Abstract
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). Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS. 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. 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. 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.
Highlights
Dopamine (DA) release from neurons has often been conceptualized as occurring via two separable mechanisms: tonic, referring to low levels of DA in extrasynaptic spaces that may be more accessible to microdialysis, and phasic, referring to synaptic DA release at synapses following presynaptic action potentials[1]
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
Summary
Dopamine (DA) release from neurons has often been conceptualized as occurring via two separable mechanisms: tonic, referring to low levels of DA in extrasynaptic spaces that may be more accessible to microdialysis, and phasic, referring to synaptic DA release at synapses following presynaptic action potentials[1]. The radioligand [11C]raclopride (hereinafter RAC*) binds to dopamine D2-like (D2, D3 and D4) receptors loosely enough to be displaced by physiological increases of dopamine at the synapse. This property has been exploited to detect changes in synaptic DA release induced by experimental manipulations including the administration of amphetamine[9]. Amphetamine has some disadvantages in this context—primarily, that it does not really produce phasic dopamine release in the usual, temporal, sense of the word. Rather, it causes prolonged, substantial dopamine release regardless of environmental demands. A pharmacological challenge drug to test phasic dopamine release would not produce effects noticed by the subject
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