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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

Study overview.
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f1: Study overview.

Mentions: Each subject had 4 RAC* PET scans: two scans on each of two days at least a week apart (Figure 1). After oral carbidopa and the baseline PET scan, an infusion of levodopa or saline placebo was begun by vein at an individualized dose intended to produce a steady-state levodopa plasma concentration of 600ng/mL. After allowing 30 minutes to approach steady-state levodopa concentration, a second scan was done while the infusion continued. The order (levodopa on day 1 and placebo on day 2, or the reverse) was assigned randomly to each subject, and subjects and PET staff were blind to drug assignment during all 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)

Study overview.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Study overview.
Mentions: Each subject had 4 RAC* PET scans: two scans on each of two days at least a week apart (Figure 1). After oral carbidopa and the baseline PET scan, an infusion of levodopa or saline placebo was begun by vein at an individualized dose intended to produce a steady-state levodopa plasma concentration of 600ng/mL. After allowing 30 minutes to approach steady-state levodopa concentration, a second scan was done while the infusion continued. The order (levodopa on day 1 and placebo on day 2, or the reverse) was assigned randomly to each subject, and subjects and PET staff were blind to drug assignment during all 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