Parkinson’s Disease 1755-1824 • Progressive neurodegenerative disease • Described by James Parkinson in 1817 • Idiopathic (pesticides, genetics) • Prevalence: 3% of 65+ (500,000!) • Symptoms: resting tremor, pill rolling, slowness of movement • Tx: L-DOPA + peripheral AADC-I3 min: http://www.youtube.com/watch?v=ZHRT0uUo7Qs1 min: http://www.youtube.com/watch?v=_L_WF6gv5BI
Thanks, home chemists!• Barry Kidston develops Parkinson’s after synthesizing MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)• Later cases were described as: – “Three of the four patients were hospitalized with 14 days to 6 weeks of first use of the drug. Examination in each revealed near total immobility, marked generalized increase in tone, a complete inability to speak intelligibly, marked diminution of blinking, fixed stare, constant drooling” – Stopping L-DOPA resulted in “complete immobility & rigidity, being only able to move his eyes” Langston et al. (1983). Science, 219, 979-980.
MPTP= Parkinson’s model Immunocytochemistry for tyrosine hydroylase in rhesus monkeysParkinson’s Disease Normal Masilamoni et al. (2011). Brain, 134, 2057-2073.
Dopamine Release• VMAT2: vesiciular monoamine transporter, packages DA into vesicle• Dopamine Transporter (DAT): found on cell membrane, recycles dopamine• Receptor Families: – D1: – D2:
Dopamine Transmission• VMAT2: vesiciular monoamine transporter, packages DA into vesicle• DAT: Dopamine Transporter, found on cell membrane, recycles dopamine• Receptor Families: – D1: D1 & D5 – D2: D2 D3 D4
Dopamine Neuroanatomy 1 Mesocortical• Label: Soma-Axon Location, Mesencephalon-Cortex• Important for Schizophrenia
Dopamine Neuroanatomy 2 Mesolimbic• Limbic: amygdala, hippocampus, nucleus accumbens• Important for Drug-Abuse
Dopamine Neuroanatomy 3 Nigrostriatal• Nigro: substantia nigra• Striatum: caudate and putamen• Important for movement
Embryonic Transplants: An (Overly?)Optimistic Therapy
Dopaminergic DrugsDrug MechanismResperine VMAT inhibitor (irreversible)AMPT Inhibits tyrosine hydroxylase Rauvolfia serpentina6-OHDA Destroys DA (& NE) neurons (snakeroot)SCH 23390 D1 antagonistHaloperidol D2 antagonistCocaine Inhibits reuptake of DA (& NE)methylphenidate Inhibits reuptake of DA (& NE) Tyrosine hydroylase staining following 6-OHDA lesion of left-fibers of nigro- striatal pathway.
Catecholamine InactivationNET (norepinephrine transporter): membraneboundMAO (monoamine oxidase): found in neurons &gliaCOMT (catechol-O-methyl-transferase):intracellular & extracellular
ADHD Inattention• Symptoms present at school/work and home• 6+ symptoms that have persisted 6+ months and are inconsistent with developmental level – Often fails to give close attention or makes careless mistakes at school or at work. – Has difficulty sustaining attention in tasks or play. – Does not listen when spoken to directly. – Often does not follow through on instructions. – Has difficulty organizing activities. – Is easily distracted. – Is often forgetful in daily activities. 23
ADHD: Hyperactive-Impulsive• Symptoms present at school/work and home• 6+ symptoms that have persisted 6+ months and are inconsistent with developmental level – Often fidgets with hands or feet, leaves seat when staying seated is expected, runs or climbs excessively – Often blurts answer before ? completed – Has difficulty waiting turn – Often interrupts others 24
“Peculiar” Effects of Methylphenidate in Adolescents• Ritalin (Schedule II) is FDA approved for narcolepsy & ADHD• Pharmacological MRI was conducted in adolescent (PD35) and adult rats (PD 60+)Canese et al. (2009). Psychopharm, 203, 143-153.
Is crystal methamphetamine the new crack? • Q) Is methamphetamine a national epidemic? • Q) Are there similarities between meth & crack? Dopamine Methamphetamine0-29:20http://www.justicetalking.org/ShowPage.aspx?ShowID=576