Acute effect of the anti-addiction drug bupropion on extracellular dopamine
concentrations in the human striatum: An [11C]raclopride PET study
Alice Egertona,b,c,⁎, John P. Shotbolta,b,d, Paul R.A. Stokesa,b, Ella Hiranie, Rabia Ahmade, Julia M. Lappina,b,c,
Suzanne J. Reevesa,b,c, Mitul A. Mehtaa,b,c, Oliver D. Howesa,b,c, Paul M. Grasbya,b
aPsychiatric Imaging, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
bDivision of Neurosciences and Mental Health, Imperial College London, UK
cInstitute of Psychiatry, King's College London, London SE5 8AF, UK
dGlaxoSmithKline Clinical Imaging Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
eMDX Research, GE Healthcare, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
a b s t r a c ta r t i c l e i n f o
Received 17 October 2009
Revised 25 November 2009
Accepted 26 November 2009
Available online 5 December 2009
Imaging positron emission tomography
Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation.
Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown
whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of
bupropion on extracellular dopamine levels in the striatum were investigated using [11C]raclopride positron
emission tomography (PET) imaging in rats administered saline, 11 or 25 mg/kg bupropion i.p. and in
healthy human volunteers administered either placebo or 150 mg bupropion (Zyban® Sustained-Release). A
cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly
decreased [11C]raclopride specific binding in the striatum, consistent with increases in extracellular
dopamine concentrations. In man, no significant decreases in striatal [11C]raclopride specific binding were
observed. Levels of dopamine transporter occupancy in the rat at 11 and 25 mg/kg bupropion i.p. were
higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of
dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular
dopamine levels. These findings have important implications for understanding the mechanism of action
underlying bupropions' therapeutic efficacy and for the development of novel treatments for addiction and
© 2009 Elsevier Inc. All rights reserved.
Bupropion is an effective medication in smoking cessation and has
a good safety and side effect profile (Aubin, 2002; Hurt et al., 1997;
Jorenbyet al.,1999). In addition to its original indication for treatment
of depressive disorders, bupropion may also be effective in the
treatment of methamphetamine addiction and pathological gambling
(Dannon et al., 2005; Elkashef et al., 2008). Elucidation of the
pharmacological features of bupropion which most contribute to its
clinical efficacy may aid development of novel treatments for smoking
cessation and other disorders of addiction.
The precise pharmacological mechanisms that underlie the
therapeutic effects of bupropion are unclear (Dwoskin et al., 2006;
Paterson, 2009; Warner and Shoaib, 2005). Bupropion weakly inhibits
monoamine reuptake to presynaptic terminals through dopamine
transporters (DAT), and, to a lesser extent, noradrenaline transporters
(Ascher et al., 1995; Damaj et al., 2004; Ferris and Beaman, 1983). Via
interaction with vesicular monoamine transporter-2, bupropion
increases sequestration of cytoplasmic dopamine to vesicles (Rau
et al., 2005). At similar concentrations to those which inhibit
monoamine transporter function, bupropion also acts as a noncom-
1999; Miller et al., 2002; Slemmer et al., 2000).
In rats, microdialysis studies show that acute, systemic, bupropion
administration reproducibly and dose-dependently increases striatal
extracellular dopamine levels (Bredeloux et al., 2007; Brown et al.,
1991; Gazzara and Andersen, 1997; Li et al., 2002; Nomikos et al.,
1989; Sidhpura et al., 2007). It has been suggested that increases in
striatal dopamine concentrations following bupropion administration
may help combat the anhedonia associated with withdrawal from
nicotine (or other addictive drugs) and anhedonia in depression
(Paterson et al., 2007; Paterson, 2009; Warner and Shoaib, 2005;
Shiffman et al., 2000). However, what is unclear is whether
therapeutic doses of bupropion are sufficient to increase extracellular
dopamine levels in the human striatum.
NeuroImage 50 (2010) 260–266
⁎ Corresponding author. Neuroimaging P067, Department of Psychological Medicine
and Psychiatry, Institute of Psychiatry, King's College London, SE5 8AF, UK. Fax: +44
207 848 0976.
E-mail address: Alice.Egerton@iop.kcl.ac.uk (A. Egerton).
1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/ynimg
imaging with dopamine transporter radioligands to estimate the
degree of DAT occupancy which occurs following repeated bupropion
et al., 2003; Meyer et al., 2002) or acute administration of the
bupropion active metabolite hydroxybupupropion (Volkow et al.,
2005). Overall, these studies indicate that, in man, only a small
proportion – at most, 20–25% – of striatal DAT sites are occupied at
clinical doses of bupropion. This observation has led to proposals that
DAT inhibition alone does not explain the therapeutic efficacy of
bupropion (Meyer et al., 2002; Kugaya et al., 2003; Paterson, 2009;
Warner and Shoaib, 2005).
A more direct approach is to investigate the effects of bupropion
administration on extracellular dopamine concentrations in the
human striatum. Using positron emission tomography (PET) in
combination with the D2/3 dopamine receptor radiotracer [11C]
raclopride, it is possible to index changes in extracellular dopamine
levels in both man and experimental animals, as [11C]raclopride
competes with dopamine for D2/3 receptor binding (Laruelle, 2000).
As bupropion has negligible affinity at D2/3 dopamine receptors and
therefore will not compete with [11C]raclopride directly (Ferris and
Beaman, 1983), this noninvasive imaging approach is viable for
assessing bupropion-induced changes in extracellular dopamine
concentrations in man.
As the relationship between microdialysis and [11C]raclopride PET
measures of extracellular DA is complex (Laruelle, 2000), we
performed an initial [11C]raclopride PET study in rats to confirm
whether bupropion-induced increases in dopamine concentrations
are detectable using [11C]raclopride PET. Following positive confir-
mation, this approach was translated to man in order to determine
whether the dose of bupropion used in the UK to aid smoking
cessation (150 mg Zyban®Sustained-Release) increases extracellular
dopamine concentrations in the human striatum.
We investigated the effects of bupropion on striatal dopamine
levels while volunteers completed a spatial planning task, previously
shown to decrease striatal [11C]raclopride binding potential in healthy
volunteers (Lappin et al., 2009), as increases in extracellular
dopamine concentrations following dopamine reuptake inhibition
are most apparent when dopamine release is stimulated (Volkow
et al., 2002). This approach was also selected as stimulation of
dopamine release via administration of a behavioral task in combi-
nation with dopamine reuptake inhibition by bupropion would
additionally provide a relatively safe method of probing striatal
dopaminergic function in clinical populations in future studies.
Initial animal study
Doses of 11 and 25 mg/kg bupropion i.p. were selected for the
initial study in rats. Microdialysis studies have previously shown
increases in extracellular dopamine levels in the rat within this dose
range (Bredeloux et al., 2007; Brown et al., 1991; Li et al., 2002;
Nomikos et al., 1989; Sidhpura et al., 2007) and the 11 mg/kg dose is
equivalent to the 150 mg human dose as calculated using dose-scaling
factors (Mordenti and Chappell, 1989).
All animal experiments were carried out in accordance with the
UK Animals (Scientific Procedures) Act, 1986 and associated guide-
lines. Under isoflurane anesthesia, 14 adult male Sprague–Dawley
rats (Harlan Olac, UK) (body weight: mean±S.D.=315±46 g)
were administered either vehicle (0.9% saline, n=5), 11 mg/kg
bupropion (Sigma, UK) (n=3) or 25 mg/kg bupropion (n=6) i.p.
30 min prior to [11C]raclopride injection. Rats were positioned in a
stereotaxic frame and PET data were acquired using a quad-HIDAC
(high-density avalanche chamber) small animal tomograph (Oxford
Positron Systems). [11C]Raclopride was administered via a previously
catheterized lateral tail vein. The mean±SD injectate was 0.311±
0.23 nmol/kg. Emission data were acquired in list mode for 60 min.
Toreconstructscansinograms,list modeemissiondata werebinned
into 0.5 mm isotropic voxels using filtered back-projection (Hamming
filter, 0.6 cutoff), resulting in a spatial resolution of ∼0.5 mm full width
at half-maximum (FWHM) (Myers and Hume, 2002). Image volumes
were then transferred into ANALYZE (www.analyzedirect.com) (Robb
al., 2001), data were sampled from the dorsal striatum (2×140 voxels)
the specific binding ratio (SBR: the ratio of specifically bound
radiotracer (striatum) to free and nonspecifically bound radiotracer
min after [11C]raclopride injection, in order to improve count statistics
(Hume et al., 2001). Previous studies have shown that [11C]raclopride
to 60 min after [11C]raclopride injection (Hume et al., 1996) and ratio
data acquired in the 20- to 60-min time frame correlates well with
individual binding potential measurements derived from time–activity
curves (Houston et al., 2004).
We estimated DAT occupancy under the same experimental
conditions as used above: anaesthetized rats were administered
vehicle (0.9% saline), 11 mg/kg bupropion or 25 mg/kg
bupropion i.p. Thirty minutes later, ∼10 μCi [3H]cocaine (Perkin
Elmer Life Sciences, UK) was administered i.v., and rats were
euthanized 20 min following [3H]cocaine administration. The striata
and cerebellum were dissected out, solubilized (Soluene®-350, Perki-
nElmer, UK), and counted for3H using a LKB scintillation counter with
automatic quench factor (Beckman, UK). Counts were normalized
against standards, and data were calculated as percent injected activity
per gram of tissue, normalized for body weight, giving ‘uptake units.’
The cerebellum, which contains a very low level of dopamine
transporters (Panagopoulos et al., 1991), was used to represent free
and nonspecifically bound [3H]cocaine. Data are expressed as the
striatal:cerebellar SBR. Percentage occupancy of dopamine transporter
sites following bupropion administration was calculated as:
Ten healthy participants were recruited by public advertisement
(80% male; 90% right handed; average age: 47±6.7 years; age range
37–58 years). Nine of the 10 subjects were nonsmokers; the single
participant who smoked consumed ∼10 cigarettes/day. None of the
participants were currently taking any prescribed medication. All
participantsgave theirwritten, informedconsent tobe included in the
study. Exclusion criteria were pregnancy, any contraindication to PET
imaging, current or previous neurological, psychiatric or medical
illness including head injury, and alcohol or other recreational drug
use or dependency according to DSM-IV criteria. The absence of illicit
drugs was confirmed by a urine drugs screen. The study was approved
by Hammersmith and Queen Charlotte's and Chelsea Research Ethics
Committee, London, UK and the Administration of Radioactive
Substances Advisory Committee.
Each participant underwent three [11C]raclopride PET scans,
performed on separate days and administered in a predetermined
randomized order. The scan conditions were as follows: (A) Baseline:
subjects were administered placebo and the data were acquired at
A. Egerton et al. / NeuroImage 50 (2010) 260–266
rest; (B) Placebo_Task: subjects were administered placebo and data
were acquired as subjects performed a spatial planning task; (C)
Bupropion_Task: subjects were administered bupropion and data
were acquired as subjects performed a spatial planning task.
Bupropion hydrochloride (150 mg Zyban® Sustained Release Tablets,
GlaxoSmithKine) and placebo tablets were administered 2.5 h prior to
[11C]raclopride injection, in order that PET data acquisition coincided
with peak bupropion plasma levels (Hsyu et al., 1997). All tablets
were consumed in the presence of one of the investigators. The
participants, but not the study investigators, were blind to the
contents of the tablet. Although blood samples were taken mid-way
through the scan to assay plasma bupropion levels, these data are not
available for technical reasons. The spatial planning task was an
adapted one-touch Tower of London task (Owen, 1997) presented on
a computer touch-screen during the scan, as previously described
(Lappin et al., 2009).
PET image acquisition
Data were acquired on an ECAT HR+ 962 scanner (CTI/Siemens)
in three-dimensional mode, with an axial field of view of 15.5 cm.
Head movement was monitored and minimized using a light head-
strap. A 10-minute transmission scan was performed prior to
radiotracer injection to correct for attenuation and scatter. The spatial
planning task commenced 5 min before radiotracer injection. [11C]
raclopride was administered as a bolus injection followed by constant
rate infusion with a Kbolof 85 min (Stokes et al., 2009). The total
administered activity was 10.72±0.36 mCi (396.8±13.3 MBq) per
scan, with an associated stable content of 2.175±1.355 μg.
Head movement was corrected using frame-by-frame (FBF)
realignment. Nonattenuation corrected images were used to optimize
the FBF realignment process (Dagher et al., 1998). The nonattenuation
corrected images were denoised using a level 2, order 64 Battle
Lemariewaveletfilter(Turkheimer et al.,1999). A mutualinformation
algorithm (Studholme et al., 1996) was applied for frame realignment
to a single frame acquired 40 min post-injection, in which there was a
high signal-to-noise ratio. Transformation parameters were applied to
the corresponding attenuation-corrected dynamic images to generate
a movement-corrected dynamic image.
atlas (Hammers et al., 2003) in Montreal Neurologic Institute (MNI)
functional subdivisions (Martinez et al., 2003). An [11C]raclopride
template (Meyer et al., 1999) was spatially transformed into the
individual PET space of each FBF-corrected dynamic image within
SPM5 (Wellcome Department of Cognitive Neurology, London; www.
fil.ion.ucl.ac.uk/spm), and the resulting transformation parameters
were then used to transform the ROI map into individual PET space.
A weighted average add image for the 40–85 min steady-state
time period was generated from each FBF-corrected dynamic image
using in house software, written in Matlab (version 5; The Math-
Works,Inc, Natick,MA).The transformed ROI mapwas usedto sample
counts from the steady-state add image using ANALYZE software.
Binding potential (BPND), the ratio at equilibrium of specifically bound
radioligand to that of nondisplaceable radioligand in tissue (Innis
et al., 2007), was calculated as the ratio of total radioactivity counts in
the striatal subdivisions compared to the cerebellum, minus 1, during
the 40- to 85-min steady-state sampling period.
In the rat study, the effects of 11 and 25 mg/kg bupropion on
striatal [11C]raclopride SBR and striatal DAT occupancy were deter-
mined using two-tailed independent sample t-tests. For the human
study, differences in the amount and specific activity of injected [11C]
raclopride across conditions were explored using analysis of variance.
[11C]raclopride BPND values in the associative, sensorimotor and
limbic subdivisions were compared across the three scan conditions
using repeated measures analysis of variance (ANOVA), with scan
condition and side (left or right) as within-subjects factors. Potential
effects of scan order on [11C]raclopride BPNDwere explored using the
same approach. Body surface area (BSA) was calculated for each
participant using the formula BSA=(W0.425×H0.725)×0.007184,
where W is weight in kilograms and H is height in centimeters
(DuBois and DuBois, 1916). Relationships between BSA and percent-
age change in [11C]raclopride BPNDin the bupropion_task compared
to placebo_task condition were explored using Pearson's correlation
coefficient. All statistical analysis was performed in SPSS 16.0
(Chicago, IL), and the threshold for statistical significance was set at
an alpha level of 0.05. All data are reported as mean±standard
Initial rat study
Fig. 1 illustrates the images that were obtained in control and
bupropion-treated rats using the quad-HIDAC tomograph system. In
Fig. 1, the reduction in [11C]raclopride SBR following the higher dose
of 25 mg/kg bupropion compared to control values is clearly visible.
Individual SBR values obtained in the striatum of control, 11 mg/kg
bupropion and 25 mg/kg bupropion-treated animals are presented
kg bupropion significantly reduced [11C]raclopride SBR (11 mg/kg t(6)
=3.203; p=0.019; 25 mg/kg bupropion t(6.58)= 9.157; pb0.001).
These decreases in SBR were to the magnitude of 6± 3% following
11 mg/kg bupropion and 23±7% following 25 mg/kg bupropion.
Table 1 also presents the [3H]cocaine dopamine transporter
occupancy data that were obtained at doses of 11 and 25 mg/kg
bupropion in the rat. 25 mg/kg bupropion produced significant
occupancy of the dopamine transporter (t4=5.984; p=0.004)
and there was a trend for the same effect at the lower dose of
11 mg/kg (t4=2.678; p=0.055). These values corresponded to
35±18% dopamine transporter occupancy with 11 mg/kg bupropion
and 60± 11% dopamine transporter occupancy with 25 mg/kg
Spatial planning accuracy offline (mean±S.D.=74.4±22.7%;
range=50–100%) and in the scanner following placebo administra-
tion (mean±S.D.=77.3±19.6%; range=43.8–96.3%) were correlat-
ed (r=0.745; p=0.013). Planning accuracy in the scanner following
bupropion administration (mean±S.D.=76.3±15.2%; range=50–
91.3%) and placebo administration also correlated (r=0.879;
p=0.001). Bupropion did not significantly affect planning accuracy
in the scanner (t(9)=0.329; p=0.750). No significant correlations
were apparent between planning accuracy and age.
There was no significant difference in either the amount of [11C]
raclopride radioactivity injected (pN0.36) or associated stable content
(pN0.21) across the three scan conditions. Similarly, scan order did
not influence BPNDin any of the striatal subdivisions (sensorimotor:
F2=1.167; p=0.334; associative: F2=0.326; p=0.726; limbic:
F2=0.801; p=0.464). As there were no significant associations
between age and BPNDin the whole striatum or any of the striatal sub-
regions, age was not used as a covariate in subsequent analysis.
Planning accuracy did not correlate with [11C]raclopride BPNDin any
of the striatal subdivisions under either the Placebo_Task or
A. Egerton et al. / NeuroImage 50 (2010) 260–266
The BPNDvalues that were obtained in each of the three scan
conditions are presented in Table 2. In the associative striatum, there
was a significant overall effect of scan condition (F2=4.021; p=
0.036) and side (F1=44.895; pb0.001) on [11C]raclopride BPNDbut
no significant condition by side interaction (F2=1.031; p=0.297).
Post hoc analysis revealed a significant (4.4±5%) increase in [11C]
raclopride BPNDin the associative striatum in the Bupropion_Task
compared to Placebo_Task condition (F2=4.021; p=0.036), but this
did not survive correction for multiple comparisons (p=0.081).
Individual BPNDvalues in the associative striatum in the Placebo_Task
andBupropion_Task conditionsare presentedin Fig. 2. Changein [11C]
raclopride BPNDin the associative striatum in the Bupropion_Task
compared to Placebo_Task condition was not significantly correlated
with BSA (r=0.462; p=0.179). There was no significant difference in
[11C]raclopride BPND in the associative striatum in the Baseline
compared to Placebo_Task conditions (F1=1.279; p=0.287).
No significant effects of scan condition on [11C]raclopride BPND
were apparent in the sensorimotor (F2=2.919; p=0.080) or limbic
(F1=0.213; p=0.810) striatal subdivisions. As in the associative
striatum, therewere significant effects of side (left or right) onBPNDin
the sensorimotor (F1=48.074; pb0.001) and limbic subdivisions
(F1=15.36; p=0.004) but no significant condition by side inter-
actions were detected.
Using [11C]raclopride PET, we sought to determine whether
bupropion administration increases extracellular dopamine levels in
the rat and human striatum. In rats, bupropion administration
decreased striatal [11C]raclopride specific binding, consistent with
increases in extracellular dopamine concentrations resulting from
inhibition of dopamine reuptake. However, when this approach was
translated to man, bupropion administration did not decrease striatal
[11C]raclopride BPND, indicating that extracellular dopamine levels
were not increased to levels detectable using this approach. These
results indicate that, in man, bupropion's therapeutic efficacy is
unlikely to principally derive from marked increases in striatal
The decreases in [11C]raclopride SBR which we report in
anaesthetized rats are accordant with the increases in extracellular
dopamine concentrations that are detected using microdialysis
following administration of similar doses of bupropion in awake
animals (Brown et al., 1991; Li et al., 2002; Nomikos et al., 1989;
Sidhpura et al., 2007). While the relationship between dopamine
release and change in [11C]raclopride binding potential varies
according to the pharmacological nature of the challenge stimulus
(Schiffer et al., 2006; Tsukada et al., 1999), previous studies
Striatal [11C]raclopride SBR and [3H]cocaine SBR in control rats and following administration of 11 or 25 mg/kg bupropion i.p. All data were acquired in anaesthetized animals. [11C]
raclopride SBR was determined from summed PET data acquired 20–60 min following [11C]raclopride administration. [3H]cocaine SBR was determined from ex vivo dissection data
collected 20 min following [3H]cocaine administration. Bupropion produced significant (pb0.05) increases in extracellular dopamine concentrations, as indexed by change (Δ) in
[11C]raclopride SBR compared to control values, and significant occupancy of dopamine transporter sites as indexed by difference in [3H]cocaine SBR compared to control values.
[11C]raclopride SBR (mean±S.D.)
11 mg/kg bupropion
25 mg/kg bupropion
[3H]cocaine SBR (mean±S.D.)
11 mg/kg bupropion
25 mg/kg bupropion
Fig. 1. Mean [11C]raclopride coronal SBR images obtained in rats treated with saline (control), 11 or 25 mg/kg bupropion. The images represent addimages of data collected 20–60
min after [11C]raclopride injection. Distances from bregma (mm) are indicated along the top of the figure.
A. Egerton et al. / NeuroImage 50 (2010) 260–266
combining microdialysis and [11C]raclopride PET in animals following
administration of the dopamine transporter inhibitor methylpheni-
date, estimate that a 1% change in [11C]raclopride BP relates to a 17%
change in dopamine concentration as measured using microdialysis
(Schiffer et al., 2006). Applying this relationship to the current data,
the 6% and 22% change in SBR observed at 11 mg/kg and 25 mg/kg
bupropion respectively, would translate to a 102% and 374% change in
dopamine concentration as measured using microdialysis. These
values are in the range of the percentage increases in striatal
dopamine concentrations that have been reported using microdialysis
in rats afteradministrationof bupropion at similardoses (Brownetal.,
1991; Li et al., 2002; Nomikos et al., 1989; Sidhpura et al., 2007) and
therefore validate the use of [11C]raclopride PET imaging to measure
changes in striatal dopamine concentrations following bupropion
In the human study, we did not observe any significant decreases
in [11C]raclopride BPNDin the striatum following bupropion admin-
istration, despite the presence of a behavioral task applied to
stimulate dopamine release and therefore maximize the influence of
dopamine reuptake inhibition. We therefore conclude that bupropion
administration does not markedly increase striatal extracellular
dopamine concentrations. Indeed to the contrary, in the associative
striatum we detected a small increase in [11C]raclopride BPND,
consistent with decreases in extracellular dopamine concentrations,
although this did not survive correction for multiple comparisons.
In rats, decreases in [11C]raclopride BPND occurred at 11 and
25 mg/kg bupropion i.p. The 11 mg/kg bupropion dose is equivalent
to the human dose of 150 mg as simply estimated using dose-scaling
factors (Mordenti and Chappell, 1989). However, the extensive
metabolism of bupropion to the active metabolites hydroxybupropion
and threohydrobupropion in man (Schroeder, 1983), occurs to a far
lesser extent in rats (Suckow et al., 1986). We did not compare the
plasma concentrations of bupropion and its metabolites that were
achieved in the rat and human subjects, although, as brain
concentrations of bupropion may be some order of magnitude higher
than those measured in plasma (Schroeder, 1983; Suckow et al.,
1986), interpretation would be limited. A better indication of dose
equivalence is provided by comparing the degree of striatal DAT
occupancy resulting from bupropion administration in rats and man.
Here, the lowest (11 mg/kg) dose of bupropion investigated in the rat
was estimated to occupy at least 35% of DAT sites; in contrast,
previous data show the levels of DAT occupancy achieved in man
following chronic bupropion dosing are, at most, ∼20–25% (Argyelán
et al., 2005; Kugaya et al., 2003; Learned-Coughlin et al., 2003; Meyer
et al., 2002). This suggests that higher levels of DAT occupancy were
achieved in the rat than the human study, which might explain why
significant decreases in [11C]raclopride BPND following bupropion
were observed in rats, but not in man.
In the animal literature, the central effects of bupropion are often
investigated using doses of 10 mg/kg or more. The results of the
present study and those previously examining DAT occupancy
following bupropion administration in man (Argyelán et al., 2005;
Kugaya et al., 2003; Learned-Coughlin et al., 2003; Meyer et al., 2002),
suggest that investigation of the effects of bupropion within a lower
dose range would be of increased relevance to human, clinical
The human study was powered (0.8) to reliably detect a 5% change
in [11C]raclopride BPND between scan conditions, based on both
previous published data (Mawlawi et al., 2001), and unpublished data
acquired in-house on the same scanner. It is unlikely that lack of
power precluded observation of decreases in [11C]raclopride BPND, as
in both the associative and sensorimotor striatal divisions [11C]
raclopride BPNDwas actually increased rather than decreased in 8 of
10 volunteers in the Bupropion_Task compared to Placebo_Task
condition. Although we scanned volunteers 2.5 h after bupropion
administration to coincide with peak bupropion plasma concentra-
tions, bupropion metabolite concentrations peak approximately 6 h
followingbupropion administration (Hsyu et al., 1997). This raises the
possibility that scanning at a later time point, when dopamine
transporter occupancy may have been higher, may have revealed
differential effects on [11C]raclopride BPND. It is also possible that
repeated administration of bupropion is required to increase striatal
dopamine concentrations in man; this hypothesis could be tested
using a similar [11C]raclopride PET approach to the present study.
However, the low levels of dopamine transporter occupancy observed
in man following repeated bupropion administration (Argyelán et al.,
2005; Kugaya et al., 2003; Learned-Coughlin et al., 2003; Meyer et al.,
2002) suggest that this is unlikely.
In contrast to our previous study (Lappin et al., 2009), in this
sample we did not detect significant decreases in striatal [11C]
raclopride BPNDduring the spatial planning task. Differences between
the two studies may explain this. In particular the current but not
alter dopamine levels, may have masked an effect (Yoder et al., 2008).
Furthermore spatial planning accuracy was poorer and more variable
in the current sample both offline (74±23% versus 90±10%) and
within the scanner (77±20% versus 90±4%), although the age range
of subjects in the two studies was similar (mean 47±7 years, range
37–58 years in the present study, mean 53±9 years, range 39–68
Fig. 2. Individual [11C]raclopride BPNDin the associative striatum in the Placebo_Task
and Bupropion_Task conditions. Bupropion administration significantly increased BPND
[11C]raclopride BPNDvalues (mean±S.D.) in the functional subdivisions of the human striatum under each scan condition. AST: associative striatum; SMS: sensorimotor striatum;
LS: limbic striatum. Effect of condition denotes overall effect of scan condition (Baseline, Placebo_Task or Bupropion_Task) in repeated measures ANOVA, Effect of side denotes
overall effect of side (left or right) in repeated measures ANOVA. ⁎pb0.05.
Baseline Placebo_TaskBupropion_Task Effect of conditionEffect of side
A. Egerton et al. / NeuroImage 50 (2010) 260–266
years in Lappin et al., 2009). This suggests that ability to observe
dopamine release during behavioral tasks using [11C]raclopride PET
may be particularly sensitive to the precise experimental conditions.
We conclude that application of this task, with or without concurrent
dopamine reuptake inhibition, does not provide a robust approach to
probing striatal dopamine function in man.
In conclusion, as acute administration of bupropion administration
did not result in detectable increases in extracellular dopamine
concentrations in the human striatum, this study does not support the
involvement of striatal dopamine in the clinical efficacy of bupropion.
Disclosure/Conflicts of Interest
This study was performed in collaboration with GlaxoSmithKline UK.
We would like to thank all the volunteers who participated in this
study and the radiographers and radiochemists at GE Healthcare,
Cyclotron Unit, Hammersmith Hospital who made this study possible.
This study was funded by the Medical Research Council and
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