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

Previous studies have suggested neurotoxicity of the recreational drug ecstasy
(3,4-methylenedioxymethamphetamine, MDMA) to the serotonergic system. This is
illustrated by reductions of serotonin transporter densities (SERT) assessed
using single photon emission computed tomography (SPECT) in cortical brain
regions in male (Semple et al, 1999) and female (Reneman et al, 2001b) ecstasy
users. However, these findings are still debated because of the presumed
limited sensitivity of [123I]*-CIT SPECT imaging to measure SERT density in the
cerebral cortex (Heinz et al, 2000; Ricaurte and McCann 2001; Kish 2002).
Recent work suggests that the serotonin (5-HT) system can also be evaluated
non-invasively using magnetic resonance imaging (MRI) by measuring hemodynamic
changes following a
5-HT challenge, 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 labelling (ASL). However, the reliability of
these techniques in assessing 5-HT function have not yet been assessed and
directly compared to each other. Therefore, this study will assess the
reliability of BOLD-, PWI and ASL based phMRI by assessing cerebral 5-HT
function when compared to SERT (123I *-CIT) SPECT in 10 healthy male
volunteers, and 10 users of ecstasy in order to identify the best phMRI
technique in doing so. Ultimately, it is expected that 5-HT phMRI will add
crucial information on the effects of ecstasy in adolescents and young adults
using this drug.

- To assess the usefulness of 5-HT phMRI (BOLD-, PWI and ASL based phMRI) in
assessing cerebral 5-HT neurotoxicity when compared to SERT SPECT.
- To assess which MRI technique (BOLD-, PWI or ASL) is best in assessing
cerebral 5-HT neurotoxicity when compared to SERT SPECT.

BOLD-, PWI and ASL 5-HT-phMRI studies will be conducted and compared to a SERT
SPECT scan as reference (gold standard). First, a SERT SPECT scan will be
conducted. With an interval of 2-3 weeks, the BOLD and ASL 5-HT-phMRI studies
can be studied in one scan session following a low dose challenge with the
serotonin reuptake inhibitor (SSRI) citalopram. In a second MRI study with
gadolinium (PWI based phMRI), again a low dose citalopram challenge will be
given.

Non-invasive 3.0 Tesla MR imaging of cerebral hemodynamics following an
intravenous bolus injection of citalopram (7,5 mg). For the PWI studies in
addition two intravenous bolus injections of a contrast agent (gadobutrol;
Gadovist) will be administered. For the SPECT studies a registrated and
well-validated radioligand ([123I]*-CIT) will be administered intravenously.

No serious side effects are foreseen. MRI itself is a non-invasive imaging
modality. In this study, a low dose citalopram challenge (7.5 mg injected over
7.5 min.) will be administered during the two MRI studies, along with a
contrast agent during the PWI MRI study. There is no expected risk associated
with participation. Gadobutrol (Gadovist, Bayer) is routinely administered for
contrast enhanced MRI studies at the departments of Radiology worldwide, also
in healthy human volunteers. Intravenous citalopram (5*10 mg) has been
developed as probe of central 5-HT function by measuring increased prolactin
secretion following its administration (Seifritz et al. 1996; Attenburrow et
al. 2001), and has also been used as a probe for 5-HT modulation in phMRI
studies (for review see Anderson et al., 2008, McKie 2005). It is the only SSRI
available for intravenous administration. This formulation has been shown to
increase the plasmatic concentration of the molecule faster than the oral one
with a larger therapeutic effect in either controlled and open trials with
depressed patients. Citalopram infusion followed by oral citalopram may be an
effective and well-tolerated treatment for severely depressed patients, also
being not associated with higher severity of side effects. In fact * 50%
patients report no adverse events during chronic treatment with i.v.citalopram
at much higher doses (20-60 mg) than employed in this study (Svestka et al.
1993a, b; Schöny 1992). Of the patients who did experience side effects,
tremor, somnolence and dizziness were reported by * 10% (Charbonnier et al.
1987). The most common adverse events associated with i.v. citalopram are
nausea, headache, tremor, and somnolence (Bouchard et al. 1997; Baumann et al.
1998; Guelfi et al. 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]*-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
venous 3 venous punctures and i.v. administration of either or a combination of
a radioligand, citalopram or contrast agent. 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 ecstasy in users of this drug.