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Critical role of the finger loop in arrestin binding to the receptors.
Zheng C, Tholen J, Gurevich VV
(2019) PLoS One 14: e0213792
MeSH Terms: Amino Acid Sequence, Arrestins, HEK293 Cells, Humans, Point Mutation, Protein Conformation, Receptor, Muscarinic M2, Receptors, Adrenergic, beta-2, Receptors, Dopamine D1, Receptors, Dopamine D2, Sequence Homology
Show Abstract · Added March 18, 2020
We tested the interactions with four different G protein-coupled receptors (GPCRs) of arrestin-3 mutants with substitutions in the four loops, three of which contact the receptor in the structure of the arrestin-1-rhodopsin complex. Point mutations in the loop at the distal tip of the N-domain (Glu157Ala), in the C-loop (Phe255Ala), back loop (Lys313Ala), and one of the mutations in the finger loop (Gly65Pro) had mild variable effects on receptor binding. In contrast, the deletion of Gly65 at the beginning of the finger loop reduced the binding to all GPCRs tested, with the binding to dopamine D2 receptor being affected most dramatically. Thus, the presence of a glycine at the beginning of the finger loop appears to be critical for the arrestin-receptor interaction.
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Genetic loss of GluN2B in D1-expressing cell types enhances long-term cocaine reward and potentiation of thalamo-accumbens synapses.
Joffe ME, Turner BD, Delpire E, Grueter BA
(2018) Neuropsychopharmacology 43: 2383-2389
MeSH Terms: Animals, Cocaine, Gene Deletion, Locomotion, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nucleus Accumbens, Receptors, Dopamine D1, Receptors, N-Methyl-D-Aspartate, Reward, Thalamus
Show Abstract · Added April 2, 2019
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.
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Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.
Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, Marks CR, Centanni SW, Folkes OM, Spiess K, Augustin SM, Mackie K, Lovinger DM, Winder DG, Patel S, Colbran RJ
(2018) Biol Psychiatry 84: 304-315
MeSH Terms: Animals, Arachidonic Acids, Autism Spectrum Disorder, Corpus Striatum, Endocannabinoids, Glycerides, Mice, Mice, Knockout, Receptor, Adenosine A2A, Receptors, Dopamine D1, Signal Transduction, Social Behavior, Synaptic Transmission
Show Abstract · Added March 21, 2018
BACKGROUND - Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored.
METHODS - Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum.
RESULTS - Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming.
CONCLUSIONS - These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.
Copyright © 2018 Society of Biological Psychiatry. All rights reserved.
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13 MeSH Terms
Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M Muscarinic Receptor.
Moehle MS, Pancani T, Byun N, Yohn SE, Wilson GH, Dickerson JW, Remke DH, Xiang Z, Niswender CM, Wess J, Jones CK, Lindsley CW, Rook JM, Conn PJ
(2017) Neuron 96: 1358-1372.e4
MeSH Terms: Acetylcholine, Animals, Basal Ganglia, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Cholinergic Neurons, Dopamine, Inhibitory Postsynaptic Potentials, Locomotion, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurotransmitter Agents, Oxygen, Pars Reticulata, Pedunculopontine Tegmental Nucleus, Receptor, Muscarinic M4, Receptors, Dopamine D1, Signal Transduction
Show Abstract · Added March 14, 2018
Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M) to oppose cAMP-dependent dopamine receptor subtype 1 (D) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D-mediated activation of motor activity. These studies provide important new insights into the unique role of M in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood G, Tanaka KF, Moore H, Ahmari SE, Veenstra-VanderWeele J
(2017) Proc Natl Acad Sci U S A 114: 5719-5724
MeSH Terms: Amphetamines, Animals, Basal Ganglia, Cell Line, Central Nervous System Stimulants, Dopamine, Excitatory Amino Acid Transporter 3, Glutamic Acid, Grooming, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Obsessive-Compulsive Disorder, Receptors, Dopamine D1, Reflex, Startle
Show Abstract · Added March 18, 2020
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in () locomotor activity, () stereotypy, and () immediate early gene induction in the dorsal striatum following amphetamine administration. Further, -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D receptor binding in the dorsal striatum of -STOP mice. -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
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Manipulating circadian clock neuron firing rate resets molecular circadian rhythms and behavior.
Jones JR, Tackenberg MC, McMahon DG
(2015) Nat Neurosci 18: 373-5
MeSH Terms: Action Potentials, Animals, Channelrhodopsins, Circadian Rhythm, In Vitro Techniques, Luminescent Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Patch-Clamp Techniques, Period Circadian Proteins, Photic Stimulation, Receptors, Dopamine D1, Sodium Channel Blockers, Suprachiasmatic Nucleus, Tetrodotoxin, Time Factors, Vasoactive Intestinal Peptide
Show Abstract · Added March 18, 2020
To examine the interaction between molecular, electrical and behavioral circadian rhythms, we combined optogenetic manipulation of suprachiasmatic nucleus (SCN) firing rate with bioluminescence imaging and locomotor activity monitoring. Manipulating firing rate reset circadian rhythms both ex vivo and in vivo, and this resetting required spikes and network communication. This suggests that SCN firing rate is fundamental to circadian pacemaking as both an input to and output of the molecular clockworks.
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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.
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22 MeSH Terms
Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load.
Smith CT, Swift-Scanlan T, Boettiger CA
(2014) J Cogn Neurosci 26: 395-407
MeSH Terms: Adult, African Continental Ancestry Group, Catechol O-Methyltransferase, DNA, Data Interpretation, Statistical, Discrimination, Psychological, Dopamine, Dopamine and cAMP-Regulated Phosphoprotein 32, Educational Status, European Continental Ancestry Group, Executive Function, Female, Genotype, Humans, Male, Memory, Short-Term, Minisatellite Repeats, Polymerase Chain Reaction, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Prefrontal Cortex, Psychomotor Performance, Receptors, Dopamine D1, Signal Transduction, Young Adult
Show Abstract · Added February 9, 2017
Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.
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25 MeSH Terms
Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease.
Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E
(2010) Sci Transl Med 2: 28ra28
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents, Behavior, Animal, Dose-Response Relationship, Drug, Dyskinesias, Endocytosis, G-Protein-Coupled Receptor Kinases, Gene Knockdown Techniques, Genetic Therapy, Humans, Lentivirus, Levodopa, Macaca, Oxidopamine, Parkinsonian Disorders, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1, Receptors, Dopamine D2, Rotation, Signal Transduction
Show Abstract · Added December 10, 2013
Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor l-dopa is the mainstay of current treatment. After several years, however, the patients develop l-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of l-dopa and even prolonged the antiparkinsonian effect of a lower dose of l-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of l-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.
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22 MeSH Terms
Specificity of prenatal cocaine exposure effects on cortical interneurons is independent from dopamine D1 receptor co-localization.
Thompson BL, Stanwood GD, Levitt P
(2010) J Chem Neuroanat 39: 228-34
MeSH Terms: Animals, Calbindin 2, Calbindins, Calcium, Cocaine, Cocaine-Related Disorders, Disease Models, Animal, Dopamine Uptake Inhibitors, Female, Immunohistochemistry, Interneurons, Male, Nervous System Malformations, Prefrontal Cortex, Pregnancy, Prenatal Exposure Delayed Effects, Rabbits, Receptors, Dopamine D1, S100 Calcium Binding Protein G
Show Abstract · Added January 20, 2015
Gestational cocaine exposure in a rabbit model leads to a persistent increase in parvalbumin immunoreactive cells and processes, reduces dopamine D1 receptor coupling to Gsalpha by means of improper trafficking of the receptor, changes pyramidal neuron morphology, and disrupts cognitive function. Here, experiments investigated whether changes in parvalbumin neurons were specific, or extended to other subpopulations of interneurons. Additionally, we examined dopamine D1 receptor expression patterns and its overlap with specific interneuron populations in the rabbit prefrontal cortex as a possible correlate for alterations in interneuron development following prenatal cocaine exposure. Analysis of calbindin and calretinin interneuron subtypes revealed that they did not exhibit any differences in cell number or process development. Thus, specific consequences of prenatal cocaine in the rabbit appear to be limited to parvalbumin-positive interneurons. Dopamine D1 receptor expression did not correlate with the selective effects of cocaine exposure, however, as both parvalbumin and calbindin cell types expressed the receptor. The findings suggest that additional, unique properties of parvalbumin neurons contribute to their developmental sensitivity to in utero cocaine exposure.
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19 MeSH Terms