Neurotransmitters Flashcards

1
Q

Neurotransmitter groupings

A
  1. Classical – active reuptake, synthesized at synapse, stored in small(er) vesicles.
    a. Biogenic amine
    b. (modified) Amino acid
  2. Peptide
  3. Others: nitric oxide (gas), cannabinoids (lipids), ATP (nucleotides), adenosine (nucleosides) – know that these exist.

Glutamate is the predominate excitatory neurotransmitter in the brain and spinal cord. The primary inhibitory neurotransmitter in the brain is GABA, while that in the spinal cord is glycine.

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2
Q

Major Biogenic Amine Neurotransmitters in the Central Nervous System (CNS)

A
Dopamine (DA)
Norepinephrine (NE) 
(a.k.a. noradrenaline)
Serotonin (5-HT)
Acetylcholine (ACh)
Histamine
Epinephrine (a.k.a. adrenaline)
Others (e.g. tyramine, octopamine)
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3
Q

Major (modified) Amino Acid neurotransmitters

A

Glutamate (Asparate)

Gamma-Amino Butyric Acid (GABA)

Glycine

Receptors are named after the neurotransmitter in the case of GABA and glycine, but not for the ionotropic forms of glutamate receptors (e.g., NMDA, AMPA, kainate)

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4
Q

Source of dopamine

A

substantia nigra par compacta (SNc) and ventral tegmental area (VTA)

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5
Q

Source of epinepherine

A

locus coeruleus (LC), much smaller amounts in lateral pontomesencephalic tegmentum

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6
Q

source of serotonin

A

raphe nuclei (there are multiple subdivisions)

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7
Q

source of histamine

A

tuberomammilary nucleus of the posterior hypothalamus

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8
Q

source of acetylcholine

A

septal nuclei, nucleus basalis of Meynert, reticular formation, lesser amounts in interneurons of caudate and putamen (striatum)

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9
Q

source of glutamate

A

major excitatory neurotransmitter in brain and spinal cord projection neurons. Used by most neurons in cerebral cortex sending projects to other parts of cortex, brain stem and spinal cord.

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10
Q

Source of GABA

A

principle inhibitory neurotransmitter of interneurons in the brain. GABAergic neurons in striatum project to the substantia nigra pars reticulata (SNr). GABAergic projections neurons also present in globus pallidus and Purkinje cells of cerebellum.

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11
Q

Source of Glycine

A

principle inhibitory neurotransmitter of interneurons in the brain stem and spinal cord.

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12
Q

Peptides Neurotransmitter classifications

A
Pituitary peptides
Brain-gut peptides
Opioids (produce analgesia) – enkephalins
and dynorphins (widely distributed), and
endorphins (localized distribution)
Neurohypophyseal hormones
Hypothalamic-releasing hormones
Circulating hormones
Others
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13
Q

Catecholamine Biosynthesis Overview

A

Phenylalanine-> Tyrosine-> L-DOPA-> Dopamine-> Norepinephrine-> Epinephrine

Catecholaminergic neurotransmitters share a common biosynthetic pathway.
The amino acid tyrosine is the biosynthetic precursor and it is taken up into the brain by active transport.
The enzyme tyrosine hydroxylase (TH), which adds a hydroxyl group to tyrosine, is the rate limiting enzyme in catecholamine biosynthesis. In essence, this means that it determines the level of catecholamines. Tetrahydrobiopterin (BH4) is a cofactor. The activity of TH is decreased by end-product inhibition via displacement of a tetrahydrobiopterin cofactor. Phosphorylation of TH increases its activity by allowing it to overcoming end-product inhibition.
Catecholaminergic cells are often identified as being positive for the enzyme tyrosine hydroxylase. Aromatic amino acid decarboxylase (AAAD) is an enzyme involved in biosynthesis of neurotransmitters having tyrosine or tryptophan (e.g., serotonin, 5-HT) precursors. Its cofactor is pyridoxal phosphate (vitamin B6).
Dopamine-beta-hydroxylase (DBH) is the only biosynthetic enzyme located inside synaptic vesicles. It transforms DANE.
Phenylethanolamine-N-methyltransferase (PNMT) has a very restricted distribution in the brain (highest concentrations in parts of the hypothalamus), brainstem (reticular formation, periaqueductal gray, floor of the fourth ventricle) and in the central part of the adrenal gland.

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14
Q

Catecholamine Metabolism Pathway

A

Phenylalanine (Phe hydroxylase)-> tyrosine
Tyrosine (Tyr hydroxylase)-> dihydroxyphenylalanine (L-DOPA)
L-DOPA (aromatic AA decarboxylase)-> dopamine
dopamine (dopamine beta-hydroxylase)-> norepinepherine
norepinepherine (phenylethanolamine-N-methyl transferase)-> epinepherine

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15
Q

homovallinic acid formation

A

HVA is formed as a metabolic byproduct of dopamine and can be used to determine dopamine levels in the brain and be used to diagnose brain cancer

dopamine (monoamine oxidase B)-> 3,4-dihydroxyphenylacetaldehyde
3,4-DHPA (aldehyde dehydrogenase)-> 3,4 dihydroxyphenyl acetic acid (DOPAC)
DOPAC (catechol-O-methyltransferase aka COMT)-> homovanillic acid (HVA)

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16
Q

VMAT

A

vesicular monoamine transporter (VMAT) pumps neurotransmitters from the cytosol into synaptic vesicles. Its has very promiscuous substrate specificity.
VMAT-1 localized in adrenal gland cells
VMAT-2 localized in catecholaminergic, serotoninergic and histaminergic neurons

  • DA, NE, 5HT, and histamine (HA) are all packaged by VMAT2
  • Acetylcholine has its own transporter (VAChT)
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17
Q

Reserpine

A

inhibit VMAT-2 and thus “depletes” neurons of vesicular neurotransmitters available for release.

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18
Q

tetrabenazine

A

inhibit VMAT-2 and thus “depletes” neurons of vesicular neurotransmitters available for release.

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19
Q

Types of NT release

A

Calcium-dependent (stimulus-dependent) vesicular release

Reversal of catecholamine transporters such as (DAT, NET and SERT).

Dendritic release (calcium-independent)

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20
Q

Indoleamine Biosynthesis Overview

A

Tryptophan (tryptophan hydroxylase)-> 5-hydroxytryptophan
5-HTP (aromatic AA decarboxylase)-> serotonin
Serotonin (other steps)-> Melatonin

Indoleamine biosynthesis and metabolism has much in common with the catecholamines: amino acid precursor, rate–limiting hydroxylase (ring hydroxylation), AAAD and MAO-type metabolism.
Two genotypically distinct isoforms of tryptophan hydroxylase have been discovered
A. TPH1 is expressed in gut, pineal gland, spleen, thymus
B. TPH2 is predominantly expressed in the brain stem

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21
Q

MAO-A

A

monoamine oxidase A

primarily NE, EPI, 5HT (serotonin) and tyramine metabolism

tranylcypromine is an inhibitor

inhibitor plus selective-serotonin reuptake inhibitor (SSRI) may result in serotonin syndrome; dangerously high synaptic levels of serotonin producing hyperthermia, muscular rigidity, abrupt changes in mental status and vital signs

22
Q

Serotonin Metabolism

A

tryptophan (tryptophan hydroxylase)-> 5-hydroxytryptophan

5-hydroxytryptophan (aromatic AA drcarboxylase (AAAD))-> serotonin

23
Q

MAO-B

A

monoamine oxidase B

primarily dopamine metabolism

rasagiline is an inhibitor

24
Q

COMT

A

Catechol-O-methyltransferase

involved in catecholamine degradation

Major inactivator in adrenal gland

tolcapone is an inhibitor.

25
Q

Histamine Biosynthesis and Metabolism Overview

A

histidine (histidine decarboxylase)-> histamine

degradation
histamine (histamine N-methyltransverse)-> N-methylhistamine
N-methylhistamine (MAO-B)-> N-methylimidazole acetaldehyde
N-methylimidazole acetaldehyde (xanthine oxidase)-> N-methylimidazole acetic acid

Histidine is converted to histamine in a single enzymatic step by loss of a carboxyl group by the enzyme histidine decarboxylase (it has its own unique decarboxylase unlike the catecholamine and indoleamine neurotransmitters which share the aromatic amino acid decarboxylase)

Histidine can undergo degradation by different pathways but the predominate one, and the one occurring in the brain, is by inactivation by histamine-N-methyltransferase. This metabolite can then be further degraded by monoamine oxidase B (MAO-B)

Vesicular monoamine transporter 2 (VMAT2) packages histamine into synaptic vesicles. Histamine is a particularly high affinity VMAT2 substrate.

While it is unclear which reuptake transporter is involved both neurons and glia cells are involved in histamine reuptake from the synaptic cleft.

26
Q

Acetylcholine Biosynthesis and Metabolism Overview

A

phosphatidylcholine (phospholipase)-> phosphocholine
phosphocholine (phosphatase)-> choline
choline (choline acetylasej)-> acetylcholine
acetylcholine (acetylcholinesterase)-> choline

The choline is derived from the membrane lipid phosphatidylcholine

The “acetyl” donor, acetyl-CoA, is derived from pyruvate the end product of glycolysis (metabolism of glucose).

Although there is only one enzymatic step in the synthesis of acetylcholine from choline, the enzyme that does this step choline acetyltransferase (ChAT) (a.k.a. choline acetylase) is not rate-limiting rather it appears that other factors may be limiting such as the availability of choline or transport of acetyl-CoA (as citrate) out of the mitochondria; pyruvate transported into mitochondria, converted to acetyl-CoA then citrate which is exported degrading to provide acetyl-CoA.

A vesicular choline transporter (VAChT) packages ACh into synaptic vesicles.

Inactivation is primarily metabolic: acetylcholine esterases (AChE) (brain) and butyrylcholine esterase (little in brain but a lot in liver).

AChE is a membrane associated protein secreted into the extracellular (synaptic) space and the choline derived is taken back up into the pre-synaptic side by a high affinity choline (uptake) transporter.

27
Q

Physostigmine

A

Physostigmine and tacrine are examples of reversible AChE inhibitors

28
Q

tacrine

A

Physostigmine and tacrine are examples of reversible AChE inhibitors

29
Q

Overview of GABA Biosynthesis and Metabolism

A

Gutamate (glutamate decarboxylase (GAD)-> gamma-amino butyric acid (GABA)
GABA (GABA transaminase using alpha KG)-> glutamate and succinic semialdehyde
succinic semialdehyde (succinic semialdehyde dehydrogenase)-> succinic acid

GABA is packaged into vesicles by a vesicular GABA transporter (VGAT)/vesicular inhibitory amino acid transporter (VIAAT) whose substrate specificity is lax (e.g., it also transporters glycine another inhibitory amino acid neurotransmitter).

Glutamate uses its own transporter (VGluT). Enzymes to make glutamate from α KG are also present in the vesicles

GABA-B receptors are metabotropic GPCRs which in the CNS primarily serve an autoreceptor function. GABA-A receptors are ionotropic and primarily post-synaptic.

Like for the catecholamines and indoleamine, reuptake is the main method for inactivation of GABA at synapses.

Inactivation of GABA is primarily via reuptake by GABA transporters (GAT). Different GAT subtypes are expressed on neurons, glia or both. Four GABA transporters (GAT) have been characterized.

30
Q

Overview of Glycine Biosynthesis, Metabolism, Release and Inactivation

A

Serine (serine hydroxymethyltransferase)-> glycine
glycine (glycine cleavage system)-> CO2 and ammonia

Glycine can be obtained from one’s diet but can also be synthesized from serine

There are two glycine transporters named GlyT1 and GlyT2. Though small amounts of glycine are released into the synaptic cleave by glycinergic neurons, apparently quite a bit is released by reversal of GLY-T1 which is located on glia cells. Reuptake of glycine into glial cells is performed by GLY-T1 or via a neutral amino acid transporter. GlyT2 is located on presynaptic neurons serves to reuptake small amounts of glycine released by glycinergic neurons and also serves as a vesicular storage transporter

Vesicular GABA transporter/vesicular inhibitory amino acid transporter (VGAT/VIAAT) is the vesicular storage transporter for glycine and GABA

31
Q

rasagiline

A

MAO-B inhibitor

32
Q

tranylcypromine

A

MAO-A inhibitor

33
Q

D2 dopamine receptor antagonism

A

helps treat psychosis in schizophrenia, dyskinesias in Huntingtons, and tics in Tourette’s

34
Q

D1/D2 dopamine receptor agonsim

A

helps treat dyskinesias in parkinsons and DOPA-responsive dystonia (use L-DOPA)

35
Q

M1 muscarinic antagonism

A

helps with nausea in motion sickness

36
Q

5-HT1A receptor agonism

A

acts as anxiolytic for anxiety

37
Q

5-HT2A/2C antagonism

A

acts as antidepressant

Blockage of serotonin receptors HT2A/2C can treat depression or depression-like behaviors like bipolar depression, post partum depression, schizophrenia (has a component where the patient has abolition-inability to feel pleasure in normally pleasurable activities), etc

38
Q

NMDA weak antagonism

A

helps with dyskinesias in parkinsons and slows deterioration in Alzheimers

  • Weak NMDA blockers are used to treat Parkinson’s and Alzheimers by blocking excess glut release from subthalamic nuclei in Parkinson’s and preventing excessive (toxic) Glu buildup in Alzheimers
39
Q

GABA-A potentiation

A

has antiseizure effect in epilepsy and anxiolytic effect in anxiety

  • Allosteric potentiation of GABA A receptor with benzodiazepines help decrease seizures (need to already have GABA present). Preventing GABA reuptake with GAT1 to treat seizures.
    • Note: vitamin B6 is necessary for making GABA, so deficiency leads to seizures (seizures are due to global hyperactivity). Giving allosteric potentiator would not work because GABA is not present to be increased by allosteric modulator
    • Vigabaterin inhibit GABA-T resulting in increased NT levels to treat seizures. GABA potentiators enhance this because of the increased levels of GABA
    • Huntingtons disease is mostly due to degeneration of GABAergic neurons in the striatum. GABA-A receptor potentiators like benzodiazepines can compensate for loss of GABAergic neurons and help; also help treat the anxiety component of Huntington’s disease
40
Q

GABA-B agonism

A

acts as spasmolytic in amyotrophic lateral sclerosis (ALS) and in multiple sclerosis (MS)

  • Activation of GABA-B receptors can be used to treat muscle spasticity amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by acting presynaptically to decrease subsequent GABA release. Also has post synaptic effect of decreasing Ca channel excitability and activating K channels
41
Q

NET and NET/DAT antagonism

A

helps treat ADHD

Presynaptic reuptake transporters for DA, NE, and 5HT are DAT, NET, and SERT. Blockage of DAT and NET help treat ADHD inattention and impulsivity. Blockage of NET and/or SERT is used to treat depression (unipolar or depression component of bipolar disorder) or OCD

42
Q

SERT and SERT/NET antgonism

A

acts as antidepressant in depression, bipolar disorder, and post-partum depression and helps treat OCD

Presynaptic reuptake transporters for DA, NE, and 5HT are DAT, NET, and SERT. Blockage of DAT and NET help treat ADHD inattention and impulsivity. Blockage of NET and/or SERT is used to treat depression (unipolar or depression component of bipolar disorder) or OCD

43
Q

VMAT-2 antagonism

A

helps treat dyskinesias in Huntingtons

44
Q

GAT-1 antagonism

A

helps treat seizures in epilepsy

45
Q

D2 dopaminurgic antagonism side effects

A

also affects extrapyramidal leading to Parkinsonism and tardive dyskinesia and the neuroendocrine system leading to gynecomastia (man boobs) and amenorrhea (no periods)

46
Q

D2 dopamine agonism side effects

A

can lead to D2 agonist-induced psychosis

47
Q

H1 histaminergic antagonism

A

can lead to sedation

  • H1 receptor (histamine receptor) is in the vestibular system and involved in motion sickness which can be prevented by H1 antagonists (only effective before nausea is experienced)
    • Histamine intolerance- results in accumulation of His or diminished degradation of His leading to motion sickness like symptoms
    • Activation of histaminergic cells affects sleep. Penetrating H1 antagonists lead to drowsiness (esp with alcohol) because histaminergic neurons in the posterior hypothalamus is involved in waking mechanisms
48
Q

serotonergic (some 5-HT1A and more 5-HT2A/2C) side effects

A

can lead to decreased libido and delayed ejaculation

49
Q

5-HT2B agonism side effects

A

can led to precipitate valvular heart failure

50
Q

DOPA responsive dystonia

A

Missing tetrahydrobiopterin cofactor or loss of enzyme to make L DOPA leads to inability to synthesize dopamine, so gives Parkinson’s like disease- DOPA responsive dystonia

Dopamine can be replaced by L-DOPA because LDOPA crosses BBB and dopamine doesn’t, but increased dopamine in the gut leads to nausea, so giving peripheral AAAD inhibitor (doesn’t cross BBB e.g. carbidopa) decreases dopamine in periphery, but allows dopamine increase in the CNS

51
Q

reserpine

A

VMAT 2 is involved in uptake of NT in CNS, so drugs like reserpine deplete neurons overtime. In lower doses, can cause decreased DA in synapse and treat dyskinesias like Huntingtons disease, Tourettes, and autism. Also used to be used for psychosis and high blood pressure because depletes DA to treat psychosis and NE to treat HBP. NOT used to treat dyskinesias like Parkinsons because it is caused by a decrease in DA

52
Q

alzheimers disease

A
  • In alzheimers disease, cholinergic neurons degenerate in the septal nuclei (memory) and the nucleus basais of Meiner (vigilance- damage leads to abnormal sleep cycles). Treated by centrally active reversible* AChE inhibitors (irreversible AChE inhibitors cause increased ACh levels that cause paralysis and death