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Dopamine effects on frontal cortical blood flow and motor inhibition in Parkinson's disease.
Trujillo P, van Wouwe NC, Lin YC, Stark AJ, Petersen KJ, Kang H, Zald DH, Donahue MJ, Claassen DO
(2019) Cortex 115: 99-111
MeSH Terms: Aged, Cerebrovascular Circulation, Dopamine Agonists, Female, Frontal Lobe, Humans, Inhibition, Psychological, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Parkinson Disease, Psychomotor Performance, Reaction Time
Show Abstract · Added April 15, 2019
Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off- and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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1 Members
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14 MeSH Terms
Nigrostriatal and Mesolimbic D Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors.
Stark AJ, Smith CT, Lin YC, Petersen KJ, Trujillo P, van Wouwe NC, Kang H, Donahue MJ, Kessler RM, Zald DH, Claassen DO
(2018) J Neurosci 38: 3230-3239
MeSH Terms: Aged, Benzamides, Compulsive Behavior, Dopamine Agonists, Dopamine D2 Receptor Antagonists, Female, Humans, Limbic System, Male, Middle Aged, Parkinson Disease, Positron-Emission Tomography, Radiopharmaceuticals, Receptors, Dopamine D2, Receptors, Dopamine D3, Reward, Substantia Nigra
Show Abstract · Added March 21, 2018
The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with ( = 17) and without ( = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [F]fallypride, a high affinity D-like receptor ligand that can measure striatal and extrastriatal D nondisplaceable binding potential (BP). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BP In this group, self-reported severity of ICB symptoms positively correlated with midbrain D receptor BP Group differences in regional D BP relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response. The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.
Copyright © 2018 the authors 0270-6474/18/383231-10$15.00/0.
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17 MeSH Terms
Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease.
Petersen K, Van Wouwe N, Stark A, Lin YC, Kang H, Trujillo-Diaz P, Kessler R, Zald D, Donahue MJ, Claassen DO
(2018) Hum Brain Mapp 39: 509-521
MeSH Terms: Analysis of Variance, Antiparkinson Agents, Brain Mapping, Cerebrovascular Circulation, Dopamine Agonists, Female, Humans, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Neuropsychological Tests, Oxygen, Parkinson Disease, Reward, Ventral Striatum
Show Abstract · Added March 21, 2018
A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n = 19) or without (n = 18) ICB. An incentive-based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018. © 2017 Wiley Periodicals, Inc.
© 2017 Wiley Periodicals, Inc.
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2 Members
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17 MeSH Terms
Spontaneous Eye Blink Rate (EBR) Is Uncorrelated with Dopamine D2 Receptor Availability and Unmodulated by Dopamine Agonism in Healthy Adults.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Newhouse PA, Zald DH
(2017) eNeuro 4:
MeSH Terms: Adult, Benzamides, Blinking, Brain, Bromocriptine, Dopamine Agonists, Dopamine D2 Receptor Antagonists, Double-Blind Method, Female, Healthy Volunteers, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Pyrrolidines, Receptors, Dopamine D2, Young Adult
Show Abstract · Added March 21, 2018
Spontaneous eye blink rate (EBR) has been proposed as a noninvasive, inexpensive marker of dopamine functioning. Support for a relation between EBR and dopamine function comes from observations that EBR is altered in populations with dopamine dysfunction and EBR changes under a dopaminergic manipulation. However, the evidence across the literature is inconsistent and incomplete. A direct correlation between EBR and dopamine function has so far been observed only in nonhuman animals. Given significant interest in using EBR as a proxy for dopamine function, this study aimed to verify a direct association in healthy, human adults. Here we measured EBR in healthy human subjects whose dopamine D2 receptor (DRD2) availability was assessed with positron emission tomography (PET)-[18F]fallypride to examine the predictive power of EBR for DRD2 availability. Effects of the dopamine agonist bromocriptine on EBR also were examined to determine the responsiveness of EBR to dopaminergic stimulation and, in light of the hypothesized inverted-U profile of dopamine effects, the role of DRD2 availability in EBR responsivity to bromocriptine. Results from 20 subjects (age 33.6 ± 7.6 years, 9F) showed no relation between EBR and DRD2 availability. EBR also was not responsive to dopaminergic stimulation by bromocriptine, and individual differences in DRD2 availability did not modulate EBR responsivity to bromocriptine. Given that EBR is hypothesized to be particularly sensitive to DRD2 function, these findings suggest caution in using EBR as a proxy for dopamine function in healthy humans.
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18 MeSH Terms
Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors.
Claassen DO, Stark AJ, Spears CA, Petersen KJ, van Wouwe NC, Kessler RM, Zald DH, Donahue MJ
(2017) Mov Disord 32: 1574-1583
MeSH Terms: Aged, Animals, Cerebral Cortex, Cerebrovascular Circulation, Dopamine Agonists, Female, Humans, Impulsive Behavior, Magnetic Resonance Imaging, Male, Middle Aged, Parkinson Disease, Periaqueductal Gray, Severity of Illness Index, Spin Labels, Ventral Striatum
Show Abstract · Added March 21, 2018
BACKGROUND - PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation.
OBJECTIVES - We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors.
METHODS - Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity.
RESULTS - Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions.
CONCLUSIONS - These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.
© 2017 International Parkinson and Movement Disorder Society.
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2 Members
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16 MeSH Terms
Impulse Control Disorders and Related Complications of Parkinson's Disease Therapy.
Lopez AM, Weintraub D, Claassen DO
(2017) Semin Neurol 37: 186-192
MeSH Terms: Disruptive, Impulse Control, and Conduct Disorders, Dopamine, Dopamine Agonists, Humans, Impulsive Behavior, Parkinson Disease
Show Abstract · Added April 10, 2018
Impulsive and compulsive behaviors in Parkinson's disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic system accounts for this behavioral phenotype. The clinical presentation is commonly termed (ICD): Behaviors include hypersexuality, compulsive eating, shopping, pathological gambling, and compulsive hobby participation. However, not all PD individuals taking dopamine agonists develop these behavioral changes. In this review, the authors focus on the similarities between the phenotypic presentation of ICDs with that of other reward-based behavioral disorders, including binge eating disorder, pathological gambling, and substance use disorders. With this comparison, we emphasize that the transition from an impulsive to compulsive behavior likely follows a ventral to dorsal striatal pattern, where an altered dopaminergic reward system underlies the emergence of these problematic behaviors. The authors discuss the neurobiological similarities between these latter disorders and ICDs, emphasizing similar pathophysiological processes and discussing treatment options that have potential for translation to PD patients.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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6 MeSH Terms
Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers.
Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, Engers DW, Rodriguez AL, Loch MT, Daniels JS, Lindsley CW, Hopkins CR, Javitch JA, Conn PJ
(2016) ACS Chem Neurosci 7: 1201-11
MeSH Terms: Allosteric Regulation, Animals, Antiparkinson Agents, Antipsychotic Agents, Apomorphine, Brain, Catalepsy, Disease Models, Animal, Dopamine Agonists, Forelimb, Glutamic Acid, HEK293 Cells, Haloperidol, Humans, Oxidopamine, Parkinson Disease, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Transfection
Show Abstract · Added March 3, 2020
Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson's disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are coexpressed, whereas other compounds potentiate mGlu4 responses regardless of mGlu2 coexpression. We report here the discovery and characterization of VU0418506, a novel mGlu4 PAM with activity in rodent PD models. Using pharmacological approaches and Complemented Donor-Acceptor resonance energy transfer (CODA-RET) technology, we find that VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized, suggesting that the antiparkinsonian action of mGlu4 PAMs can be induced by compounds without activity at mGlu2/4 heteromers.
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1 Members
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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.
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22 MeSH Terms
Circadian perinatal photoperiod has enduring effects on retinal dopamine and visual function.
Jackson CR, Capozzi M, Dai H, McMahon DG
(2014) J Neurosci 34: 4627-33
MeSH Terms: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, Animals, Animals, Newborn, Benzamides, Circadian Rhythm, Contrast Sensitivity, Dopamine, Dopamine Agonists, Embryo, Mammalian, Female, Gene Expression, Light, Male, Mice, Mice, Inbred C57BL, Nystagmus, Optokinetic, Photoperiod, Piperazines, Pregnancy, Retina, Time Factors
Show Abstract · Added March 18, 2020
Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.
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MeSH Terms
Intrarenal dopaminergic system regulates renin expression.
Zhang MZ, Yao B, Fang X, Wang S, Smith JP, Harris RC
(2009) Hypertension 53: 564-70
MeSH Terms: Animals, Catechol O-Methyltransferase, Cyclooxygenase 2, Dopamine, Dopamine Agonists, Female, Fenoldopam, Kidney Tubules, Distal, Kidney Tubules, Proximal, Male, Mice, Mice, Knockout, Rats, Receptors, Dopamine D1, Renin, Renin-Angiotensin System, Sodium Chloride
Show Abstract · Added December 10, 2013
Dopamine is a major regulator of proximal tubule salt reabsorption and is a modulator of renin release. Dopamine has been reported to stimulate renin release in vitro through activation of D1-like receptors. However, previous studies investigating dopamine regulation of renin release in vivo have provided contradictory results, indicating stimulation, inhibition, or no effect. We have reported previously that macula densa cyclooxygenase-2 (COX-2) is suppressed by dopamine. Because macula densa COX-2 stimulates renal renin expression, our current studies investigated dopamine regulation of renal renin release and synthesis in vivo. Acute treatment with a D1-like receptor agonist, fenoldopam, significantly inhibited renin release, as did acute inhibition of proximal tubule salt reabsorption with acetazolamide. In catechol-O-methyl transferase knockout (COMT(-/-)) mice, which have increased kidney dopamine levels because of deletion of the major intrarenal dopamine metabolizing enzyme, there was attenuation in response to a low-salt diet of the increases of renal cortical COX-2 and renin expression and renin release. A high-salt diet led to significant decreases in renal renin expression but much less significant decreases in COMT(-/-) mice than wild type mice, resulting in higher renal renin expression in COMT(-/-) mice. In high salt-treated wild-type mice or COX-2 knockout mice on a normal salt diet, fenoldopam stimulated renal renin expression. These results suggest that dopamine predominantly inhibits renal renin expression and release by inhibiting macula densa COX-2, but suppression of renal cortical COX-2 activity reveals a contrasting effect of dopamine to stimulate renal renin expression through activation of D1-like receptors.
1 Communities
2 Members
1 Resources
17 MeSH Terms