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Boris Quednow: Brain Serotonin Function in MDMA (Ecstasy) Users

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Boris Quednow: Brain Serotonin Function in MDMA (Ecstasy) Users BrainBrain serotoninserotonin functionfunction inin MDMAMDMA (( ““ecstasyecstasy ””)) usersusers Boris B. Quednow 1, Felix Hasler 1, Valerie Treyer 2, Matthias T. Wyss 2, Katharina M. Rentsch 3, Gerrit Westera 4, Schubiger PA 4, Alfred Buck 2, Franz X. Vollenweider 1 1University Hospital of Psychiatry, Zurich, Switzerland 2Department of Nuclear Medicine, University Hospital Zurich, Switzerland 3Department of Clinical Chemistry, University Hospital Zurich, Switzerland 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland EcstasyEcstasy • The use of Ecstasy is increasingly spreading since the end of the 1980s. • Lifetime prevalence of Ecstasy use in European adolescents and young adults is about 4-5%. • In Europe, Ecstasy is the second most popular illicit drug in adolescents and young adults following cannabis. • Over the past 15 years, in Germany and Switzerland more than 90% of the confiscated Ecstasy pills contained exclusively the substituted amphetamine derivative MDMA. • Ecstasy pills comprise of 60-65 mg MDMA on average, but with a great range (0-360 mg). SerotonergicSerotonergic neurotransmissionneurotransmission Holmes, Neurosci Biobehav 2008 MDMA SelectiveSelective serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMAMDMA Sagittal plane of 5-HT immunoreaktive axons in the frontal cortex of squirrel monkeys after a treatment of 5 mg/kg MDMA 2x/die for 4 days. Control 2 weeks after MDMA 7 years after MDMA Hatzidimitriou et al., J Neurosci 1999 TheThe serotoninserotonin systemsystem Birbaumer & Schmidt, 1999 SerotoninSerotonin isis involvedinvolved inin nearlynearly allall brainbrain functionsfunctions •• MotorMotor activity activity •• MoodMood • • • CircadianCircadian rhythm rhythmSerotoninSerotonin isis anan enigma;enigma;• AnxietyAnxiety •• SleepSleep •• StressStress itit isis atat onceonce implicatedimplicated inin virtuallyvirtually everythingeverything •• AppetiteAppetite •• AggressionAggression •• SexualSexual regulation regulationbutbut responsibleresponsible forfor•• nothingnothingLearningLearning an .an. Memory Memory • • • PainPain processing processing JacobsJacobs && FornalFornal 19991999• ImpulseImpulse control control •• NeuroendocrineNeuroendocrine •• ExecutiveExecutive functions functions functions functions •• SocialSocial behavior behavior PsychopathologyPsychopathology andand MDMAMDMA useuse • MDMA user display an elevated risk for psychiatric comorbidities such as depression and anxiety disorders (Schifano et al., 1998, 2000 ). • However, the onset of comorbid psychiatric diseases mostly precedes the onset of the MDMA use (Lieb et al., 2002 ). • Psychiatric symptoms of MDMA users are associated rather with cannabis co- consume or polytoxic drug use patterns (Daumann et al., 2004; Thomasius et al., 2003; Parrott et al., 2001; Roisier et al., 2004 ). • Whether MDMA use increases the risk for psychiatric diseases is not clear so far (Gouzoulis-Mayfrank & Daumann, 2006). • In contrast, MDMA users consistently exhibit memory deficits and impaired executive functions (see meta-analysis of Kalechstein et al., 2007 ). Auditory Verbal Learning Test (RAVLT) 18 16 14 12 RAVLT recall 10 *** Words ••• 8 6 4 2 0 Quednow etTrial al., J 1Psychopharmacol 2006 *** ••• Trial 2 *** MDMA ••• Trial 3 Trial 4 Cannabis Trial 5 List B Controls Trial 6 MeansHelmstaedter and SD Trial 7 et al., 2001 CompositeComposite measuresmeasures ofof thethe RAVLTRAVLT Correlation of drug use patterns and performance MDMA Cannabis Controls F df/df err p Years of MDMA use (n=19,learning ♂) (n=19,performance ♂) (n=19, ♂) r=-0.56 Learning performance delayed recall r=-0.70 56,2 (±8,16) 64,8 (±6,21) 64,7 (±5,72) 10,09 2/54 0,0002 Σ trials 1-5 loss after consolidation r= 0.63 Recall consistency 86,6 (±8,61) 94,8 (±3,94) 95,1 (±4,8) 11,85 2/54 0,00005 in percent recognition list A r=-0.62 Retroactive interference 2,26 (±2,47) 0,32 (±0,89) 0,58 (±0,90) 8,28 2/54 0,001 Lifetimetrial 5 minus dosetrial 6 MDMA recall after interference r=-0.55 Loss after consolidation 2,05 (±2,04)delayed 0,05 recall (±0,85) 0,52 (±1,02) 10,51r=-0.61 2/54 0,0001 trial 5 minus trial 7 Adjusted recognition A 0,85 (±0,10) 0,93 (±0,05) 0,90 (±0,08) 4,60 2/54 0,015 Peakp(A) list dose A MDMA recall after interference r=-0.66 Adjusted recognition B 0,74 (±0,03)delayed 0,84 recall (±0,02) 0,81 (±0,03) 4,64r=-0.65 2/54 0,014 p(A) list B retroactive interference r= 0.57 loss after consolidation r= 0.65 Means and SD Quednow et al., J Psychopharmacol 2006 (all p<.0005) IOWAIOWA --GamblingGambling --TaskTask Bechara et al., Neuropsychologia 2001 IOWAIOWA --GamblingGambling --TaskTask IOWA-Gambling-Task ** p< 0.01 *** p< 0.001 30 25 ANOVA Interaction: Quartile*Group 20 MDMA vs. Kont.: p < 0.05 15 10 *** 5 ** 0 -5 good vs. bad decks bad vs. good -10 -15 1.Quartile 2. Quartile 3. Quartile 4. Quartile Difference MDMA Cannabis Controls Means and SEM Quednow et al., Psychopharmacology 2007 Neuropsychological performance in MDMA users Psychopharmacology 2007 Confounding factors in MDMA research Cannabis? Co-use? Content of Ecstasy pills? Lifestyle? Predispositions? Gouzoulis-Mayfrank & Daumann, Addiction 2006 Positron Emission Tomography PETPET imagingimaging studiesstudies suggestingsuggesting serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMA:MDMA: serotoninserotonin transportertransporter SERT density measured by [ 11 C]McN5652 and [ 11 C]DASB Methodological concerns: ⇒ Selectivity of the radiotracer? ⇒ Low density of SERT in cortical regions resulting in a worse signal-to-noise ratio ⇒ Decreased SERT density is not necessarily correlated with loss of serotonin axon terminals ⇒ SERT density can be up- and down-regulated McCann et al., Neuropsychopharmacology 2005 PETPET imagingimaging studiesstudies suggestingsuggesting serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMA:MDMA: serotoninserotonin receptorsreceptors Mapping 5-HT 2A receptor density Methodological concerns: ⇒ Changes of a mostly postsynaptic expressed receptor may not reflect loss of (presynaptic) axon terminals ⇒ 5-HT 2A receptor density can be up- and down-regulated Reneman et al., Neuropsychopharmacology 2002 MagneticMagnetic resonanceresonance spectroscopyspectroscopy inin MDMAMDMA usersusers Methodological concerns: ⇒ Low inherent sensitivity ⇒ Spatial resolution ⇒ Not specific for serotonin neurotoxicity Cowan et al., Psychopharmacology 2007 HowHow cancan wewe measuremeasure serotoninserotonin functionfunction inin vivo?vivo? Serotonin 18F-Altanserin Hypothetical normal state: Dexfenfluramine 60% of the serotonin receptors are occupied Forced serotonin release by dexfenfluramine: 90% of the serotonin receptors are occupied Serotonin release capacity: Normal state minus dexfenfluramine-condition in percent AreAre MDMAMDMA usersusers sufferingsuffering fromfrom lowlow serotoninserotonin levels?levels? Serotonin 18F-Altanserin Dexfenfluramine Impaired serotonin release capacity: Hypothesis: Compared to drug-naïve controls, MDMA users should display more available serotonin receptors under dexfenfluramine challenge. Assessment of serotonin release capacity in the living human bra in using dexfenfluramine challenge and [ 18 F]altanserin positron emission tomography (PET)? Idea: Combination of a forced 5-HT release with a subsequent measurement of postsynaptic 5-HT 2A receptors with PET. Procedure: 1. Forced 5-HT release by dexfenfluramine compared to placebo. 2. Two hours later, injection of the radioligand [ 18 F]altanserin to assess the density of postsynaptic 5-HT 2A receptors with PET. Hypothesis: If MDMA users suffer from a loss of serotonin axon terminals they should release less serotonin after dexfenfluramine challenge and more postsynaptic receptors should be available for the [ 18 F]altanserin in comparison to drug-naive controls. PositronPositron EmissionEmission TomographyTomography (PET)(PET) imagingimaging [18 F]altanserin PET: • Selective 5-HT 2A antagonist • Injection: slow bolus (250 Mbq, 30 s) • Aquisition: 90 min in rest • Arterial blood sampling • Total distribution volume (DV) calculated Dexfenfluramine challenge: by Logan Plot model • Serotonin releaser (metabolite corrected). • Negligible affinity for the 5-HT 2A receptor (K i <10,000) • Dosage: 40 mg vs. 60 mg F-18 • Administration: 2 h before PET-Scan • Placebo-controlled, double-blind, and randomized (2 PET-Scans per subject) [18 F]altanserin PositronPositron EmissionEmission TomographyTomography (PET)(PET) imagingimaging Advance General Electrics PET-CT MeasuringMeasuring serotoninserotonin releaserelease capacitycapacity inin healthyhealthy malemale humanhuman volunteersvolunteers Placebo: n = 13 40 mg (+)FEN: n = 6 Placebo 60 mg (+)FEN: n = 7 2.7 ~8% decrease in 40mg (+)FEN cortical V tot ~17% DV log decrease in cortical V tot 60mg (+)FEN 0.5 Logan plot model voxel-based Quednow et al. in preparation MeasuringMeasuring regionalregional serotoninserotonin releaserelease capacitycapacity inin healthyhealthy malemale humanhuman volunteersvolunteers Quednow et al. in preparation Percent reduction of [ 18 F]Altanserin binding after dexfenfluramine challenge 25 *** ** * 20 Pla/Pla 15 40 mg 60 mg 10 5 Vtot Vtot reduction in % 0 -5 Prefrontal Insula Occipital Thalmus Caudatum Total Pla/Pla: n = 3 Distribution volumes Means and SEM 40 mg (+)FEN: n = 6 calculated with the Significant drug effects: 60 mg (+)FEN: n = 7 Logan plot model *p<.05, **p<.01 SampleSample characteristicscharacteristics current MDMA Ex-MDMA* Controls (n=15, ♂) (n=12, ♂) (n=15, ♂) Age 27.7 (±7.2) 27.0
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