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The Role of Norepinephrine in the Pharmacology of 3,4

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The Role of Norepinephrine in the Pharmacology of 3,4 !"#$%&'#$&($)&*#+,-#+"*,-#$,-$."#$/"0*102&'&34$&($ 56789#."4'#-#:,&;41#."01+"#.01,-#$<9=9>6$?#[email protected]@4AB$ $ C-0D3D*0':,@@#*.0.,&-$$ ! $ ED*$ F*'0-3D-3$:#*$GH*:#$#,-#@$=&I.&*@$:#*$/",'&@&+",#$ J&*3#'#3.$:#*$ /",'&@&+",@2"8)0.D*K,@@#-@2"0(.',2"#-$L0ID'.M.$ :#*$N-,J#*@,.M.$O0@#'$ $ $ J&-$ $ PQ:*,2$90*2$R4@#I$ 0D@$O#''1D-:6$OF$ $ O0@#'6$STU5$ $ $ V*,3,-0':&ID1#-.$3#@+#,2"#*.$0D($:#1$=&ID1#-.#-@#*J#*$:#*$N-,J#*@,.M.$O0@#'W$#:&2XD-,Y0@X2"$ $ =,#@#@$ G#*I$ ,@.$ D-.#*$ :#1$ Z#*.*03$ [P*#0.,J#$ P&11&-@$)01#-@-#--D-38\#,-#$I&11#*E,#''#$)D.ED-38\#,-#$ O#0*Y#,.D-3$ SX]$ ^2"K#,E_$ ',E#-E,#*.X$ =,#$ J&''@.M-:,3#$ `,E#-E$ I0--$ D-.#*$ 2*#0.,J#2&11&-@X&*3a',2#-2#@aY48-28 -:aSX]a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Liechti Prof. Dr. Stefan Borgwardt Basel, den 26. Juni 2012 Prof. Dr. Jörg Schibler Dekan !"#$%&'(&)'*+%*+,& >2I-&K'#:31#-.@$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$CCC$ ^D110*4$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$U$ C-.*&:D2.,&-$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$b$ UXU$ G"0.$,@$9=9>c$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$d$ UXS$ ^0(#.4$0-:$*,@I@$&($9=9>$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$UU$ UX5$ G"0.$:&$K#$I-&K$0Y&D.$."#$+"0*102&'&34$&($9=9>c$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$U5$ UX7$ %&'#$&($-&*#+,-#+"*,-#$,-$."#$+"0*102&'&34$&($9=9>$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$U]$ UX]$ ^,3-,(,20-2#$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$Ub$ UXe$ >,1@$f$R4+&."#@,@$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$Ub$ /0+#*$V-#W$%&'#$&($P0**,#*89#:,0.#:$)F$%#'#0@#$,-$."#$/@42"&@.,1D'0-.$F((#2.@$XXXXXXXXXXXXX$Ud$ /0+#*$!K&W$%&'#$&($Z#@,2D'0*$)F$%#'#0@#XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$5U$ /0+#*$!"*##W$%&'#$&($gU$0-:$h$>:*#-#*3,2$%#2#+.&*@$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$75$ /0+#*$L&D*W$%&'#$&($."#$h$>:*#-#*3,2$%#2#+.&*$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$]b$ /0+#*$L,J#W$%&'#$&($."#$gU$>:*#-#*3,2$%#2#+.&*XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$e5$ /0+#*$^,;W$%&'#$&($P&1Y,-#:$P0**,#*81#:,0.#:$)F$0-:$]8R!$%#'#0@#XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$dU$ /0+#*$^#J#-W$F((#2.@$&($9=9>$&-$Z0@&+*#@@,-$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$UT5$ /0+#*$F,3".W$F((#2.@$&($9=9>$&-$F1&.,&-$%#2&3-,.,&-$<9,-:$%#0:,-3B$XXXXXXXXXXXXXXXXXXXXXXXXXX$UU5$ /0+#*$),-#W$F((#2.@$&($9=9>$&-$/D+,''0*4$LD-2.,&-$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$US]$ =,@2D@@,&-$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$U]U$ %#(#*#-2#@$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$U]b$ PD**,2D'D1$Z,.0#$XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX$Ue5$ ! ! !"#$*#@#0*2"$,-$.",@$."#@,@$,@$+*#@#-.#:$,-$."#$(&*1$&($@2,#-.,(,2$+0+#*@$."0.$"0J#$#,."#*$Y##-$ +DY',@"#:$ &*$ 0*#$ ,-$ +*#+0*0.,&-X$ %#(#*#-2#$ ',@.@$ (&*$ #02"$ +0+#*$ 0*#$ +*#@#-.#:$ 0.$ ."#$ #-:$ ."#$ *#'#J0-.$@#2.,&-X$>$*#(#*#-2#$',@.$2&J#*,-3$."#$3#-#*0'$,-.*&:D2.,&-$0-:$:,@2D@@,&-$,@$0.$."#$#-:$ &($."#$."#@,@X$ C$ -).*'/$%012%*+,! CCC$ !"#$%&'()*+($,-. I owe a debt of gratitude to all the people who have accompanied me during my PhD as mentors, collaborators, scientist, colleagues, friends, and family. Their contributions to this work are gratefully acknowledged. In the first place I would like to record my gratitude to my supervisor PD Dr. Matthias Liechti. I benefited enormously from his knowledge and experience. He provided me unflinching encouragements and support in various ways. I also highly value his loyalty and the stimulating and relaxed environment he created for our group. Matthias, thank you! I would also like to thank Prof. Stephan Krähenbühl for his support and interest as well as for taking the role of the faculty representative. I thank Prof. Stefan Borgwardt for being co-referee on my thesis committee. Many thanks go to Linda Simmler, my fellow PhD student in the Psychopharmacology Research Group. I enjoyed playing with her in the same team and without her hard work in the lab my work would not have been possible. From the Phase I Research Unit my sincerest thanks go to Claudia Bläsi. She thought me a lot about clinical trials in the first place but mostly I am thankful for the warm and pleasant working atmosphere she created on the 6th floor. Special thanks also go to Luisa Baselgia for keeping everything on the 6th floor together. In addition I would also like to thank Susanne Müller and Silke Purschke for teaching me a lot about a proper study management. I also would like to express a massive thank you to the pharmacy and medical students for their valuable work in helping me to conduct the clinical studies. Many thanks go in particular to Martina Ineichen, Dr. Valentina Nicola, Valerie Arnold, Robin Burgger, Dr. Yasmin Schmid, Anna Rickli, Dr. Anja Fink, Nathalie Schillinger, and Nicole Meyer. Special thanks should also go to various people from the Markgräflerhof and the Lab 410 and 411: Réjane Morand, Massimiliano Donzelli, Benjiamin Berger, Carmen Franz, Swarna Maseneni, Dr. Marcel Bruggisser, Dr. Adrian Derungs, Dr. Anne Taegtmeyer, Bea Vetterli, PD Dr. Manuel Haschke, and Evelyne Rudin. My very personal thanks I would like to express to my parents, for their support throughout and for giving me the liberty to pursue my wishes. Cendrine, thank you for being such a supportive and caring sister. Words fail me to express my appreciation to /. !"#$%&'()*+($,-. Andrea whose enthusiasm, love, and persistent confidence in me, has taken the load of my shoulder. Merci! /0. 3422"56& 1. -3++!45. The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a widely used recreational drug, which produces strong psychological effects such as increased empathy and sociability. MDMA inhibits the uptake of and releases serotonin, dopamine, and norepinephrine via an interaction with the respective monoamine transporter. While the role of serotonin in the human pharmacology of MDMA has been well described, the role of norepinephrine in the mediation of the effect of MDMA is mostly unexplored. Preclinical data indicate that norepinephrine may play a crucial role in the effects of MDMA. This project focused on the role of norepinephrine in the pharmacology of MDMA in humans. We performed five experimental clinical studies and analyzed data from a previously performed study investigating the role of norepinephrine in the mechanism of action of MDMA. All studies were pharmacological interaction studies with selective medications used as research tools to inhibit the effects of MDMA in healthy subjects. All clinical studies used placebo-controlled, double-bind cross-over designs and were each performed in 16 healthy subjects in the University Hospital of Basel. In the first study, we showed that the selective
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