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Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

Badgaiyan RD, Sinha S, Sajjad M, Wack DS - PLoS ONE (2015)

Bottom Line: Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers.During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release.By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Functional Imaging Laboratory, Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America; Neuromodulation Program, University of Minnesota Twin City Campus, Minneapolis, Minnesota, United States of America; Laboratory of Advanced Radiochemistry, University of Minnesota Twin City Campus, Minneapolis, Minnesota, United States of America.

ABSTRACT
It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand (11)C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

No MeSH data available.


Related in: MedlinePlus

The rate of ligand displacement in the caudate in the Congruent and Incongruent conditions: Pictures show the location of right and left caudate where the rate of ligand displacement in the Incongruent condition was significantly greater than the rate in the Congruent condition, suggesting release of endogenous dopamine during task performance.The stereotactic coordinates (MNI) of the maxima were: 12, 14, 4 and -12, 14, 4. The curves show changes in the rate of ligand displacement over time during performance of the task under Congruent (control) and Incongruent conditions. The upper curves show the PET count (open circles) and the model fit (solid line). The lower curves (filled circle) depict the PET count in the reference region (cerebellum). Because of the lack of dopamine receptors in the cerebellum, the lower curve represents changes in nonspecific binding. Significant change after initiation of the Incongruent condition (red line) was observed in the striatum but not in the cerebellum. The ligand concentration is shown as x10, 000 mBq.
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pone.0137326.g003: The rate of ligand displacement in the caudate in the Congruent and Incongruent conditions: Pictures show the location of right and left caudate where the rate of ligand displacement in the Incongruent condition was significantly greater than the rate in the Congruent condition, suggesting release of endogenous dopamine during task performance.The stereotactic coordinates (MNI) of the maxima were: 12, 14, 4 and -12, 14, 4. The curves show changes in the rate of ligand displacement over time during performance of the task under Congruent (control) and Incongruent conditions. The upper curves show the PET count (open circles) and the model fit (solid line). The lower curves (filled circle) depict the PET count in the reference region (cerebellum). Because of the lack of dopamine receptors in the cerebellum, the lower curve represents changes in nonspecific binding. Significant change after initiation of the Incongruent condition (red line) was observed in the striatum but not in the cerebellum. The ligand concentration is shown as x10, 000 mBq.

Mentions: As mentioned earlier, the PET data were analyzed using LE-SRRM [37] and E-SRTM [38] and values of receptor kinetic parameters were estimated separately in the Congruent and Incongruent condition. To enhance reliability, results obtained in each of the models were reconciled using the criteria developed earlier [27]. Comparison of the ligand BP measured in the Congruent and Incongruent conditions in ADHD volunteers indicated significant reduction in the body of the caudate and middle part of the putamen bilaterally (Fig 2) in the Incongruent condition. In addition, there was a significant increase in the rate of ligand displacement from receptor sites in the same areas (Figs 3 and 4). Since the ligand BP is proportionally reduced by the amount of endogenously released dopamine and the rate of ligand displacement reflects amount of dopamine released [37, 41], the observation suggests endogenous release of dopamine during task performance (Incongruent condition). In healthy control volunteers reduced BP and increased rate of ligand displacement were observed in the putamen bilaterally and only in the left caudate [27]. The ligand BP measured in the right and left putamen and in the left caudate were similar in the ADHD and healthy control group but in the right caudate it was significantly lower (p = 0.004) in ADHD volunteers (Figs 5 and 6). The mean BP was 2.17±0.55 in ADHD and 2.88±0.46 in the healthy control group. Interestingly, stereotactic coordinates of the left caudate and putamen where maximum change in the rate of ligand displacement was observed during task performance were similar in the ADHD and healthy control groups (Table 2). The ‘apparent’ rate constant for ligand transfer (min-1) from receptor to the plasma (k2a) also increased significantly in the right caudate during task performance (Incongruent condition) in the ADHD but not in healthy control group (Table 3). Further, the rate constant for ligand transfer (min-1) from free to plasma compartment (k2) was higher in ADHD as compared to that in healthy control volunteers but the difference was not significant statistically (Table 4). Thus, during task performance dopamine was released in the right caudate of only ADHD volunteers. There was no change in the phasic release in the healthy control group (Figs 5 and 6; Table 2). Additionally, k2a in the right caudate was significantly higher during task performance in the ADHD but not in healthy control group (Table 3) and there was a trend for higher k2 in all striatal regions of ADHD volunteers (Table 4).


Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

Badgaiyan RD, Sinha S, Sajjad M, Wack DS - PLoS ONE (2015)

The rate of ligand displacement in the caudate in the Congruent and Incongruent conditions: Pictures show the location of right and left caudate where the rate of ligand displacement in the Incongruent condition was significantly greater than the rate in the Congruent condition, suggesting release of endogenous dopamine during task performance.The stereotactic coordinates (MNI) of the maxima were: 12, 14, 4 and -12, 14, 4. The curves show changes in the rate of ligand displacement over time during performance of the task under Congruent (control) and Incongruent conditions. The upper curves show the PET count (open circles) and the model fit (solid line). The lower curves (filled circle) depict the PET count in the reference region (cerebellum). Because of the lack of dopamine receptors in the cerebellum, the lower curve represents changes in nonspecific binding. Significant change after initiation of the Incongruent condition (red line) was observed in the striatum but not in the cerebellum. The ligand concentration is shown as x10, 000 mBq.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589406&req=5

pone.0137326.g003: The rate of ligand displacement in the caudate in the Congruent and Incongruent conditions: Pictures show the location of right and left caudate where the rate of ligand displacement in the Incongruent condition was significantly greater than the rate in the Congruent condition, suggesting release of endogenous dopamine during task performance.The stereotactic coordinates (MNI) of the maxima were: 12, 14, 4 and -12, 14, 4. The curves show changes in the rate of ligand displacement over time during performance of the task under Congruent (control) and Incongruent conditions. The upper curves show the PET count (open circles) and the model fit (solid line). The lower curves (filled circle) depict the PET count in the reference region (cerebellum). Because of the lack of dopamine receptors in the cerebellum, the lower curve represents changes in nonspecific binding. Significant change after initiation of the Incongruent condition (red line) was observed in the striatum but not in the cerebellum. The ligand concentration is shown as x10, 000 mBq.
Mentions: As mentioned earlier, the PET data were analyzed using LE-SRRM [37] and E-SRTM [38] and values of receptor kinetic parameters were estimated separately in the Congruent and Incongruent condition. To enhance reliability, results obtained in each of the models were reconciled using the criteria developed earlier [27]. Comparison of the ligand BP measured in the Congruent and Incongruent conditions in ADHD volunteers indicated significant reduction in the body of the caudate and middle part of the putamen bilaterally (Fig 2) in the Incongruent condition. In addition, there was a significant increase in the rate of ligand displacement from receptor sites in the same areas (Figs 3 and 4). Since the ligand BP is proportionally reduced by the amount of endogenously released dopamine and the rate of ligand displacement reflects amount of dopamine released [37, 41], the observation suggests endogenous release of dopamine during task performance (Incongruent condition). In healthy control volunteers reduced BP and increased rate of ligand displacement were observed in the putamen bilaterally and only in the left caudate [27]. The ligand BP measured in the right and left putamen and in the left caudate were similar in the ADHD and healthy control group but in the right caudate it was significantly lower (p = 0.004) in ADHD volunteers (Figs 5 and 6). The mean BP was 2.17±0.55 in ADHD and 2.88±0.46 in the healthy control group. Interestingly, stereotactic coordinates of the left caudate and putamen where maximum change in the rate of ligand displacement was observed during task performance were similar in the ADHD and healthy control groups (Table 2). The ‘apparent’ rate constant for ligand transfer (min-1) from receptor to the plasma (k2a) also increased significantly in the right caudate during task performance (Incongruent condition) in the ADHD but not in healthy control group (Table 3). Further, the rate constant for ligand transfer (min-1) from free to plasma compartment (k2) was higher in ADHD as compared to that in healthy control volunteers but the difference was not significant statistically (Table 4). Thus, during task performance dopamine was released in the right caudate of only ADHD volunteers. There was no change in the phasic release in the healthy control group (Figs 5 and 6; Table 2). Additionally, k2a in the right caudate was significantly higher during task performance in the ADHD but not in healthy control group (Table 3) and there was a trend for higher k2 in all striatal regions of ADHD volunteers (Table 4).

Bottom Line: Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers.During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release.By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Functional Imaging Laboratory, Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America; Neuromodulation Program, University of Minnesota Twin City Campus, Minneapolis, Minnesota, United States of America; Laboratory of Advanced Radiochemistry, University of Minnesota Twin City Campus, Minneapolis, Minnesota, United States of America.

ABSTRACT
It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand (11)C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

No MeSH data available.


Related in: MedlinePlus