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Neurochemistry of
 Catecholamines
  Brian J. Piper, Ph.D.




                      Norepinephrine
Goals
•   Biosynthesis
•   Receptors
•   Neuroanatomy
•   Diseases
•   Drugs
    – L-Dopa
    – Methylphenidate
Definition

• Catechol + amine (NH2)             catechol

• Members:
  – Dopamine
  – Norepinephrine (Noradrenaline)
  – Epinephrine (Nopepinephrine)
Precursor
• Tyrosine: amino acid found in many
  foods including cheese & dairy products
Biosynthesis




• Rate limiting (TH): controls production, found in
  axons
Biosynthesis




• L-DOPA: L-3,4-dihydroxyphenylalanine
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-I
3 min: http://www.youtube.com/watch?v=ZHRT0uUo7Qs
1 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
                                                monkeys




Parkinson’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
Neuropharmacology: Catecholamines
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 Drugs
Drug              Mechanism
Resperine         VMAT inhibitor (irreversible)
AMPT              Inhibits tyrosine hydroxylase             Rauvolfia serpentina
6-OHDA            Destroys DA (& NE) neurons                (snakeroot)

SCH 23390         D1 antagonist
Haloperidol       D2 antagonist
Cocaine           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.
Norepinephrine
Synthesis
Neuropharmacology: Catecholamines
Adrenergic Receptors
• α : α1 α2
• β : β1 β2
Functions of Norepinephrine
Catecholamine Inactivation
NET (norepinephrine transporter): membrane
bound
MAO (monoamine oxidase): found in neurons &
glia
COMT (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.
Summary
• Synthesis (TH, AADC)
• Breakdown (DAT/NET, VMAT, MAO, COMT)
• Receptors
  – D1 D2
  –αβ
Is crystal methamphetamine the new
                    crack?
  • Q) Is methamphetamine a national epidemic?
  • Q) Are there similarities between meth &
    crack?




          Dopamine                                       Methamphetamine



0-29:20
http://www.justicetalking.org/ShowPage.aspx?ShowID=576

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Neuropharmacology: Catecholamines

  • 1. Neurochemistry of Catecholamines Brian J. Piper, Ph.D. Norepinephrine
  • 2. Goals • Biosynthesis • Receptors • Neuroanatomy • Diseases • Drugs – L-Dopa – Methylphenidate
  • 3. Definition • Catechol + amine (NH2) catechol • Members: – Dopamine – Norepinephrine (Noradrenaline) – Epinephrine (Nopepinephrine)
  • 4. Precursor • Tyrosine: amino acid found in many foods including cheese & dairy products
  • 5. Biosynthesis • Rate limiting (TH): controls production, found in axons
  • 7. 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-I 3 min: http://www.youtube.com/watch?v=ZHRT0uUo7Qs 1 min: http://www.youtube.com/watch?v=_L_WF6gv5BI
  • 8. 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.
  • 9. MPTP= Parkinson’s model Immunocytochemistry for tyrosine hydroylase in rhesus monkeys Parkinson’s Disease Normal Masilamoni et al. (2011). Brain, 134, 2057-2073.
  • 10. Dopamine Release • VMAT2: vesiciular monoamine transporter, packages DA into vesicle • Dopamine Transporter (DAT): found on cell membrane, recycles dopamine • Receptor Families: – D1: – D2:
  • 11. 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
  • 13. Dopamine Neuroanatomy 1 Mesocortical • Label: Soma-Axon Location, Mesencephalon-Cortex • Important for Schizophrenia
  • 14. Dopamine Neuroanatomy 2 Mesolimbic • Limbic: amygdala, hippocampus, nucleus accumbens • Important for Drug-Abuse
  • 15. Dopamine Neuroanatomy 3 Nigrostriatal • Nigro: substantia nigra • Striatum: caudate and putamen • Important for movement
  • 16. Embryonic Transplants: An (Overly?) Optimistic Therapy
  • 17. Dopaminergic Drugs Drug Mechanism Resperine VMAT inhibitor (irreversible) AMPT Inhibits tyrosine hydroxylase Rauvolfia serpentina 6-OHDA Destroys DA (& NE) neurons (snakeroot) SCH 23390 D1 antagonist Haloperidol D2 antagonist Cocaine 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.
  • 20. Adrenergic Receptors • α : α1 α2 • β : β1 β2
  • 22. Catecholamine Inactivation NET (norepinephrine transporter): membrane bound MAO (monoamine oxidase): found in neurons & glia COMT (catechol-O-methyl-transferase): intracellular & extracellular
  • 23. 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
  • 24. 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
  • 25. “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.
  • 26. Summary • Synthesis (TH, AADC) • Breakdown (DAT/NET, VMAT, MAO, COMT) • Receptors – D1 D2 –αβ
  • 27. Is crystal methamphetamine the new crack? • Q) Is methamphetamine a national epidemic? • Q) Are there similarities between meth & crack? Dopamine Methamphetamine 0-29:20 http://www.justicetalking.org/ShowPage.aspx?ShowID=576