Application of Cell-Specific Isolation to the Study of Dopamine Signaling in Drosophila

Background: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. Aim: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. Methods: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. Results/outcomes: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. Conclusions/interpretations: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

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Are FXR Family Proteins Integrators of Dopamine Signaling and Glutamatergic Neurotransmission in Mental Illnesses?

Frontiers in Synaptic Neuroscience ◽

10.3389/fnsyn.2018.00022 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 7

Author(s):

Jivan Khlghatyan ◽

Jean-Martin Beaulieu

Keyword(s):

Mental Illnesses ◽

Glutamatergic Neurotransmission ◽

Dopamine Signaling

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Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder

Human Molecular Genetics ◽

10.1093/hmg/ddaa122 ◽

2020 ◽

Vol 29 (14) ◽

pp. 2408-2419

Author(s):

Cian-Ling Jhang ◽

Hom-Yi Lee ◽

Jin-Chung Chen ◽

Wenlin Liao

Keyword(s):

Movement Control ◽

Motor Dysfunction ◽

Signaling Proteins ◽

Cyclin Dependent Kinase ◽

Serine Threonine Kinase ◽

Hyperactivity Disorder ◽

Dopamine Content ◽

Therapeutic Development ◽

Dopamine Signaling ◽

Core Symptoms

Abstract Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.

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Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding

Current Biology ◽

10.1016/j.cub.2019.11.029 ◽

2020 ◽

Vol 30 (2) ◽

pp. 196-208.e8 ◽

Cited By ~ 6

Author(s):

Ryan M. Grippo ◽

Qijun Tang ◽

Qi Zhang ◽

Sean R. Chadwick ◽

Yingnan Gao ◽

...

Keyword(s):

Weight Gain ◽

Suprachiasmatic Nucleus ◽

Dopamine Signaling

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Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Molecular Psychiatry ◽

10.1038/s41380-021-01194-y ◽

2021 ◽

Author(s):

Clio Korn ◽

Thomas Akam ◽

Kristian H. R. Jensen ◽

Cristiana Vagnoni ◽

Anna Huber ◽

...

Keyword(s):

Decision Making ◽

Behavioral Flexibility ◽

Dopamine Neurons ◽

Nucleus Accumbens Core ◽

Comt Inhibition ◽

Improved Performance ◽

Dopamine Signaling ◽

Precise Relationship ◽

And Behavior ◽

Kinetics Of

AbstractDopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after action-state transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating different aspects of the kinetics of striatal and cortical dopamine, respectively.

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