The Role of NEUROIMAGING In Diagnostic and Clinical Practice

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1 The Role of NEUROIMAGING In Diagnostic and Clinical Practice ADHD Schizophrenia Autism Addiction Altzheimer s Disease Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

2 Natural & Drug Reinforcers Increase Dopamine in NAc frontal cortex nucleus accumbens VTA/SN % of Basal Release AMPHETAMINE hr Time After Amphetamine Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction % of Basal Release FOOD Empty Box Feeding Time (min) Di Chiara et al.

3 DA & the Rewarding Effects of Drugs in Humans D DA A raclopride R T Y R O S I N E D O P A R R R DA R T Y R O S I N E D O P A R methylphenidate raclopride DA increases induced by intravenous but not by oral administration of MPH were associated with the high. WHY? High (0-10) Intravenous MPH (1 min) Volkow et al., JPET 291: , High (0-10) Oral MPH (60 minutes) Change in DA (% change Bmax/Kd)

4 H 3 C N CO 2 CH 3 O O [ 11 C]Cocaine % Peak "High" H N CO 2 CH [ 11 C]Methylphenidate % Peak Time (min) "High"

5 Pharmacokinetics of Oral and iv MPH in Baboon Brain MP in Striatum! (peak concentration)! Time (min)! Oral (slow: NO high )! iv (fast: intense high )! Thus reinforcing effects of drugs are due to FAST DA increases that emulate phasic DA cell signaling (15-30 Hz), which is implicated in reward and conditioning rather than tonic DA cell signaling (2-10 Hz), which is implicated in cognitive, motivational and motoric systems. IMPLICATIONS: Drug Development

6 Repeated Drug Use Changes the Brain Weakens the Brain Dopamine System Control Cocaine Abuser T Y R O S I N E T Y R O S I N E T Y R O S I N E DA D O P A D DA A D O P A D DA A D O P A COCAINE PLEASURE REPEATED USE OF COCAINE OR OTHER DRUGS REDUCES LEVELS OF DOPAMINE D2 RECEPTORS`

7 Dopamine D2 Receptors are Lower in Addiction Normal Controls Controls! Cocaine Abusers! Meth! Alcohol! 4! 3.5! 3! 2.5! 2! 1.5! 15! 20! 25! 25! 30! 30! 35! 40! 45! 50! 3.2`! 3! 2.8! Bmax/Kd! DA D2 Receptor Availability! Cocaine! DA D2 Receptors! (Ratio Index)! 4.5! 2.6! 2.4! 2.2! 2! 1.8! 1.6! Heroin! 20! control! addicted! 35! 40! 45! 50! Volkow et al., Neuro Learn Mem 2002.

8 Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors Overexpression of DA D2 receptors reduces alcohol self-administration Thanos, et al., J Neurochem,, 2001.! DA! DA! DA! DA! DA! DA! DA! DA! IMPLICATIONS: Treatment development! Percent Change in D2R!!! % Change in Alcohol Intake! 60! 50! 40! 30! 20! 10! 1st D2R Vector! 0! 0! 0! -20! -40! -60! -80! -100! 0! p < ! p < ! p < 0.005! p < 0.10! 2nd D2R Vector! p < 0.005! 4! 6! 8! 10! 24! p < 0.001! p < 0.001! p < 0.01! p < 0.01! 4! 6! 8! 10! 24! Time (days)! Null Vector! p < 0.001!

9 Nicotine More than just effects on Dopamine circuitry Aromatase* (Estrogen synthase, CYP19A1) C H O H 3 C H O H 3 C H 3 a r o m a t a s e O t e s t o s t e r o n e H O 1 7 β - e s t r a d i o l Mediates sexual differentiation of the brain during development (Wu et al., Cell 139, 139: 61, 2009) Elevated in brain injury (neuroprotective effects of estrogen)

10 Acute nicotine dose dependently inhibits aromatase in baboon at concentrations relevant to smoking (Biegon et al., Biological Psychiatry, 2010). ) Baseline mg/kg 0.03 mg/kg IMPLICATIONS: Female smokers show hypo-estrogenic effects including early menopause Fetal development

11 Tobacco Smoke More than just nicotine 4000 chemical compounds in smoke Monoamine Oxidase (MAO) Breaks down neurotransmitter like dopamine (reward), serotonin (mood) and norepinephrine (arousal) MAO inhibitor drugs are used to treat depression and Parkinson's disease 11 CH 3 N D D [11C]Deprenyl

12 Smoking inhibits MAO B in the human brain non-smoker (female 48 yrs) Brain MAO B 0.3! 0.2! 0.1! smoker (female 51 yrs) 0! Nonsmokers Smokers Former smokers Low brain MAO in smokers is caused by the tobacco smoke and not by biology or genetics not IMPLICATIONS: Could this contribute to smoking? Fetal development?

13 Smoking does not just affect the BRAIN Throat! Larynx (voice box)! Esophagus! Mouth! Lung! Kidn ey! Bladder! Leukemia (blood)! Stomach! Pancreas! Cervix! Smokers have 35-45% reduction in MAO B in heart, lungs, kidneys and spleen Fowler et al PNAS 2003.! IMPLICATIONS: Mechanisms of tobacco toxicity!

14 Nicotine Gets into the Fetus Brain [11C]Nicotine and metabolites Maternal Brain Placenta Fetal brain Fetal brain Fetal Liver kbq/cc [11C]Nicotine and metabolites - Subject #MK Time (min) mat-midbrain mat-cerebellum fetal-midbrain fetal-cerebellum Benveniste et al., PNAS 2010! IMPLICATIONS: Understanding fetal toxicity!! How about NRT as treatment during pregnancy?!

15 Effect of Secondhand Smoke on Occupancy of Nicotinic Acetylcholine Receptors in Brain Brody et al. Arch General Psych Control Second Hand Smoke Secondhand smoke (SHS) decreased 2-FA binding demonstrating! 4 " 2 * receptor occupancy. -22% receptor occupancy IMPLICATIONS:! Policy re: smoking in households with children!

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