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Levodopa effects on [ (11)C]raclopride binding in the resting human brain.

Black KJ, Piccirillo ML, Koller JM, Hseih T, Wang L, Mintun MA - F1000Res (2015)

Bottom Line: Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups.However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects.We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding.

View Article: PubMed Central - PubMed

Affiliation: Departments of Psychiatry, Neurology, Radiology, and Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

ABSTRACT

Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ (11)C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS).

Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS.

Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain.

Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects.

Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.

No MeSH data available.


Related in: MedlinePlus

Automated striatal VOIs.Atlas-based VOI outlines are shown on an axial section from one subject (Cd yellow, Pu light blue, Pl white, Th red; NA does not appear on this section).
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f2: Automated striatal VOIs.Atlas-based VOI outlines are shown on an axial section from one subject (Cd yellow, Pu light blue, Pl white, Th red; NA does not appear on this section).

Mentions: Nine subcortical volumes of interest (VOIs) were defined for each subject from that subject’s MRI by a high-dimensional semi-automated method of known high test-retest reliability38 (Figure 2). These VOIs corresponded to the thalamus and the left and right putamen, caudate, nucleus accumbens, and globus pallidus. An additional VOI was created from the average (weighted by region volume) of 22 FreeSurfer-labeled gray matter regions comprising frontal cortex (11 left- and 11 right-hemisphere VOIs). This large frontal VOI produced adequate counting statistics for modest noise in the time-activity curve (Figure 3). A cerebellum VOI was traced on each subject’s MR image. All VOIs were transferred to each subject’s realigned PET images using the optimized MRI-to-PET transformation matrix computed in the alignment step. The cerebellar VOI was trimmed if needed so that no voxel in the VOI corresponded to any of the inferior-most four slices in any frame of that subject’s original PET images. Thus in each subject each VOI was identical for all four PET scans.


Levodopa effects on [ (11)C]raclopride binding in the resting human brain.

Black KJ, Piccirillo ML, Koller JM, Hseih T, Wang L, Mintun MA - F1000Res (2015)

Automated striatal VOIs.Atlas-based VOI outlines are shown on an axial section from one subject (Cd yellow, Pu light blue, Pl white, Th red; NA does not appear on this section).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4490799&req=5

f2: Automated striatal VOIs.Atlas-based VOI outlines are shown on an axial section from one subject (Cd yellow, Pu light blue, Pl white, Th red; NA does not appear on this section).
Mentions: Nine subcortical volumes of interest (VOIs) were defined for each subject from that subject’s MRI by a high-dimensional semi-automated method of known high test-retest reliability38 (Figure 2). These VOIs corresponded to the thalamus and the left and right putamen, caudate, nucleus accumbens, and globus pallidus. An additional VOI was created from the average (weighted by region volume) of 22 FreeSurfer-labeled gray matter regions comprising frontal cortex (11 left- and 11 right-hemisphere VOIs). This large frontal VOI produced adequate counting statistics for modest noise in the time-activity curve (Figure 3). A cerebellum VOI was traced on each subject’s MR image. All VOIs were transferred to each subject’s realigned PET images using the optimized MRI-to-PET transformation matrix computed in the alignment step. The cerebellar VOI was trimmed if needed so that no voxel in the VOI corresponded to any of the inferior-most four slices in any frame of that subject’s original PET images. Thus in each subject each VOI was identical for all four PET scans.

Bottom Line: Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups.However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects.We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding.

View Article: PubMed Central - PubMed

Affiliation: Departments of Psychiatry, Neurology, Radiology, and Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

ABSTRACT

Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ (11)C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS).

Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS.

Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain.

Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects.

Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.

No MeSH data available.


Related in: MedlinePlus