clamped at -80 mV. However, depolarization of MSNs to -50 mV revealed a SAG-loading dependent decrease in the amplitude of excitatory currents that was accompanied by an increase in paired pulse ratio, consistent with decreased glutamate release. Both effects of loading SAG at -50 mV were blocked by chelation of postsynaptic Ca(2+) using BAPTA or by bath application of tetrahydrolipstatin (THL), a DGL inhibitor. Loading of SAG into glutamatergic pyramidal neurons of the amygdala similarly inhibited excitatory synaptic inputs and increased the PPR. SAG-induced depression was absent in both regions from mice lacking CB1Rs. These data show that increasing substrate availability alone is insufficient to drive 2-AG mobilization and that DGL-dependent synaptic depression via CB1R activation requires postsynaptic Ca(2+) signals.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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2 Members
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12 MeSH Terms
Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles.
Rook JM, Tantawy MN, Ansari MS, Felts AS, Stauffer SR, Emmitte KA, Kessler RM, Niswender CM, Daniels JS, Jones CK, Lindsley CW, Conn PJ
(2015) Neuropsychopharmacology 40: 755-65
MeSH Terms: Allosteric Regulation, Amphetamine, Animals, Benzamides, Calcium, Cerebellum, Corpus Striatum, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Locomotion, Male, Maze Learning, Niacinamide, Piperidines, Positron-Emission Tomography, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Thiazoles
Show Abstract · Added February 19, 2015
Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.
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21 MeSH Terms
Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
Maltese M, Martella G, Madeo G, Fagiolo I, Tassone A, Ponterio G, Sciamanna G, Burbaud P, Conn PJ, Bonsi P, Pisani A
(2014) Mov Disord 29: 1655-65
MeSH Terms: Animals, Biophysics, Cholinergic Antagonists, Corpus Striatum, Electric Stimulation, Excitatory Postsynaptic Potentials, In Vitro Techniques, Long-Term Potentiation, Mice, Mice, Transgenic, Molecular Chaperones, Mutation, Neurons, Patch-Clamp Techniques, Synapses, Thalamus
Show Abstract · Added February 19, 2015
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
© 2014 International Parkinson and Movement Disorder Society.
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16 MeSH Terms