Clinical Neurochemistry Clinical Neurochemistry

“The Soup”“The Soup”

A good working knowledge of clinical A good working knowledge of clinical neurochemistry is essential for neurochemistry is essential for

understanding and treating neurological understanding and treating neurological and psychiatric disorders. It is important to and psychiatric disorders. It is important to

learn the basics now so you can update learn the basics now so you can update your clinical management as new your clinical management as new information becomes available.information becomes available.

What You Should KnowWhat 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 NeurochemistryAdvances 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 NeurochemistryClinical Neurochemistry

Monoamines Dopamine Norepinephrine Serotonin

Others Acetylcholine GABA Glutamate

CatecholaminesCatecholamines

Dopamine

Norepinephrine

Epinephrine

Dopamine (Main Cell Bodies)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

Dopamine cell bodies and tracts

SN

VTA

DR

Weigert stain of the midbrainSN=substantia nigra, VTA=ventral tegmental area, DR=dorsal raphe

Phenylalanine

Phenylalanine hydroxylase

Rate-Limiting Step and Rate-Limiting Step and Termination of Action of DopamineTermination 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)

Monoaminergic ReceptorsMonoaminergic 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 ReceptorsDopamine 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 systemDrugs 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.

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.

Clinical SignificanceClinical Significance

Thalamus Cingulate Gyrus

Amygdaloid BodyOlfactory and Entorhinal

Cortices

Hippocampus

Locus Ceruleus

Lateral Tegmental NA Cell System

To Spinal Cord

Cerebellar Cortex

NE cell bodies are in the locus ceruleus at the upper dorsal pons.

Noradrenergic Cell Bodies in Noradrenergic Cell Bodies in the Dorsal Ponsthe Dorsal Pons

LCLC AS

Weigert myelin stain of pons. LC=locus ceruleus, AS=aqueduct of Sylvius

Metabolism—TerminationMetabolism—Termination

Reuptake—main route of termination

COMT Normetanephrine + MAO VMA (3 methoxy 4 hydroxy-mandelic acid)

MAO MHPG (3 methoxy-4 hydroxy-phenylglycol)

Alpha and betareceptors in a noradrenergic synapse

Noradrenergic ReceptorsNoradrenergic 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

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

Clinical SignificanceClinical Significance

SerotoninSerotonin

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

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

SynthesisSynthesis

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

Methysergide is an antagonist

Buspirone is an agonist

6 LSD is an agonist 7

5

4

32

1

Fenfluramineincreases release

Reserpine depletesvesicular stores

Fluoxetine (Prozac) andtricyclics block reuptake

MAO inhibitorsdecrease degradation

Tryptophan

5-OH-tryptophan

5-HT

5-HIAA

5-HT

5-HT

MAO5-HT

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

Clinical SignificanceClinical Significance

Serotonergic ReceptorsSerotonergic 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 SyndromeSerotonin Syndrome

MS—confusion, agitation, restlessness

Motor—myoclonus, rigidity, hyperreflexia

Autonomic-shivering, flushing, fever, diaphoresis

GI—nausea, diarrhea

AcetylcholineAcetylcholine

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

NBM=nucleus basalis of Meynert

AcetylcholineAcetylcholine

Involved in:

Memory and attention

Induction of REM sleep

Regulation of behavior

Motor function

Autonomic nervous system

Clinical SignificanceClinical 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

Cholinergic ReceptorsCholinergic 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

GABAGABA

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 ReceptorsGABA 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 NeuronGABA Neuron

GABA FunctionGABA 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

GlutamateGlutamate

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 FunctionGlutamate 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

QuestionsQuestions

1. Why does cocaine chorea?a. It is a dopamine agonistb. It reduces GABA levelsc. It enhances serotonind. It increases endogenous dopamine

2. Which glutamate reactions are neurotoxic?a. Glutamate-ACh c. Glutamate-NMDAb. 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

QuestionsQuestions

4. The primary cell bodies for dopamine are located in the nucleus accumbens?a. True b. False

Matching Type:5. Dopamine a. Locus ceruleus6. Serotonin b. Nucleus basalis of Meynert7. Acetylcholine c. Substantia nigra8. Norepinepherine d. Dorsal raphe

9. Dopamine a. Pons 10. Serotonin b. Midbrain 11. Acetylcholine c. Basal forebrain 12. Norepinepherine d. Cerebellum

QuestionsQuestions

13. What is the rate-limiting step in norepinepherine synthesis?a. Phenylalanine to tyrosine d. Tyrosine to dopab. 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

AnswersAnswers

1. D2. C3. A4. B5. C6. D7. B8. A9. B10. B11. C

12. A13. D14. A15. B

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