1. Clinical Neurochemistry “The Soup”

2. Talk: Diagnosis, Biology and Treatment of OCD
Speaker: Michael A. Jenike, M.D.
Mtg: CME Vancouver 2001

3. A good working knowledge of clinical neurochemistry is essential for understanding and treating neurological and psychiatric disorders. It is important to learn the basics now so you can update your clinical management as new information becomes available.

4. What You Should Know
Primary cell bodies, sites of action and metabolic pathways for dopamine, norepinepherine, serotonin, acetylcholine, GABA and glutamate
Know the main mechanism of action and termination of action of the most common neurotransmitters
Be aware of the most common receptor subtypes for each neurotransmitter
Be familiar with examples of the mechanism of action of commonly used drugs for each neurotransmitter and the diseases they treat

5. Advances in Neurochemistry
Slow neurotransmitters include the monoamines and work through G proteins and second messengers
Fast neurotransmitters include GABA and glutamate and bind directly on ion-gated channels
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

6. Clinical Neurochemistry
Monoamines
Dopamine
Norepinephrine
Serotonin
Others
Acetylcholine
GABA
Glutamate
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

7. Catecholamines Dopamine Norepinephrine Epinephrine
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

8. Dopamine (Main Cell Bodies)
Long tracts
Substantia nigra  primarily to striatum
Ventral tegmental area  striatum plus the mesolimbic and mesocortical systems
Intermediate
Hypothalamic—pituitary (DA inhibits prolactin)
Short
Olfactory
Retina
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

9. Weigert stain of the midbrain SN=substantia nigra, VTA=
ventral tegmental area, DR=
dorsal raphe
VTA SN
Dopamine cell bodies
and tracts DR

10. Phenylalanine hydroxylase
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

11. Rate-Limiting Step and Termination of Action of Dopamine
Action of tyrosine hydroxylase is the rate-limiting step
The main termination of action for the monoamines is presynaptic reuptake
Monoamine oxidase (MAOB), catechol- O-methyltransferase (COMT)
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

12. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

13. Monoaminergic Receptors
Formed by 7 membrane spanning regions with an intracellular carboxy tail and an intracellular amino region
The structure of the receptors are highly conserved with small changes in amino acid sequence leading to changes in receptor affinity
Monoaminergic receptors exert their effect through G-proteins and other 2nd, 3rd and 4th messengers that often cause protein phosphorylation and regulation of an ion channel

14. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

15. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

16. Dopamine Receptors
D1 is the most common and thought to involve stimulation of adenylate cyclase and increased production of cyclic AMP
D1 receptors are found in the striatum but also abundantly in cortical and limbic regions
D2 receptors are located primarily in the striatum and inhibit adenylate cyclase
The D3, D4 and D5 receptors occur primarily in cortical and limbic regions
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

17. Drugs that affect the dopaminergic system
Neuroleptics are classified as typical or typical based on their degree of blockade of the D2 receptor
Haloperidol is a potent D2 blocker and typical antipsychotic. It is an effective antipsychotic but can cause Parkinsonism, tardive dyskinesia (TD) and cognitive slowing.
Clozapine is an atypical antipsychotic with weak antagonism at D1 and D2 receptors and blocks 5HT2 serotonin receptors. It may exert its antipsychotic effect by blocking D4 receptors, thereby sparing the striatum. Clozapine does not normally cause extrapyramidal symptoms, TD, or increased prolactin.

18. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

19. Clinical Significance
Too much dopamine can cause euphoria, confusion and psychosis. Too little produces Parkinsonism
Dopamine does not cross the blood-brain barrier. Replace dopamine in Parkinson’s disease with L-dopa.
Cocaine blocks reuptake. Amantadine and amphetamine promote presynaptic release.
MAO-B inhibitors such as deprenyl are specific for blocking dopamine breakdown at the usual doses of 5 mg/bid.
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

20. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

21. Olfactory and Entorhinal Cortices Lateral Tegmental NA Cell System
NE cell bodies
are in the
locus
ceruleus
at the upper
dorsal pons.
Thalamus
Cingulate Gyrus
Amygdaloid Body
Olfactory and Entorhinal Cortices
Hippocampus
Locus Ceruleus
Lateral Tegmental NA Cell System
To Spinal Cord
Cerebellar Cortex
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

22. Noradrenergic Cell Bodies in the Dorsal PonsLC AS LC
Weigert myelin
stain of pons. LC=locus ceruleus, AS=aqueduct of Sylvius

23. Metabolism—Termination
Reuptake—main route of termination
COMT  Normetanephrine + MAO  VMA (3 methoxy 4 hydroxy-mandelic acid)
MAO  MHPG (3 methoxy-4 hydroxy- phenylglycol)
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

24. Alpha and beta receptors in a noradrenergic synapse
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

25. Noradrenergic Receptors
Phenoxybenzamine and phentolamine are A1 blockers and are used in the treatment of hypertension
Clonidine is an alpha2 presynaptic autoreceptor agonist and causes a decrease in sympathetic tone. It is useful in the treatment of hypertension and opiate withdrawal
Yohimbine is primarily an alpha2 presynaptic antagonist and causes an increase in sympathetic tone which may lead to increased arousal, panic anxiety and sexual potency. The beta receptors are thought to activate cyclic AMP
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

26. Clinical Significance
The amygdala is richly innervated by nonadrenergic neurons in the locus ceruleus. Norepinephrine plays an important role in panic disorder, maintenance of attention and transmission of pleasurable stimuli via the brainstem reticular activating system and medial forebrain bundle. NE enhances emotional memories and beta blockers can inhibit the formation of emotional memories
There is a dropout of noradrenergic neurons in the locus ceruleus in patients with Parkinson’s disease which may contribute to the high incidence of depression and anxiety in PD
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

27. Serotonin
Cell bodies
Main cell bodies are in the dorsal raphe nuclei surrounding the cerebral aqueduct in the midbrain. They project diffusely to the striatum, limbic system, cortex and cerebellum. Caudal raphe nuclei in the pons and medulla project to the spinal cord and probably play a role in the mediation of pain in the dorsal horn of the cord
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

28. Cingulate gyrus To hippocampus Cerebellar cortex Caudal raphe nuclei
Thalamus
Ventral striatum
Amygdaloid body
Hypothalamus
Olfactory and entorhinal
cortices
Hippocampus
Rostral raphe nuclei
Striatum
Neocortex
Cingulum
To hippocampus
Cerebellar cortex
Caudal raphe nuclei
To spinal cord
Cingulate gyrus
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

29. Synthesis
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review
Availability of tryptophan is the rate limiting step in serotonin synthesis

30. Clinical significance
Metabolism
Reuptake—primary method of inactivation
MAO 5-HIAA
Clinical significance
Serotonin has effects on:
Sleep induction
Mood
Pain/headache
Nausea
Anxiety
Extrapyramidal system
Pleasure
Vasomotor tone
Psychosis
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

31. Fenfluramine increases release MAO inhibitors decrease degradation
Methysergide is an antagonist
Buspirone is an agonist
6 LSD is an agonist 7 5 4 3 2 1
Fenfluramine increases release
Reserpine depletes vesicular stores
Fluoxetine (Prozac) and tricyclics block reuptake
MAO inhibitors decrease degradation
Tryptophan
5-OH-tryptophan
5-HT
5-HIAA
MAO
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

32. Clinical Significance
Availability of tryptophan is the rate-limiting step, Activity of Tryptophan hydroxylase is also important
Reserpine depletes vesicular stores and may exacerbate depression
Fenfluramine promotes presynaptic release
MAOI pre- and postsynaptically slows metabolism
Tricyclic antidepressants such as amitriptyline, and fluoxetine inhibit reuptake
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

33. Serotonergic Receptors
A very active area of research. 5-HT1-7 receptors have been described; subtypes of each group have been identified
5-HT1 works primarily  or  adenylate cyclase, Imitrex, used to treat acute migraine, is a 1D agonist
5-HT receptors affect phosphatidylinositol systems methysergide, LSD
Ondansetron a 5-HT3 antagonist is a potent antiemetic
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

34. Serotonin Syndrome MS—confusion, agitation, restlessness
Motor—myoclonus, rigidity, hyperreflexia
Autonomic-shivering, flushing, fever, diaphoresis
GI—nausea, diarrhea
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

35. Acetylcholine Primary cell bodies Termination of action by both:
Found in the patchy forebrain nuclei of the nucleus basalis of Mynert and septal nuclei
Rich connections to the hippocampus and amygdala
Ach is the main neurotransmitter at the neuromuscular jct and in the autonomic nervous system
Termination of action by both:
Enzymatic cholinesterase- choline plus acetate
By reuptake of choline
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

36. NBM NBM=nucleus basalis of Meynert
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review
Put midbrain slide here
NBM

37. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

38. Acetylcholine Involved in: Memory and attention Induction of REM sleep
Regulation of behavior
Motor function
Autonomic nervous system
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

39. Clinical Significance
Choline acetyltransferase (CAT) is the enzyme involved in the synthesis of Ach, CAT decreases in AD
Botulinum toxin inhibits release of acetylcholine and is useful for the treatment of focal dystonia. Lambert-Eaton syndrome, a paraneoplastic disorder, leads to decreased release of Ach
Acetylcholinesterase inhibitors such as Aricept, Exelon and Reminyl are approved for the Rx of mild-mod AD. Reminyl also modulates presynaptic nicotinic receptors. Exelon also inhibits butyrylcholinesterase
Mestinon, a peripheral cholinesterase inhibitor, improves motor symptoms in myasthenia gravis
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

40. Cholinergic Receptors
Nicotinic at NMJ and ANS. Antibodies formed against nicotinic cholinergic receptors at the neuromuscular junction cause myasthenia gravis
M1-5 muscarinic receptors in the brain. Nicotinic receptors also in brain. M2 and 4 decrease cAMP and M1,3,5 work via PI
Atropine and scopolamine block muscarinic receptors. Atropine increases heart rate, slows GI motility and dilates the pupils. Scopolamine can cause memory disturbance. Urecholine, an autonomic agonist, promotes bladder emptying. Ditropan, an autonomic antagonist, promotes retention of urine
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

41. GABA Distribution Synthesis
The major inhibitory neurotransmitter in the brain
Ubiquitously distributed
High concentrations in the striatum, hypothalamus, spinal cord, colliculi and medial temporal lobe
Synthesis
Glutamate (amino acid precursor)
 Glutamic acid decarboxylase (GAD)
GABA
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

42. GABA Receptors GABA A-chloride channel GABA B-Baclofen
GABA binding opens the chloride channel
Benzodiazepines enhance GABA affinity and activity
Bicuculline is a receptor antagonist and induces seizures
Barbiturates and alcohol help open the chloride channel at another site in the receptor
Picrotoxin inhibits the chloride channel and produces seizures
GABA is found to be decreased in the striatum in Huntington’s disease
GABA B-Baclofen
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

43. Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

44. GABA Neuron Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review
Put GABA neuron slide here

45. GABA Function
Benzodiazepines are used to treat anxiety, seizures, and muscle spasms
GABA transaminase inhibitor vigabatrin used in Europe for epilepsy
The anticonvulsant tiagabine (Gabatril) blocks reuptake of GABA
Topiramate (Topamax), divalproex (Depakote), gabapentin (Neurontin) and other AC’s modulate GABA
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

46. Glutamate The most common excitatory neurotransmitter in the CNS.
Amino acid involved in excitotoxic injury, seizures, learning, memory, anxiety, depression, psychosis
Blockade of glutamate receptors may have a protective role for tissue at risk in acute stroke and for TBI. MK801 and PCP are NMDA antagonists and both cause psychotic symptoms
Riduzole and lamotrigine medication for ALS and epilepsy decrease glutamatergic transmission. Memanatine an NMDA antagonist is being tried for advanced AD
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

47. Talk: Diagnosis, Biology and Treatment of OCD
Speaker: Michael A. Jenike, M.D.
Mtg: CME Vancouver 2001

48. Glutamate Receptor Function
Glutamate, at NMDA receptors, leads to opening of an ion channel and influx of Ca and Na
The block of Mg is removed by activation of an AMPA receptor
Glycine must also bind to its receptor to allow Ca and Na influx
Some glutamate receptors are metabotropic and use 2nd messengers
Glutamate reuptake is tightly regulated
Talk: Clinical Neurochemistry and Neuroimaging
Speaker: Stephen Salloway, M.D.
Meeting: 2001 Board Review

49. Feeling stuck?
Check out the Neurotransmitter Table on p. 73

50. Questions 1. Why does cocaine chorea? a. It is a dopamine agonist
b. It reduces GABA levels
c. It enhances serotonin
d. It increases endogenous dopamine
2. Which glutamate reactions are neurotoxic?
a. Glutamate-ACh c. Glutamate-NMDA
b. Glutamate-dopamine d. Glutamate-serotonin
3. Stimulation of which dopamine receptor(s) increases adenyl cyclase activity?
a. D1 receptors c. Both D1 and D2
b. D2 receptors d. Neither

51. Questions
4. The primary cell bodies for dopamine are located in the nucleus accumbens?
a. True b. False
Matching Type:
5. Dopamine a. Locus ceruleus
6. Serotonin b. Nucleus basalis of Meynert
7. Acetylcholine c. Substantia nigra
8. Norepinepherine d. Dorsal raphe
9. Dopamine a. Pons
10. Serotonin b. Midbrain
11. Acetylcholine c. Basal forebrain
12. Norepinepherine d. Cerebellum

52. Questions
13. What is the rate-limiting step in norepinepherine synthesis?
a. Phenylalanine to tyrosine d. Tyrosine to dopa
b. Tyrosine to tyrosine e. Dopa to norepinephine
hydroxylase
14. Clozapine does not increase prolactin.
a. True b. False
15. The activity of the monoamines is primarily terminated by:
a. breakdown by MAO d. phosphorylation
b. reuptake into the e. Ion channel inactivation presynaptic neuron
c. Conversion to choline and acetate

53. Answers
1. D
2. C
3. A
4. B
5. C
6. D
7. B
8. A
9. B
10. B
11. C
12. A
13. D
14. A
15. B

54. People and Pills
and the Art of Medicine

55. Surgical Treatment- Cavernous Hemangioma

56. 9/29/2003

57. 9/29/2003