Mapping dopaminergic function using pharmacologic Magnetic Resonance Imaging (phMRI) in healthy subjects and users of amphetamine

RATIONALE:
Amphetamines are regularly used for recreational purposes in the party and
clubbing circuit. However, amphetamine and some of its analogues have been
shown to be neurotoxic to dopamine (DA) and/or serotonin (5-HT) neurones in
animals. For instance, after administration of methamphetamine, animals develop
long-lasting decreases in brain DA and 5-HT axonal markers, including the
neurotransmitters themselves (i.e. DA and 5-HT), and their transporter sites
(DAT). Administration of amphetamine to animals, results in reductions in
striatal [ 18 F]fluoro-L-dopa uptake in vervet monkeys (Melega et al. 1996,
1997), and studies on rat striatal DA system have established that chronic
amphetamine exposure results in neurotoxicity characterised by decreases in
dopamine levels and DAT, swollen nerve terminals and degenerated axons. We have
previously shown that recreational use of combined amphetamine and ecstasy use
might be neurotoxic to DA neurones (Reneman 2002).
The apparent lack of studies on amphetamine*s dopaminergic potential in humans
may be related to the fact that most in vivo imaging modalities (such as PET
and SPECT) involve radiation exposure and 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 drug
challenge with for instance amphetamine or methylphenidate, called
pharmacological MRI (phMRI). There are three ways of assessing
pharmacological-induced changes in hemodynamic responses with MRI: using BOLD
(blood oxygenation-level dependent) contrast, perfusion weighted imaging (PWI)
and arterial spin labeling (ASL). However, the usefulness of these phMRI
techniques in assessing DA-neurotoxicity have not yet been assessed and
directly compared to each other. Therefore, this study will assess the
usefulness of DA-phMRI in assessing amphetamine induced DA-neurotoxicity when
compared to DAT (123I-FP-CIT) SPECT in 10 healthy male volunteers using a
methylphenidate challenge and will identify the best phMRI technique in doing
so. DAT SPECT is used as a *gold standard* in this study. 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, but may be used for other
indications as well, such as children suffering from neuropsychiatric
disorders, such as attention deficit hyperactivity disorder (ADHD).

OBJECTIVES:
-to assess the usefulness of DA-phMRI (task related fMRI, steady state fMRI and
ASL based phMRI) in assessing amphetamine induced DA-neurotoxicity when
compared to DAT SPECT.
-to assess which MRI technique (task related fMRI, steady state fMRI, or ASL
based phMRI) is best in assessing cerebral DA neurotoxicity in the amphetamines
users when compared to DAT SPECT.
SECONDARY OBJECTIVES:
- to determine the sensitivity of other MRI sequences sensitive to
DA-neurotoxicity (MR Spectroscopy and diffusion tensor imaging) when compared
to DAT SPECT.

Task related fMRI, steady state fMRI, and ASL based phMRI studies will be
conducted and compared to a DAT SPECT scan as reference (gold standard). First,
a DAT SPECT scan will be conducted. With an interval of 1-2 weeks, task related
fMRI, followed by a combined steady state fMRI-, and ASL based phMRI study will
conducted, following a low dose oral challenge with methylphenidate. Steady
state fMRI and ASL can be studied in one scan session. DTI data on DA
microprojections and MRS data will also be acquired.

No serious side effects are foreseen. MRI itself is a non-invasive imaging
modality. Task-related MRI studies are routinely conducted at the AMC without
any side effects. With respect to the administration of a single low dose of
oral methylphenidate: methyphenidate is registered in the Netherlands for
treatment of ADHD and narcolepsy in adults and children over 6 years of age
(Novartis, RVG 03957). Methylphenidate (0.5 mg/kg, approx. 35 mg) has been
administered as an oral bolus in previous MRI studies (Rao 2000, Silveri 2004),
up to 50 mg (Mehta 2000). The 0.5 mg/kg dose was well tolerated in previous
studies by the study participants. This dose causes an increase in heart rate,
and systolic blood pressure (Heil 2002, Silveri 2000). 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]FP-CIT is a registered
radioligand, which is produced routinely using GMP-criteria. In conclusion, the
nature of the burden is classified as moderate, considering that subjects will
have to come to the AMC on 3 different occasions, undergo 3 different types of
scans, involving 1 venous puncture and 2 oral administrations of
methylphenidate. The risks involved are negligible, as all the agents and
techniques employed are registered for their use and/or routinely performed at
the AMC. There is no direct potential benefit for the participants, other than
indirect benefits as the current study will hopefully be able to shed a new
light on the discussion on the presumed neurotoxic effects of amphetamine in
users of this drug