The document discusses the neurochemistry of catecholamines such as dopamine, norepinephrine, and epinephrine, outlining their biosynthesis from tyrosine, receptors, neuroanatomy in different brain regions, related diseases like Parkinson's, and example drugs that impact their function like L-Dopa and methylphenidate. The catecholamine neurotransmitters are synthesized from tyrosine, packaged and released from neurons, and broken down through reuptake and enzymatic degradation, playing important roles in conditions like attention deficit hyperactivity disorder.

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

6. Biosynthesis
• L-DOPA: L-3,4-dihydroxyphenylalanine

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.

18. Norepinephrine
Synthesis

20. Adrenergic Receptors
• α : α1 α2
• β : β1 β2

21. Functions of Norepinephrine

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