MDMA-Evoked Changes in Cerebral Blood Flow in Living Porcine Brain: Correlation With Hyperthermia PEDRO ROSA-NETO, * AAGE K. OLSEN, ALBERT GJEDDE, HIDEAKI WATANABE, AND PAUL CUMMING Center for Functionally Integrative Neuroscience, Aarhus University and PET Center, Aarhus University Hospitals, Denmark 8000 KEY WORDS 3,4-methylenedioxymethamphetamine; MDMA; brain; drug effects; CBF; thermoregulation; hyperthermia ABSTRACT 3,4-Methylenedioxymethamphetamine (MDMA) acutely releases intra- neuronal dopamine and serotonin and evokes hyperthermia which is linked to toxicity for serotonin fibers. The acute effects of MDMA on cerebral blood flow (CBF) in living brain have not been described in an animal model of MDMA intoxication. We predicted that MDMA-induced hyperthermia should correlate with increased CBF in the hypo- thalamus, a serotonin-rich brain region subserving thermoregulation. To test this pre- diction, we used positron emission tomography with statistical parametric mapping for exploratory analysis of the focal changes in the magnitude of CBF in the anesthetized female Landrace pig (n = 9) at 30 and 150 min after acute challenge with MDMA-HCl (1 mg/kg, i.v.). The MDMA treatment was followed by increased CBF in the occipital cortex and in the medial mesencephalon overlapping the dorsal raphe ´ nucleus, and reduced CBF in the cerebellar vermis and in a cluster in the medulla encompassing the left locus coeruleus. The individual increase of body temperature correlated positively with increased CBF in the vicinity of the raphe ´ nucleus, in the hypothalamus (regions linked to thermoregulation), and also in the medial frontal cortex, which together comprise the regions receiving the most dense serotonin innervations in pig brain. Thus, individual differences in the susceptibility to MDMA-induced hyperthermia in this population correlated with the magnitude of focal increases in CBF within specific brain regions endowed with a dense serotonin innervation, including regions linked to ther- moregulation. Synapse 53:214 –221, 2004. © 2004 Wiley-Liss, Inc. INTRODUCTION The psychostimulant 3,4-methylenedioxymetham- phetamine (MDMA, “Ecstasy”) remains widely used for recreational purposes (Landry, 2002), although there is now considerable evidence that exposure to MDMA can have long-term effects on cognitive performance, auto- nomic function, and brain serotonin innervations in humans and other species (Morgan, 2000; Parrott, 2000; Taffe et al., 2002). MDMA, like d-amphetamine, releases catecholamines by a mechanism of facilitated exchange-diffusion at the neuronal plasma membrane transporters. Unlike d-amphetamine, MDMA also evokes a dose-dependent increase in the interstitial concentration of serotonin in rat cerebral cortex and increases interstitial serotonin and dopamine to a sim- ilar extent in striatum (Green et al., 2003). Thus, acute effects of MDMA can be mediated by both serotonin and catecholamine innervations, depending on the brain region. Previous imaging studies of psychostimu- lants indicate that potentiation of these neurotrans- mitter systems can evoke focal alterations in cerebral blood flow (CBF), a phenomenon conventionally linked to altered activity of local neurons. However, focal CBF changes are now understood to be a consequence of perturbed afferent activity, rather than depolarization of neurons at the site of altered CBF (Gjedde et al., 2002; Caesar et al., 2003; Hershey et al., 2003). Thus, psychostimulant-evoked alterations in CBF need not be restricted to the sites of increased release of mono- amine neurotransmitters, but might also reveal altered Contract grant sponsors: NovoNordisk, Denmark’s Basic Science Foundation (Center for Functionally Integrative Neuroscience), National Health Research Council. *Correspondence to: Pedro Rosa-Neto, Aarhus General Hospital, Nørrebro- gade 44, Building 10, Aarhus C, Denmark DK-8000. E-mail: pedro@pet.auh.dk Received 13 March 2004; Accepted 18 May 2004 DOI 10.1002/syn.20052 Published online in Wiley InterScience (www.interscience.wiley. com). SYNAPSE 53:214 –221 (2004) © 2004 WILEY-LISS, INC.