MDMA‐evoked changes in [¹¹C]raclopride and [¹¹C]NMSP binding in living pig brain

Abstract

Positron emission tomography (PET) studies with radiolabeled dopamine D2-like receptor ligands reveal d-amphetamine-evoked increases in the competition from endogenous dopamine. However, the corresponding effects of methylenedioxymethamphetamine (MDMA, "Ecstasy"), which releases catecholamines and also serotonin, are unknown. Using PET, we measured the binding potentials (pBs) of the benzamide [11C]raclopride and the butyrophenone N-[11C]methylspiperone ([11C]NMSP) in brain of living pigs first in a baseline condition and at 45 and 165 min after infusion of (+/-)-MDMA-HCl (1 mg/kg, i.v.). Concomitant studies of cerebral blood flow did not reveal significant perfusion changes in the cerebellum reference region or in striatum, supporting the present use of reference tissue methods for the mapping of MDMA-evoked pB changes. Relative to the baseline pB of [11C]raclopride for dopamine D(2/3) receptors in striatum (pB = 1.5-2.2), MDMA-treatment reduced pB by 35% in the first posttreatment scan and by 22% in the second posttreatment scan, comparable to changes typically evoked by d-amphetamine at a similar dose. In most previous studies, the in vivo binding of butyrophenones has been nearly insensitive to d-amphetamine-evoked dopamine release. However, we found the baseline pB of [11C]NMSP for dopamine D2-like receptors in striatum (pB = 4-5) was decreased by 30% in the first post-MDMA scan and by 50% in the second post-MDMA scan, irrespective of assumptions about the extent of equilibrium binding attained during the 90-min-long PET recordings. Distinct properties of MDMA such as simultaneous release of dopamine and serotonin in brain may account for the present finding of progressive decline in the availability of [11C]NMSP binding sites in striatum.

Parametric and Regional Maps of Free Serotonin 5HT1A Receptor Sites in Human Brain as Function of Age in Healthy Humans

“…Using cerebellum as reference region, average uptakes in ROIs were also analyzed by the Logan et al, SRTM (Gunn et al, 1998;Lammertsma and Hume, 1996) and ERliBiRD methods (Rosa-Neto et al, 2004). The ERLiBiRD method fits the following Equation…”

“…To this end, we applied standard tissue reference methods to regions of interest (ROIs) and image voxels to obtain parametric estimates in the form of pB of [ 11 C]WAY. In addition, we compared the results to the results from the tissue reference method ERLiBiRD (Gjedde, 2003;Rosa-Neto et al, 2004). This method obtains estimates of extrapolation of specific uptakes ratios towards a predicted steady-state.…”

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(Gjedde, 2003;Rosa-Neto et al, 2004), which extrapolates measures of specific binding to an estimated steady-state. We compared these estimates in the two age groups with results obtained with the conventional Logan Plot and Simplified Reference Tissue Method (SRTM) applied to both regions of interestbased as parametric analyses.

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Food preferences and aversions in human health and nutrition: how can pigs help the biomedical research?

“…Minuzzi et al (2006), however, reported that several usual radioligands failed to bind to DAT in the pig brain, although they revealed the presence of DAT in rat, ferret, monkey and human brains. However, according to previous studies using a 11 C-raclopride paradigm, pigs possess functional DAT (Rosa-Neto et al, 2004). These discrepancies may be due to the aberrant binding properties of DAT in pigs compared with those in other species.…”

The pig model in brain imaging and neurosurgery

“…Thanks to the development of methods for measuring cerebral uptake and metabolism of [ 18 F]fluoro-L-DOPA (FDOPA) (Danielsen et al, 1999 and 2001b), it is possible to analyse the activity of DOPA decarboxylase in living pig and apply this strategy to investigate the effect of neuroleptics (Danielsen et al, 2001a). Similarly, PET studies with [ 11 C]raclopride, a radioligand binding in competition with the endogenous dopamine, have been conducted to analyse the effect of psychoactive drugs such as amphetamine (Lind et al, 2005b), nicotine (Cumming et al, 2003), MDMA (Rosa-Neto et al, 2004b) and lysergic acid diethylamide (Minuzzi et al, 2005). It has been shown that these psychoactive agents reduced the availability of [ 11 C]raclopride binding sites for dopamine D(2,3) receptors in the striatum of Gö ttingen minipigs.…”