Mapping dopaminergic function using phMRI in healthy volunteers and amphetamine users

Amphetamine (AMPH) is a drug that is used to treat disorders such as narcolepsy
and attention-deficit hyperactivity disorder (ADHD), but it is also regularly
used for recreational purposes. However, animal studies have revealed that
repeatedly administration of high doses of AMPH may be neurotoxic to the
dopaminergic (DA) neurotransmitter system. For example, repeated amphetamine
treatment in nonhuman primates damages dopaminergic nerve terminals as is
evident from decreases in DA concentration, density of the dopamine transporter
(DAT) and the vesicular monoamine transporter (VMAT-2) (Ricaurte, 2005).
Furthermore, amphetamine administration resulted in reductions in striatal
[18F]DOPA uptake in the striatum (Melega, 1996). In humans, there is evidence
that recreational and repeated use of combined d-AMPH and ecstasy use might be
neurotoxic to DA neurons (Reneman, 2002).
There is an apparent lack in studies on d-AMPH neurotoxicity in humans, which
might be related to the fact that most in vivo imaging modalities (such as PET
and SPECT) involve radioactive exposure and also are relatively expensive.
Recent work suggests that DA function can also be evaluated non-invasively
using magnetic resonance imaging (MRI) by measuring hemodynamic changes
following a d-AMPH challenge, called pharmacological MRI (phMRI).
Pharmacological-induced changes in hemodynamic responses can be assessed using
BOLD (blood oxygenation-level dependent) contrast and arterial spin labelling
(ASL). Jenkins et al. (2004) showed that MPTP-lesioned primates show a blunted
hemodynamic response to a d-AMPH challenge compared to controls. In a recent
explorative study we applied ASL-phMRI and SPECT to investigate dopaminergic
abnormalities in AMPH users. The results indicated a blunted hemodynamic
response in DAergic regions and a decrease in striatal DAT in AMPH users
compared to controls (Schouw, submitted 2012). However, no correlation was
found between the changes in the hemodynamic response and changes in DAT. Both
studies demonstrate that phMRI is a highly promising technique to assess
DAergic function, but in order to maximize its potential it is important to
investigate the underlying correlates of the changes we observe. However, it is
unclear what the neural underpinnings of this hemodynamic response are. One
possibility is that it reflects DA release from the synaptic terminal. To
investigate this possibility phMRI could be compared to other well-validated
techniques such as PET or SPECT measuring DA release.
To this end, in this study we want to assess whether phMRI and (123I-IBZM)
SPECT are both able to detect an increase in DA release as induced by AMPH
administration in 20 healthy male volunteers and 20 amphetamine users.
Ultimately, it is expected that DA phMRI will open a new horizon in the
diagnosis and treatment of individuals exposed to this drug of abuse as well as
patients suffering from neuropsychiatric disorders, such as ADHD.

- to assess whether signal loss on phMRI (BOLD or ASL) in d-AMPH users is
related to DA release and/or D2 receptor density
-to assess which MRI technique (BOLD or ASL) is best in assessing cerebral DA
neurotoxicity when compared to SPECT.

BOLD- and ASL DA-phMRI studies will be conducted and compared to a [123I]IBZM
SPECT scan as reference (gold standard). One 123I-IBZM SPECT scan session with
a d-AMPH challenge will be conducted. In addition, the BOLD and ASL DA-phMRI
studies can be studied in one scan session following an i.v. challenge with the
dopamine releaser d-AMPH. These sessions will take place with an interval of 3
weeks. The order of the SPECT and phMRI scan will be randomized to control for
order effects.

No serious side effects are foreseen. MRI itself is a non-invasive imaging
modality. In this study, a low dose amphetamine challenge (0.3 mg/kg i.v.) will
be administered during the MRI study. Furthermore, low dose amphetamine (0.3
mg/kg) is nowadays frequently
administered in PET and SPECT studies, to study amphetamine induced dopamine
release. The pharmacy of
the AMC will provuide the d-amphetamine, conform GMP annex 13 criteria. No
serious side effects of the low
dose d-ampehtamine are foreseen. It has been shown that while some subjects
experience large increases in
happiness, restlessness and energy, other subjects experience almost no
subjective effects following 0.3
mg/kg, and that the quality and intensity of the subjective responses to low
dose amphetamine were similar
during a second exposure (Abi-Dargham 2003). The radiation exposure of the
SPECT scan is classified as
category II, and routinely conducted at the AMC also in healthy human
volunteers. Moreover, [123I]IBZM is
a registated radioligand, which is produced routinely using GMP-criteria.