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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

RAC* binding on levodopa vs. placebo, by diagnosis.Differences in the RAC* binding response to levodopa between TS and control subjects, thresholded at uncorrectedp = 0.001, in color, laid over the MRI template image in grayscale.a,b: Significant clusters, with blue lines crossing at the peakt value in midbrain (a, three views) and in parahippocampal gyrus (b). A third statistically significant cluster was centered at the posterior edge of the occipital lobe, but both the location and the observation that in this cluster the BPND on placebo was negative in half the subjects suggests that this cluster likely does not reflect specific binding.c: Levodopa-induced change in BPND, TS vs. control, in the clusters shown in A and B. R., Right; PHG, parahippocampal gyrus. Asterisks indicate that mean BPND differs significantly from zero.d: The blue lines cross at the voxel with the highest t value in the whole-brain SPM analysis of levodopa effect ΔDVR images (t=11.62, 8 df).
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f8: RAC* binding on levodopa vs. placebo, by diagnosis.Differences in the RAC* binding response to levodopa between TS and control subjects, thresholded at uncorrectedp = 0.001, in color, laid over the MRI template image in grayscale.a,b: Significant clusters, with blue lines crossing at the peakt value in midbrain (a, three views) and in parahippocampal gyrus (b). A third statistically significant cluster was centered at the posterior edge of the occipital lobe, but both the location and the observation that in this cluster the BPND on placebo was negative in half the subjects suggests that this cluster likely does not reflect specific binding.c: Levodopa-induced change in BPND, TS vs. control, in the clusters shown in A and B. R., Right; PHG, parahippocampal gyrus. Asterisks indicate that mean BPND differs significantly from zero.d: The blue lines cross at the voxel with the highest t value in the whole-brain SPM analysis of levodopa effect ΔDVR images (t=11.62, 8 df).

Mentions: The whole-brain analysis identified a similar but statistically significant effect in two clusters, where RAC* binding decreased with levodopa in controls, consistent with increased dopamine release during the levodopa infusion, but RAC* binding increased in the TS group. The first cluster included 38 voxels in midbrain (1.0 ml, FDR correctedp=0.002), with a peakt value of 9.0 (8 df) at atlas coordinate (1.5, −21, −15) and extending laterally in approximately the right substantia nigra/ventral tegmental area (Figure 8a). A second significant cluster of 19 voxels (0.5 ml, correctedp=0.023) occurred in parahippocampal gyrus, with peakt=7.92 at (22.5, −39, −6) (Figure 8b). The mean change in BPND with levodopa in these regions is shown inFigure 8c. In both these clusters, the BPND on placebo was positive in all subjects (p < 0.001, binomial distribution), consistent with nontrivial RAC* binding. The highestt value in the whole-brain comparison, 11.62, occurred in Brodmann’s area 13, but the cluster volume was only 0.1 ml, not significant by FDR correction (Figure 8d).


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)

RAC* binding on levodopa vs. placebo, by diagnosis.Differences in the RAC* binding response to levodopa between TS and control subjects, thresholded at uncorrectedp = 0.001, in color, laid over the MRI template image in grayscale.a,b: Significant clusters, with blue lines crossing at the peakt value in midbrain (a, three views) and in parahippocampal gyrus (b). A third statistically significant cluster was centered at the posterior edge of the occipital lobe, but both the location and the observation that in this cluster the BPND on placebo was negative in half the subjects suggests that this cluster likely does not reflect specific binding.c: Levodopa-induced change in BPND, TS vs. control, in the clusters shown in A and B. R., Right; PHG, parahippocampal gyrus. Asterisks indicate that mean BPND differs significantly from zero.d: The blue lines cross at the voxel with the highest t value in the whole-brain SPM analysis of levodopa effect ΔDVR images (t=11.62, 8 df).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: RAC* binding on levodopa vs. placebo, by diagnosis.Differences in the RAC* binding response to levodopa between TS and control subjects, thresholded at uncorrectedp = 0.001, in color, laid over the MRI template image in grayscale.a,b: Significant clusters, with blue lines crossing at the peakt value in midbrain (a, three views) and in parahippocampal gyrus (b). A third statistically significant cluster was centered at the posterior edge of the occipital lobe, but both the location and the observation that in this cluster the BPND on placebo was negative in half the subjects suggests that this cluster likely does not reflect specific binding.c: Levodopa-induced change in BPND, TS vs. control, in the clusters shown in A and B. R., Right; PHG, parahippocampal gyrus. Asterisks indicate that mean BPND differs significantly from zero.d: The blue lines cross at the voxel with the highest t value in the whole-brain SPM analysis of levodopa effect ΔDVR images (t=11.62, 8 df).
Mentions: The whole-brain analysis identified a similar but statistically significant effect in two clusters, where RAC* binding decreased with levodopa in controls, consistent with increased dopamine release during the levodopa infusion, but RAC* binding increased in the TS group. The first cluster included 38 voxels in midbrain (1.0 ml, FDR correctedp=0.002), with a peakt value of 9.0 (8 df) at atlas coordinate (1.5, −21, −15) and extending laterally in approximately the right substantia nigra/ventral tegmental area (Figure 8a). A second significant cluster of 19 voxels (0.5 ml, correctedp=0.023) occurred in parahippocampal gyrus, with peakt=7.92 at (22.5, −39, −6) (Figure 8b). The mean change in BPND with levodopa in these regions is shown inFigure 8c. In both these clusters, the BPND on placebo was positive in all subjects (p < 0.001, binomial distribution), consistent with nontrivial RAC* binding. The highestt value in the whole-brain comparison, 11.62, occurred in Brodmann’s area 13, but the cluster volume was only 0.1 ml, not significant by FDR correction (Figure 8d).

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