Neuroimaging of Addiction

Transcription

1 Neuroimaging of Addiction Sang Eun Kim, MD, PhD Department of Nuclear Medicine Seoul National University College of Medicine Seoul, Korea SNUBH Preclinical and Clinical Molecular Imaging Center (SNUBH-MIC) Seongnam, Korea

2 Dopaminergic pathways in the brain

3 Questions and Hypotheses The ability of drugs of abuse to increase brain DA concentration in limbic brain regions is considered crucial for their reinforcing effects. Drugs of abuse increase DA in naive as well as in addicted subjects. Why some people abuse drugs, whereas others do not? DA involvement in drug addiction is likely to be mediated by means of functional and structural changes in the circuits that are modulated by DA, including the frontal cortex.

4 Brain imaging techniques used in drug abuse research

5 Nuclear medicine imaging vs. Radiography

6 PET (Positron emission tomography)

7 SPECT (Single-photon emission computed tomography)

8 Radiopharmaceuticals or Radiotracers Definition: A Radiopharmaceutical is a Radioactive Drug used for Diagnosis or Therapy in a Tracer Quantities with No Pharmacological Effect. Composed of two parts - Radionuclide - Pharmaceutical No pharmacological effect anticipated 10-9 ~10-12 mol of active substances administered per unit dose (versus 10-3 mol for non-radioactive drugs) Affordable radiation effect Effective dose from FDG PET = 7 msv Natural radiation exposure = 2.5 msv/year Effective dose from chest CT = 8 msv abdomen/pelvis CT = msv

9 Nuclear medicine imaging using radiopharmaceuticals (PET, SPECT) Highly sensitive: mol/l Highly quantitative: tracer principle Most applicable to clinic

10 MRI: Methamphetamine reduces gray matter Kim et al., 2005

11 Functional MRI: The brain s response to cocaine cues Cocaine-addicted Healthy volunteer Wexler et al., 2001

12 Cocaine causes dopamine buildup in the synapse

13 Creating radiotracers for PET imaging

14 Cocaine activity in the striatum underlies the cocaine high Volkow et al., 1997

15 Cocaine causes dopamine buildup in the synapse

16 Radiotracers for Imaging Dopamine Transporters NH 2 18 F N 11 CH3 O N N 11 C-Nomifensin 18 F-GBR H 3 11 C N O H 3 C N O H 3 C N O OCH 3 OCH 3 O 11 CH 3 F 123 I I 11 C-CFT (WIN 35,428) 123 I- -CIT (RTI-55) 11 C- -CIT (RTI-55) F F 123 I N O OCH 3 N O OCH 3 N O OCH 3 Cl 123 I 123 I 123 I-IPT 123 I- -CIT-FP 123 I- -CIT-FE

17 [ 3 H]WIN 35,428 Specific Binding (Region/Cerebellar Ratios) 125I RTI-55 SPEC.BINDING Drugs of abuse: Neurotoxic effects Methamphetamine Fenfluramine 2 8 CONTROLS (6) METHAMPHETAMINE (6) * CONTROLS (6) FENFLURAMINE (6) 6 4 ** 1 2 ** ** ** ** ** ** 0 OLF STR CTX 0 STR OLF HYP THAL S.COL FTCTX HIP CTX Kim et al., 1998

18 Chronic methamphetamine abuse depletes dopamine function [ 11 C]d-threo-methylphenidate PET Volkow et al., 2001

19 Stimulants reduce cellular activity in brain areas affecting judgment Cocaine abusers have reduced metabolism in the orbitofrontal cortex Healthy control Cocaine abuser Volkow et al., 1993

20 Dopamine receptor levels may determine vulnerability to abuse and addiction DA D 2 receptor availability in drug abusers ([ 11 C]raclopride PET studies)

21 DA D 2 receptor availability versus orbitofrontal metabolism in cocaine and in metamphetamine abusers Volkow et al., 2004

22 Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum Patients Controls Amphetamine-Induced [ 11 C]Raclopride Displacement Wang et al., 2004

23 Neurochemistry of drug versus behavioral addiction

24 Behavioral addiction Shares core features with drug addiction (Potenza, 2008) Continued engagement in a behavior despite adverse consequence Diminished self-control over engagement in the behavior Compulsive engagement in the behavior Craving state prior to the engagement in the behavior Tolerance/withdrawal Types of behavioral addiction Excessive gambling, eating, internet use, sex, and shopping Only excessive gambling carries a DSM (Diagnostic and Statistical Manual of Mental Disorders) diagnosis

25 DA D 2 receptor availability in pathological eating Striatal dopamine receptor availability was reduced in the obese individuals compared to controls. Whole brain and striatal glucose metabolism were comparable between groups

26 Altered regional brain metabolism in Internet game overusers Kim et al., 2010

27 Binding potential DA D 2 receptor availability in Internet game overusers 3 Binding Potential in basecondition * * * Normal Addict L-DCA L-DPU L-VST R-DCA R-DPU R-VST Regions Kim et al., 2009

28 DA D 2 receptor availability in obesity Controls Control Obese ml/g 0 2 Wang et al., 2001

29 Inverse correlation between body mass index and DA D 2 receptor availability L T-value z=7 Z = 7 z=9 Z = 9 y=4 Y = 4 Kim et al., 2009

30 Brain recovery occurs with methamphetamine abstinence Wang et al., 2004

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32 B max (fmol/mg protein) Effects of chronic nicotine on nachr and acute nicotine-induced DA release Chronic low-dose nicotine Saline Nicotine Day 1 Day 2 Day 7 after nicotine withdrawal 70 0 Bmax (fmol/mg protein)140 Chronic high-dose nicotine * *P < Saline Nicotine Day 1 Day 2 Day 7 after nicotine withdrawal P = Saline Nicotine P = Saline Nicotine Days after withdrawal from nicotine Days after withdrawal from nicotine Kim et al., 2002

33 Classical occupancy model Depleted Baseline Stimulated D 2 receptor Dopamine Radiolabeled benzamide Laruelle, 2000

34 Synthesis of [ 11 C]Raclopride H 2, Ni (cat.) I 2 11 CO 11 2 CH 11 4 CH 3 I Cl OH Cl O N H OH H N 11 CH 3 I, NaOH DMSO Cl OH Cl O N H H O 11 CH 3 N K D = 1.2 nm

35 % Change % Change Dopamine (% baseline) Dopamine (% baseline) Effects of nicotine and methamphetamine on extrasynaptic DA concentration and their relationships with in vivo binding of [ 3 H]raclopride in the striatum Nicotine Methamphetamine 180 SAL NIC 0.4 mg/kg NIC 1.8 mg/kg NIC 3.5 mg/kg SAL METH 0.1 mg/kg METH 0.5 mg/kg METH 1 mg/kg METH 5 mg/kg METH 10 mg/kg Time (min) Time (min) Extrasynaptic dopamine In vivo 3 H-raclopride binding Extrasynaptic dopamine In vivo 3 H-raclopride binding Dose of nicotine (mg/kg) Dose of methamphetamine (mg/kg) Kim et al., 1998/2006

36 Smoking-induced dopamine release PET study protocol Five male non- or ex-smokers with an abstinence period > 1 y (age 24.4±1.7 y) Thermoplastic mask MRI QSU* Urine test cigarette smoking (1-2 mg of nicotine) Blood sampling for plasma nicotine QSU* 0 min 50 min 120 min [ 11 C]raclopride PET Bolus (20 ml/min) + Constant infusion (0.20 ml/min) *QSU = Questionnaire of Smoking Urges

37 Radioactivity of [ 11 C]raclopride (count/min/pixel) Smoking-induced dopamine release in striatal subregions ([ 11 C]Raclopride PET study) Baseline (30-50 min) Smoking (65-85 min) (x1,000) Smoking cerebellum CA PU VST Time (min) Kim et al., 2005

38 Smoking-induced [ 11 C]raclopride BP changes in striatal subregions Caudate Putamen Ventral striatum Baseline 2.16 ± ± ± 0.34 Smoking 2.06 ± ± ± 0.09 BP change (% baseline) 4.7 ± 2.6% 4.0 ± 2.7% 7.7 ± 13.0% Kim et al., 2005

39 %V 3 Relationship between smoking-induced [ 11 C]raclopride BP reduction and plasma nicotine concentration in striatal subregions 10% 8% 6% 4% 2% 0% Caudate Putamen Ventral striatum 10% 8% 6% 4% 2% 0% -10% % 25% 20% 15% 10% 5% 0% -5% rho = 0.9 P = Cumulated plasma nicotine concentration (ng/ml) Kim et al., 2005

40 분당서울대학교병원전임상 임상분자영상센터 (SNUBH Preclinical and Clinical Molecular Imaging Center) 방사성나노분자화학실 (Nano-Molecular Chemistry) 사이클로트론실 (Cyclotron) 전임상영상실 (Preclinical Imaging) 임상영상실 (Clinical Imaging) 영상분석실 (Image Analysis) 질병 / 표적특이나노분자프로브와방사성추적자의개발및합성제작 신약후보물질의합성 / 표지 약물표지용방사성동위원소생산및 QA 사이클로트론기술개발 방사성추적자개발지원 전임상분자영상 영상 QA 질홖동물모델제작 / 관리 임상분자영상 영상 QA 피험자모집및관리 영상프로토콜확립 /QA 영상정량화기술개발 / 응용 영상데이터의생물학적해석 고유연구 신약개발연구지원 연구인력의교육및훈련 신약개발산업화 Mechanism-based imaging biomarker 발굴 질병 / 표적특이나노분자프로브의개발 신약후보물질평가의분자영상기술개발 전임상 / 임상분자영상응용연구 제약 바이오산업체 신약개발연구기관 대학및연구기관 제약 바이오산업체 신약개발연구기관 대학및연구기관 제약 바이오산업체 신약개발연구기관 대학및연구기관

41 나노분자화학실 / 사이클로트론실 (Nano-Molecular Chemistry/Cyclotron) 연구실핵심장비 & 설비 Medical cyclotron Hot cells F-18 synthetic module C-11 synthetic module NMR LC/MS/MS HPLC systems Radio-TLC scanners 전임상 / 임상영상실 (Preclinical/Clinical Imaging) 연구실핵심장비 & 설비 MicroPET/CT system NanoSPECT/CT system PET/CT systems SPECT systems Optical imaging system Beta-microprobe system In vivo microdialysis system Autoradiography system Dedicated animal imaging chamber Animal model production Stereotoxic device Ventilated animal cage 영상분석실 (Image Analysis) 핵심영상분석프로그램 Comprehensive PET data analysis Analyze 9.0 FMItool Statistical parametric mapping

42 Acknowledgments Neurochemistry Soo Kyung Hong In Soon Jeong Young Eun Koh Radiochemistry Byung Chul Lee Byung Seok Moon Ji Sun Kim Young Shin Jeon Kyung Il Sohn Cognitive Neuroscience Sang Soo Cho Sang Hee Kim Sung Ae Bang Jee Hee Hwang Chang Soo Park Hyun Jung Han Animal/Human imaging Yu Kyeong Kim Won Woo Lee Jae Sung Lee Jong Jin Lee Sujin Kim So Yeon Park Hyun Soo Park Eun Jin Yoon Ji Youn Sohn