neuropharmacology: catecholamines
DESCRIPTION
Lecture 17 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University.TRANSCRIPT
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Neurochemistry of Catecholamines
Brian J. Piper, Ph.D.
Norepinephrine
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Goals• Biosynthesis• Receptors• Neuroanatomy• Diseases• Drugs – L-Dopa– Methylphenidate
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Definition
• Catechol + amine (NH2)• Members: – Dopamine– Norepinephrine (Noradrenaline)– Epinephrine (Nopepinephrine)
catechol
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Precursor• Tyrosine: amino acid found in many
foods including cheese & dairy products
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Biosynthesis
• Rate limiting (TH): controls production, found in axons
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Biosynthesis
• L-DOPA: L-3,4-dihydroxyphenylalanine
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Parkinson’s Disease
• 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-I
1 min: http://www.youtube.com/watch?v=_L_WF6gv5BI3 min: http://www.youtube.com/watch?v=ZHRT0uUo7Qs
1755-1824
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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.
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MPTP= Parkinson’s model
Parkinson’s Disease Normal
Immunocytochemistry for tyrosine hydroylase in rhesusmonkeys
Masilamoni et al. (2011). Brain, 134, 2057-2073.
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Dopamine Release
• VMAT2: vesiciular monoamine transporter, packages DA into vesicle
• Dopamine Transporter (DAT): found on cell membrane, recycles dopamine
• Receptor Families:– D1: – D2:
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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
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Dopamine Neuroanatomy 1Mesocortical
• Label: Soma-Axon Location, Mesencephalon-Cortex• Important for Schizophrenia
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Dopamine Neuroanatomy 2Mesolimbic
• Limbic: amygdala, hippocampus, nucleus accumbens• Important for Drug-Abuse
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Dopamine Neuroanatomy 3Nigrostriatal
• Nigro: substantia nigra• Striatum: caudate and putamen• Important for movement
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Embryonic Transplants: An (Overly?)Optimistic Therapy
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Dopaminergic DrugsDrug Mechanism
Resperine VMAT inhibitor (irreversible)
AMPT Inhibits tyrosine hydroxylase
6-OHDA Destroys DA (& NE) neurons
SCH 23390 D1 antagonist
Haloperidol D2 antagonist
Cocaine Inhibits reuptake of DA (& NE)
methylphenidate Inhibits reuptake of DA (& NE)
Rauvolfia serpentina(snakeroot)
Tyrosine hydroylase staining following6-OHDA lesion of left-fibers of nigro-striatal pathway.
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Norepinephrine Synthesis
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Adrenergic Receptors
• α : α1 α2
• β : β1 β2
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Functions of Norepinephrine
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Catecholamine Inactivation
NET (norepinephrine transporter): membrane boundMAO (monoamine oxidase): found in neurons & gliaCOMT (catechol-O-methyl-transferase): intracellular & extracellular
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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.
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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
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“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.
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Summary
• Synthesis (TH, AADC)• Breakdown (DAT/NET, VMAT, MAO, COMT)• Receptors – D1 D2– α β
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Is crystal methamphetamine the new crack?
• Q) Is methamphetamine a national epidemic?• Q) Are there similarities between meth &
crack?
http://www.justicetalking.org/ShowPage.aspx?ShowID=5760-29:20
Dopamine Methamphetamine