Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release

RATIONALE: Several lines of evidence suggest that dopamine (DA)-influenced neuronal pathways may malfunction in Tourette Syndrome (TS). Some PET studies support the hypothesis of presynaptic abnormalities in levodopa uptake, dopamine synthesis, or dopamine release. OBJECTIVE: Directly test the presynaptic hypothesis using a new approach. METHODS: We used positron emission tomography (PET) and [11C]raclopride (RAC*) to measure synaptic dopamine release before and during levodopa and placebo infusions (with carbidopa) in 5neuroleptic-naïve adults with TS and 5 matched control subjects. The primary analysis examined RAC* binding potential (BPND) in predefined volumes of interest (VOIs). A secondary analysis compared BPND voxel by voxel over the entire brain. RESULTS: (1) Baseline RAC* BPND did not differ significantly between groups, though nucleus accumbens BPND was higher in TS (16%, p=0.051). (2) DA release declined from before to during infusions (p=0.014), including with placebo. (3) This decline was smaller in TS (p=0.080). (4) Levodopa’s effect on BPND differed significantly in right midbrain (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BPND by 74% in TS subjects, and in parahippocampal gyrus (p=0.02, corrected). DISCUSSION: Our finding that a before/after RAC* design is confounded by time and/or expectation effects may have implications for other RAC* PET studies. The smaller decrease of BPND with time in TS may be attributable to impaired habituation to the scan environment. Levodopa’s opposite effect on RAC* binding in TS dopaminergic midbrain but may signify an abnormal response to dopaminergic stimulation in TS.

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DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release

International Journal of Molecular Sciences ◽

10.3390/ijms21010060 ◽

2019 ◽

Vol 21 (1) ◽

pp. 60

Author(s):

Hye Ryeong Lim ◽

Mai-Tram Vo ◽

Dong Jun Kim ◽

Unn Hwa Lee ◽

Jong Hyuk Yoon ◽

...

Keyword(s):

Mouse Brain ◽

Dopamine Release ◽

Motor Coordination ◽

Neuronal Cell ◽

Dopamine Neurons ◽

Dopamine Synthesis ◽

Developmentally Regulated ◽

Neuronal Cell Bodies ◽

Motor Deficiency ◽

The Central Nervous System

Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

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Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2007.11.002 ◽

2008 ◽

Vol 18 (4) ◽

pp. 262-270 ◽

Cited By ~ 72

Author(s):

Fleur Zijlstra ◽

Jan Booij ◽

Wim van den Brink ◽

Ingmar H.A. Franken

Keyword(s):

Receptor Binding ◽

Dopamine Release ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Striatal Dopamine ◽

Dopamine D2

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Evidence for a selective CCKA and CCKB receptor mediated regulation of GABA and dopamine release in rat nucleus accumbens. A combined receptor binding and microdialysis study

Schizophrenia Research ◽

10.1016/0920-9964(96)85483-1 ◽

1996 ◽

Vol 18 (2-3) ◽

pp. 147-148

Author(s):

S. Tanganelli ◽

L. Ferraro ◽

W.T. O'Connor ◽

L. Beani ◽

K. Fuxe

Keyword(s):

Nucleus Accumbens ◽

Receptor Binding ◽

Dopamine Release ◽

Rat Nucleus Accumbens ◽

Microdialysis Study ◽

Cckb Receptor

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Spatial, temporal, and intensive determinants of dopamine release in the chick retina

Visual Neuroscience ◽

10.1017/s0952523804214110 ◽

2004 ◽

Vol 21 (4) ◽

pp. 627-635 ◽

Cited By ~ 10

Author(s):

W.A. LUFT ◽

P.M. IUVONE ◽

W.K. STELL

Keyword(s):

Light Intensity ◽

Visual Stimulus ◽

Dopamine Release ◽

Cell Activation ◽

Dopaminergic System ◽

Amacrine Cells ◽

Dopamine Synthesis ◽

Th Cell ◽

Stimulus Parameters ◽

Metabolite Accumulation

The retinal dopaminergic system is a global regulator of retinal function. Apart from the fact that the rates of dopamine synthesis and release are increased by increasing illumination, the visual image parameters that influence dopaminergic function are mostly unknown. Roles for spatial and temporal frequency and image contrast are suggested by the effects of form-deprivation with a diffusing goggle. Form-deprivation reduces the rates of dopamine synthesis and release, and induces myopia, which is prevented by dopamine agonists. Our purpose here was to identify visual stimulus parameters that activate dopaminergic amacrine cells and elicit dopamine release. White Leghorn cockerels 4–7 days old were exposed to 2 h of form-deprivation, reduced light intensity, or stimuli of varied temporal or spatial frequency. Activation of dopaminergic neurons, labeled for tyrosine hydroxylase (TH), was assessed with immunocytochemistry for c-Fos, and dopamine release was measured by HPLC analysis of dopamine metabolite accumulation in the vitreous body. Form-deprivation did not reduce TH+ cell activation or vitreal dopamine metabolite accumulation any more than did neutral-density filters of approximately equal transmittance. TH+ cell activation and vitreal metabolite accumulation were not affected significantly by exposure to 2, 5, 10, 15, or 20 Hz stroboscopic stimulation on a dark background, or by sine-wave gratings of 0.089, 0.44, 0.89, 1.04, or 3.13 cycles/deg compared to a uniform gray target of equal mean luminance. These data indicate that the retinal dopaminergic system does not respond readily to short-term changes in visual stimulus parameters, other than light intensity, under the conditions of these experiments.

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Levodopa-stimulated dopamine release in Tourette syndrome

10.7287/peerj.preprints.30v1 ◽

2013 ◽

Author(s):

Kevin J Black ◽

Marilyn L. Piccirillo ◽

Jonathan M. Koller ◽

Tiffany Hseih ◽

Lei Wang ◽

...

Keyword(s):

Tourette Syndrome ◽

Dopamine Release ◽

Secondary Analysis ◽

Parahippocampal Gyrus ◽

Binding Potential ◽

Dopamine Synthesis ◽

Primary Analysis ◽

New Approach ◽

Control Subjects ◽

Positron Emission

BACKGROUND: Several lines of evidence suggest that dopamine (DA)-influenced neuronal pathways may malfunction in Tourette Syndrome (TS). A dopamine-responsive abnormality of brain function in TS could be either presynaptic or postsynaptic. Some PET studies support the hypothesis of presynaptic abnormalities in levodopa uptake, dopamine synthesis, or dopamine release. Alternatively, presynaptic dopaminergic function could be normal in TS but dopamine-sensitive abnormalities could exist in striatum, pallidum, thalamus, or cortex. METHODS: In this study we directly tested the presynaptic hypothesis using a new approach. We used positron emission tomography (PET) and [11C]raclopride (RAC*) to measure synaptic dopamine release in response to levodopa and placebo infusions (with carbidopa) in 5 neuroleptic-naïve adults with TS and 5 matched control subjects. The primary analysis examined RAC* binding potential (BPND) in predefined volumes of interest (VOIs). A secondary analysis compared BPND voxel by voxel over the entire brain. RESULTS: (1) Overall, baseline RAC* BPND did not differ significantly between groups, though nucleus accumbens BPND was higher in TS (16%, p=0.051). (2) Across regions, DA release declined from before to during infusion (p=0.014), including with placebo. (3) This decline was smaller in TS (p=0.080). (4) Levodopa’s effect on BPND differed significantly in right midbrain (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BPND by 74% in TS subjects, and in parahippocampal gyrus (p=0.02, corrected). DISCUSSION: Our finding that a before/after RAC* design is confounded by time and/or expectation effects has implications for other RAC* PET studies. The smaller magnitude of the decrease with time in TS may be attributable to impaired habituation to the scan environment. Levodopa’s opposite effect on RAC* binding in TS dopaminergic midbrain was not predicted, but may signify an abnormal response to dopaminergic stimulation in TS. These findings invite confirmation in a larger sample.

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Postsynaptic Mechanisms Render Syn I/II/III Mice Highly Responsive to Psychostimulants

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz019 ◽

2019 ◽

Vol 22 (7) ◽

pp. 453-465 ◽

Cited By ~ 1

Author(s):

Vladimir M Pogorelov ◽

Hung-Teh Kao ◽

George J Augustine ◽

William C Wetsel

Keyword(s):

Open Field ◽

Knockout Mice ◽

Dopamine Release ◽

Behavioral Sensitization ◽

Dopamine Synthesis ◽

Dopamine Turnover ◽

Wild Type ◽

Field Exposure ◽

Novel Environment ◽

Motor Effects

Abstract Background Synapsins are encoded by SYN I, SYN II, and SYN III, and they regulate neurotransmitter release by maintaining a reserve pool of synaptic vesicles. Methods Presynaptic dopamine responses to cocaine were examined by microdialysis, and postsynaptic responses were evaluated to various dopamine receptor agonists in the open field with SynI/SynII/SynIII triple knockout mice. Results Triple knockout mice showed enhanced spontaneous locomotion in a novel environment and were hyper-responsive to indirect and direct D1 and D2 dopamine agonists. Triple knockout animals appeared sensitized to cocaine upon first open field exposure; sensitization developed across days in wild-type controls. When mutants were preexposed to a novel environment before injection, cocaine-stimulated locomotion was reduced and behavioral sensitization retarded. Baseline dopamine turnover was enhanced in mutants and novel open field exposure increased their striatal dopamine synthesis rates. As KCl-depolarization stimulated comparable dopamine release in both genotypes, their readily releasable pools appeared indistinguishable. Similarly, cocaine-induced hyperlocomotion was indifferent to blockade of newly synthesized dopamine and depletion of releasable dopamine pools. Extracellular dopamine release was similar in wild-type and triple knockout mice preexposed to the open field and given cocaine or placed immediately into the arena following injection. Since motor effects to novelty and psychostimulants depend upon frontocortical-striatal inputs, we inhibited triple knockout medial frontal cortex with GABA agonists. Locomotion was transiently increased in cocaine-injected mutants, while their supersensitive cocaine response to novelty was lost. Conclusions These results reveal presynaptic dopamine release is not indicative of agonist-induced triple knockout hyperlocomotion. Instead, their novelty response occurs primarily through postsynaptic mechanisms and network effects.

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