Human Imaging Studies-- Positron Emission Tomography
August 18, 2015 at 03:13 AM | categories: mri
Contents
1 Positron Emission Tomography Studies
The positron emission tomography (PET) imaging method has been very popular for studying the effects of methylphenidate (MPH) in the human brain, examining the amount of drug in the brain, its distribution, its binding to the dopamine transporter (DAT) and different dopamine (DA) receptors using various radioactive ligands, depending on the study. PET imaging limits the collection of data between 30 s and 60 s intervals, far slower than the rapid millisecond time-course of nerve-impulse-associated release of DA. Therefore, the PET image reflects the time-averaged result of the competition between endogenous DA and the [11C]ligand [4]. Thus, the PET data represent the average net effect of elevated extracellular DA arising from an increase in the resting level of DA as well as in the pulsatile release of DA.
Surprisingly, it is still debated whether DA activity is enhanced or depressed in individuals with attention-deficit/hyperactivity disorder (ADHD). Many of biological theories of ADHD suggest that the disorder is associated with abnormally high levels of DAT density, prompted by studies evaluating small samples of ADHD adults [2, 3]. These studies suggested the hypothesis that high DAT density would accelerate reuptake of synaptic DA and create a DA deficit. In one of the largest studies so far, Spencer [5] evaluated unmedicated ADHD adults and reported striatal binding potential was 2 SD above the mean for the control group, indicating high endogenous expression of DAT.
Some studies, however, suggest the reverse. In a series of PET studies using the radioligands [11C]raclopride and [11C]cocaine, Volkow et al. [12] assessed the density of DAT and DA D2/D3 receptors in the striatum of stimulant-naïve adults with ADHD. Individual differences in MPH-induced increases in synaptic DA were not related to individual differences in DAT density [11], suggesting that variability in DA release rather than the DA reuptake may be a primary factor contributing to a DA deficit in the ADHD brain and the manifestations of deficits in attention. Volkow et al. [13] found lower DAT and D2/D3 receptor density in the nucleus accumbens (NAcc) as well as the caudate nucleus. In a long-term treatment study of MPH [14], DAT density was assessed in a set of ADHD patients before and after 1 year of MPH treatment, with a 24 h washout to avoid the confusion of DAT density with DAT occupancy by MPH. A formerly decreased DAT density at study start was now increased in the same individuals, suggesting that neuroplasticity may operate in a homeostatic way to maintain DA levels in a narrow range: in response to high synaptic DA that results from blockade of DAT by clinical oral doses of MPH [9, 11], DAT density may increase and be a consequence of the DA agonist effect of MPH. This may contribute to acute tolerance [6, 8, 10, 11] and possibly long-term tolerance [1, 7] to clinical doses of stimulant medications.
Acronyms
- ADHD
- attention-deficit/hyperactivity disorder
- DAT
- dopamine transporter
- DA
- dopamine
- MPH
- methylphenidate
- NAcc
- nucleus accumbens
- PET
- positron emission tomography
References
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