migraine and 5-ht

Serotonin & Migraine

Brian J. Piper, Ph.D., M.S.

Goals

• Serotonin– Biosynthesis & elimination– Receptors

• Migraine– ergotamines– triptans

Serotonin in Different SpeciesC. Elegans (roundworm) Betta splendens (Siamese fighting fish) lobster

C57 mouse Long-Evans rat marmoset

Biosynthesis: Tryptophan • Essential amino acid

Food g tryptophan / 100 g food

salami 0.253

lentils 0.251

turkey (breast) 0.194

almonds 0.192

walnuts 0.17

asparagus 0.027

USDA National Nutrient Database for Standard Reference, Release 19 (2006).

Biosynthesis of 5-Hydroxytryptamine

• Tryptophan hydroxylase: found in axons, rate limiting step

• L-aromatic amino acid decarboxylase (AACD): not rate limiting step, also important for catecholamine

General Rule:Depleting 5-HT: easyIncreasing 5-HT: not easy

Where is 5-Hydroxytryptamine (Serotonin) localized?

• Enterochromaffin cells (90%)• Platelets: thombosis• Central nervous system (10%)

– Dorsal raphe: forebrain (lateral)– Medial raphe: forebrain (medial)– Nucleus raphe magnus: spinal

cord

Kranz et al. (2012). PNAS, 109(29), e2000.

5-HT & Aggression

• Para-chlorophenylalanine (PCPA): irreversible tryptophan hydroxylase inhibitor

• PCPA treated rats were tested for muricide• Inverse relationship between 5-HT &

aggression

Killers Non-killers

Control 0 13

PCPA 14 4

Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.

Serotonin Transporter

• SERT removes 5-HT from synapse• Localized at cleft, along axon, & on

soma

Stahl (2008). Essential Psychopharmacology. p. 93.

Serotonin Transporter (SERT) Reflects Axon Integrity

• High dose 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) damages 5-HT axons

• SERT can be measured with immunocytochemistry

Serotonin fibers in the caudate nucleus of a control squirrel monkey (A), a monkey that received 5 mg/kg MDMA 2 weeks

(B), or 7 years (C) previously.

Hatzidimitriou et al. (1999). Journal of Neuroscience, 19, 5096-5107.

Breakdown of 5-Hydroxytryptamine

Monoamine Oxidase (MAO): target of older antidepressant drugs

5-HIAA: found in Cerebral Spinal Fluid

NADH: nicotine adenine dinucleotide, reduced; increased by ethanol!

Sanders-Bush & Hazelwood (2012). In Pharmacological Basis of Therapeutics, p. 336.

Ergot Poisoning• Fungus (Claviceps purpurea) found on grain contains

ergotamine• Antiquity: Saint Anthony’s fire (convulsions & gangerine)• Modern Case: Pont St. Espirit, France 1951

– Early Symptoms (6-48 hours): diffuse abdominal pain (burning sensation throughout whole digestive tract), nausea, vomiting, insomnia lasting several days

– Middle Symptoms ( ≈2 days – 1 week): cold extremities, cramps of calves, logorrhea, visual hallucinations (themes = animal & self-accusation)

– Late Symptoms (≈post 1 week): muscular spasm & cardiovascular collapse (4 died)

Summarized from Gabbai et al. (1951). British Medical Journal, Sept 15, 650-651.

History of LSD

• Lysergic acid diethylamide was synthesized by Hoffman (1938) from ergotamine

• CIA explored use (1950s)• Counter-culture use (1960s)• 5-HT2A antagonist• Schedule I • Adjunct to psychotherapy?

Albert Hoffman, Ph.D.

1906 - 2008

History of LSD• Lysergic acid diethylamide was synthesized by Hoffman (1938)

from ergotamine• CIA explored use (1950s)• Counter-culture use (1960s)• 5-HT2A antagonist/5-HT1A agonist• Schedule I • Adjunct to psychotherapy?

1st 3 min: http://www.youtube.com/watch?v=HBOPFWmZCdM&list=LPNw1MNHLBky4&index=2&feature=plcp

5-HT Receptor Tissue Post-ReceptorMechanism

Agonist (Ag) or Antagonist (Ant)

1A Raphe, hippocampus Gi Ag: 8-OH-DPAT

1B substantia nigra (SN) Gi Ag: Sumatriptan

1C (oops, 2C)

1D brain Gi Ag: Sumatriptan

1E cortex, putamen Gi

1F cortex, hippocampus Gi

1P enteric nervous system Go Ant: Ranzapride

2A platelets, smooth muscle Gq Ag: DOI; Ant: Ketanserin

2B stomach fundus Gq Ag: DOI

2C Hippocampus, SN Gq Ag: DOI

3 area postrema Na+ channel Ag: ondansetron

Based on Katzung et al. (2012). Basic & Clinical Pharmacology, p. 282.

5-HT & Anxiety: Light Dark Test• Role of GABA or 5-HT in anxiety

--------------------------------- --------------------------------------------------

5-HT & Depression

• Methods: 15 un-medicated women with a history of 2+ episodes of depression were on a low protein diet for 1 week, then randomly assigned to receive:– Tryptophan + : L-tryptophan (1.9 g), L-alanine (4.6

g) L-arginine (4.1 g)

– Tryptophan - : L-alanine (4.6 g) L-arginine (4.1 g)

Smith et al. (1997). Lancet, 349, 915-919.

Hamilton Depression Inventory

http://www.psy-world.com/online_hamd.htm

Ham-D

http://www.psy-world.com/online_hamd.htm

Max Hamilton

1912-1988

Smith et al. (1997). Lancet, 349, 915-919.

Migraine Terminology• migraineurs: person who experiences migraines• aura: collection of symptoms that may precede or co-

occur; typically visual, lasts less than 1 hour– positive features

• scintillations: a rapidly oscillating pattern of visual distortions• photopsia: perception of flashes of light• teichopsia: spot of flickering light

– negative features• scotoma: an area of diminished vision within the visual field• hemianopsia: blindness in half of the visual field, may involve one or

both eyes

– hemiplegic aura: occurring on one side of body– basilar type aura: aura is localized to the brainstem

DiPiro et al. (2008). Pharmacotherapy: A Pathophysiologic Approach. p. 1008.

George Cruikshank: The Head Ache (1819)

2:20: http://www.mayoclinic.com/health/migraine-aura/MM00659

International Headache Society Migraine Criteria

• Migraine with aura (classic migraine)– At least 2 attacks– Aura fulfills criteria for typical aura, hemiplegic aura, or basilar type

aura– Not attributed to another disorder

• Migraine without aura– At least 5 attacks– Headache lasts 4 to 72 hours (untreated or successfully treated)– Headache has at least 2 characteristics

• Unilateral location, pulsating quality, or moderate or severe intensity– Aggravation by or avoidance of routine physical activity (walking,

climbing stairs)– During headache, at least one of the following:

• Nausea, vomiting, or both• Photophobia and phonophobia

– Not attributed to another disorder http://ihs-classification.org/en/02_klassifikation/02_teil1/01.00.00_migraine.html

Epidemiology

Pathophysiology

• limited animal models• theory: genetic (50% heritable) & neurovascular• 2 min: http://www.youtube.com/watch?v=yZr9Joe85wg• orthodromic: electrical potential following typical direction (soma

to axon)• antidromic: electrical potential traveling in the reverse direction

(axon to soma)

Ergot Alkaloids• Used for moderate to severe migraines (non-

prophylactic) but not other pain• Vasoconstrictive agents with long history (1920s)

but dirty drugs (5-HT, dopamine, adrenergic)

Effects of ergot derivatives on contraction of isolated segments of human basilar artery stripsremoved at surgery. All ergot derivatives are partial agonists, and all are more potent thanfull agonists, norepinephrine (NE) and serotonin (5-HT). Dihydroergotamine (DHE), ergotamine (ERG), methysergide (MS), and methylergometrine (MT).

Modified from Katzung (2012). Basic & Clinical Pharmacology. p. 289.

Diverse ROA

• ergotamine & caffeine (Cafergot): oral• ergotamine & caffeine (Migerot):

suppositories• ergotamine tartrate (Ergomar): sublingual• dihydroxyergotamine mesylate (Migranol):

nasal spray or injections

Adverse Effects

• Route dependent nausea & vomiting (10-20%)• weakness• tingling of extremities (think history!)• chest pain & temporary changes in heart rate

(↑↓ )

Contraindications

• pregnant women (miscarriage risk)• coronary artery disease• should not be used simultaneously with

triptans

Triptans• Recently developed (1990s) 5-HT1B/1D agonists act on

neurons & blood vessels• First line therapy for moderate to severe migraines

(non-prophylactic)• Should not be used with SSRI

Example Trial Evaluating Triptans

Effects of sumatriptan (6 mg injected subcutaneously, N=734) or placebo (N=370) on symptoms of acute migraine 60 minutes after subcutaneous injection. From Cady et al. (1991). JAMA, 265,2831-2835.

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Summary

• “neurotransmitter for all seasons”• Ergot alkaloids• Triptans

Melatonin

Goodwin (13) & Related TerminologyEnterochromaffin cells (p. 335): a type of enteroendocrine cell occuring in the epithelia lining the lumen of the digestive tract and the respiratory tracttunicate (p. 335): marine filter feeders (image, lower right)coelenterate (p. 335): outdated zoological term for 2 phyla including comb jellies (image, lower left) and sea anemoniespsychotomimetic (p. 337): drug that mimics elements of mental illness (psychosis)choroid plexus (p. 337): layer fo cells found in ventricles of brain that produce cerebral spinal fluidsuperior colliculus (p. 340): Latin: upper hill , anatomical structure (image, middle, see arrow)hyperacusis (p. 345): oversensitivity to certain frequencies of soundparesthesias (p. 346): sensation of tingling or burning, aka “pins & needles”asthenia (p. 346): weaknessprecordial (p. 348): pertaining to the region over the heart/stomachHorton’s syndome (p. 349): aka cluster headache, intense pain typically on one side of the head

Organic Chemistry (Refresher)