Transcript Clinical Neurochemistry and Neuroimaging

Clinical Neurochemistry
“The Soup”
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.
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
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
Clinical Neurochemistry
 Monoamines
 Dopamine
 Norepinephrine
 Serotonin
 Others
 Acetylcholine
 GABA
 Glutamate
Catecholamines
 Dopamine
 Norepinephrine
 Epinephrine
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
Weigert stain of the midbrain
SN=substantia nigra, VTA=
ventral tegmental area, DR=
dorsal raphe
VTA
SN
Dopamine cell bodies
and tracts
DR
Phenylalanine
Phenylalanine hydroxylase
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), catecholO-methyltransferase (COMT)
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
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
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.
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.
NE cell bodies
are in the
locus
ceruleus
at the upper
dorsal pons.
Thalamus
Cingulate Gyrus
Amygdaloid Body
Olfactory and Entorhinal
Cortices
Cerebellar Cortex
To Spinal Cord
Hippocampus
Locus Ceruleus
Lateral Tegmental NA Cell System
Noradrenergic Cell Bodies in
the Dorsal Pons
LC AS LC
Weigert myelin
stain of pons.
LC=locus
ceruleus,
AS=aqueduct of
Sylvius
Metabolism—Termination
 Reuptake—main route of termination
 COMT  Normetanephrine + MAO  VMA
(3 methoxy 4 hydroxy-mandelic acid)
 MAO  MHPG (3 methoxy-4 hydroxyphenylglycol)
Alpha and beta
receptors in a
noradrenergic
synapse
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
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
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
Thalamus
Striatum
Cingulum
Cingulate gyrus
To hippocampus
Neocortex
Ventral striatum
Amygdaloid body
Hypothalamus
Olfactory and entorhinal
cortices
Cerebellar cortex
Caudal raphe nuclei
Hippocampus
Rostral raphe nuclei
To spinal cord
Synthesis
Availability of tryptophan is the rate limiting step in serotonin synthesis
 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
Tryptophan
1
5-OH-tryptophan
Reserpine depletes
vesicular stores
MAO inhibitors
decrease degradation
5-HT
MAO
4
5-HT
2
Fenfluramine
increases release
5-HT
3
5-HT
6 LSD is
an agonist
Fluoxetine (Prozac) and
tricyclics block reuptake
5-HIAA
7
Buspirone is an agonist
Methysergide is an antagonist
5
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
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
Serotonin Syndrome
 MS—confusion, agitation, restlessness
 Motor—myoclonus, rigidity, hyperreflexia
 Autonomic-shivering, flushing, fever,
diaphoresis
 GI—nausea, diarrhea
Acetylcholine
 Primary cell bodies
 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
NBM=nucleus
basalis of Meynert
NBM
Acetylcholine
 Involved in:
 Memory and attention
 Induction of REM sleep
 Regulation of behavior
 Motor function
 Autonomic nervous system
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. LambertEaton 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
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
GABA
 Distribution
 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
GABA Receptors
 GABA A-chloride channel
 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
GABA Neuron
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
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
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
Feeling stuck?
Check out the
Neurotransmitter
Table on p. 73
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
Questions
4.
The primary cell bodies for dopamine are located in the
nucleus accumbens?
a. True
b. False
Matching Type:
5. Dopamine
6. Serotonin
7. Acetylcholine
8. Norepinepherine
9.
10.
11.
12.
Dopamine
Serotonin
Acetylcholine
Norepinepherine
a.
b.
c.
d.
Locus ceruleus
Nucleus basalis of Meynert
Substantia nigra
Dorsal raphe
a.
b.
c.
d.
Pons
Midbrain
Basal forebrain
Cerebellum
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
Answers
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
D
C
A
B
C
D
B
A
B
B
C
12.
13.
14.
15.
A
D
A
B
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