Week 1 - CNS Neurotransmitters Flashcards

1
Q

compared to other signaling molecules, what distance do neurotransmitters act over?

A

tiny distance

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2
Q

two major types of neurotransmitters and examples

A
  1. small molecules (classical neurotransmitters)
    - ACh
    - AA (glutamate, GABA, gly)
    - biogenic amines (dopamine, norepinephrine, serotonin)
  2. neuropeptides (nonclassical neurotransmitters)
    - more than 100+ different peptides (brain-gut, opiods)
    - typically 3-36 AA long
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3
Q

how is the concentration of nt in synaptic cleft regulated?

A

tightly regulated via:

  • nt synthesis
  • packaging
  • release
  • removal (terminates synaptic transmission)
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4
Q

small molecule transmitter transport

A

slow axonal transport, but signal quickly

  • synthesized w/in presynaptic terminal and packaged into vesicles by specific transport PRO in vesicle membrane
  • can respond to increased demand rapidly b/c they are synthesized in nerve terminal
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5
Q

neuropeptide transmitter transport

A

fast axonal transport, but signal slowly

  • synthesized and packaged into transport vesicles w/in cell body, then transported to nerve terminal via fast axonal transport
  • cannot respond quickly to increased demand b/c synthesized in cell body and must be transported the entire length of the axon to the release site
  • release must be carefully regulated to prevent depletion
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6
Q

2 types of neurotransmitter receptors

A
  1. ionotropic (fast ligand-gated ion channels)

2. metabotropic (slow GPCR that signal to channel)

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7
Q

ionotropic nt receptors

A

ligand-gated ion channels that open in direct response to ligand binding

  • consist of 4-5 subunits that contain 3-4 transmembrane domains
  • usually multiple subunits that can be assembled to generate diverse set of receptors
  • -there are rules that govern which set of subunits are found w/in each receptor
  • -for most receptors, depending on composition of subunits, each receptor subtype will have distinct properties, meaning some drugs may work on one patient but not another
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8
Q

metabotropic nt receptors

A

GPCR that activate G-PRO in response to ligand binding

  • activated G-PRO modulate ion channels directly or indirectly through intracellular enzymes and second messengers
  • monomeric PRO containing 7 transmembrane domains
  • wide variety for most nt, which all have different properties
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9
Q

ACh in peripheral nervous system

A

in neuromuscular junction

  • synapses in ganglia of visceral motor system
  • slows the heart
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10
Q

ACh in central nervous system

A
  • interneurons in brainstem and forebrain
  • large neurons in basal forebrain that project to cerebral cortex
  • function in CNS not well understood, but believe it’s in attention, arousal, and reward plasticity
  • -enhances sensory functions upon waking
  • damage to cholinergic system is associated with memory deficits in AD
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11
Q

ACh synthesis, packaging, and removal

A
  • synthesized enzymatically in nerve terminal from ACoA and choline
  • packaged into synaptic vessels by vesicular ACh transporter
  • removed from synaptic cleft via cleavage to acetate and choline by acetylcholinesterase
  • choline is taken up by nerve terminal via specific transporter and is used to synthesize more ACh
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12
Q

why are organophosphates and nerve gas lethal?

A

they inhibit acetylcholinesterase and cause ACh to accumulate at cholinergic synapses

  • causes continued depolarization of postsynaptic cell, making it refractory to subsequent ACh release
  • at NMJ, this causes muscle paralysis
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13
Q

what kines of receptors do ACh have?

A

both ionotropic (nicotinic) and metabotropic (muscarinic)

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14
Q

ionotropic ACh receptors

  • what do they do?
  • where are they?
  • composition?
A

excitatory cation-selective channels

  • mediate synaptic transmission at NMJ
  • also present in CNS
  • muscle and neuronal receptors have different subunit compositions, but both consist of 5 subunits total
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15
Q

metaboctropic ACh receptors

  • what do they do?
  • where are they?
  • what are antagonists and how are they used?
A

mediate most ACh effects in brain

  • highly expressed in forebrain
  • also present in peripheral panglia where they mediate responses of autonomic effector organs (heart, smooth muscle, etc.)
  • antagonists atropine (pupil dilation) and scopolamine (motion sickness) are therapeutically useful
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16
Q

myasthenia gravis epidemiology and symptoms

A

14: 100,000 people; onset in 20-30s women or 70-80s men
- muscle fatigability that worsens later in the day or after repetitive exercise, but improves with rest
- diplopia, ptosis
- difficulty speaking, swallowing, chewing
- weakness in arms and legs

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17
Q

what is myasthenia gravis caused by?

A

autoimmune disease due to antibodies against muscle nicotinic ACh receptors causing increased turnover of receptors

  • altered structure at NMJ causes:
  • -decreased concentration of receptors in postsynaptic membrane
  • sparse and shallow junctional folds
  • expanded synaptic cleft
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18
Q

what does myasthenia gravis do to neuromuscular transmission?

A

reduced efficiency of neuromuscular transmission

  • size of miniature endplate potentials (MEPPs) is reduced
  • size of endplate potentials (EPPs) is reduced
  • probability that a presynaptic AP will elicit a postsynaptic muscle action is reduced
  • during repeated stimulation, compound AP in muscle decreases in size (fatigues)
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19
Q

myasthenia gravis treatment

A
  • cholinesterase inhibitors (ACh stays in synaptic cleft longer, so more changes to bind and activate receptors)
  • thymectomy (recommended for most patients, may take years to see max results)
  • corticosteroids (respond well, but major side effects)
  • immunosuppressants (decreased autoimmune response to receptors)
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20
Q

glutamate in normal brain function

A

most prominent and common transmitter used by nearly all excitatory neurons in brain
-more than half of all brain synapses use glutamate

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21
Q

excitotoxicity of glutamate

A
  • high extracellular concentrations of glutamate are toxic to neurons
  • excessive activation of glutamate receptors can excite neuron to death
  • thought to cause neuronal damage during strokes; oxygen deprivation slows glutamate reuptake
  • considerable interest in using glutamate receptor antagonists to block excitotoxic nerve damage following stroke
  • also involved in other acute forms of neuronal insult, like hypoglycemia, trauma, and repeated intense seizures
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22
Q

synthesis, packaging, and removal of glutamate

A

can’t cross BBB, but glutamine can

  • synthesized in nerve terminal from glutamine (by glutaminase), or transamination of alpha-ketoglutarate
  • packaged into synaptic vesicles by vesicular glutamate transporter (VGLUT)
  • removed from synaptic cleft by high affinity glutamate transporters on both nerve terminal and nearby glial cells
  • in glial cells, glutamate is converted to glutamine (via glutamine synthetase) and transported out of the cell and back into nerve terminals
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23
Q

what kinds of glutamate receptors are there?

A

both ionotropic (NMDA, AMPA, kainate) and metabotropic (3 classes)

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24
Q

ionotropic glutamate receptors

A

excitatory cation-selective (Na+) channels

  • NMDA, AMPA, and kainate
  • NMDA receptors have unique properties
  • -Ca++ can pass thru
  • -ion flow is voltage-dependent b/c of Mg++ binding
  • glycine binding is required to open channel
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25
Q

metabotropic glutamate receptors

A

three classes, and activation can increase or decrease excitability of postsynaptic cell

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26
Q

what are the major inhibitory neurotransmitters in the CNS?

A

GABA and Glycine

  • GABA is widely distributed to brain; 1/3 of brain synapses use GABA, along with local interneurons and Purkinje fibers of cerebellum
  • glycine is predominantly used at synapses in spinal cord
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27
Q

GABA synthesis, packaging, and removal, and what decreased GABA function does

A

made in nerve terminals from glutamate via glutamic acid decarboxylase + pyridoxal phosphate (PLP; from B6)

  • packaged in synaptic vesicles by vesicular inhibitory AA transporter (VIATT)
  • removed from synaptic cleft by specific transporters on nerve terminals and nearby glia
  • decreased GABA function can cause epilepsy
28
Q

what does GABA-T do?

A

turns GABA into glutamate then glutamine to go into glutamate cycle

29
Q

glycine synthesis, packaging, and removal, and what defects in glycine transporters cause

A

synthesized in nerve terminals from serine

  • packaged into synaptic vesicles by vesicular inhibitory AA transport (VIATT; just like GABA)
  • removed from synaptic cleft by specific transporters on nerve terminals and nearby glia
  • excess synaptic glycine caused by defects in glycine transporter causes neonatal diseases characterized by lethargy and mental retardation
30
Q

what kinds of receptors are GABA and glycine?

A

GABA-A, GABA-C, and glycine are ionotropic inhibitory chloride channels
GABA-B is only metabotropic channel

31
Q

ionotropic GABA receptors and effects of agonists

A

GABA-A/C; inhibitory chloride channels

  • GABA receptor agonists enhance GABA-ergic transmission
  • -benzodazepines (Valium) used as tranquilizers
  • -barbiturates (phenobarbital) used as anesthetics to control epilepsy
32
Q

ionotropic glycine receptors and effects of antagonists

A

inhibitory chloride channels

  • glycine receptor antagonists like strychnine block receptors
  • -cause overreactivity of spinal cord and brainstem, leading to seizures
  • -used to poison rodents
33
Q

metabotropic GABA receptors

A

GABA-B only; widely distributed in brain

-activation produces inhibitory postsynaptic response

34
Q

how are glutamate and GABA receptors expressed in brain compared to biogenic amines?

A

glutamate and GABA are very widely made
-data shows that glutamate are made and utilized ubiquitously across brain

biogenic amines are limited and specific expression of genes, but broadly expressed receptors (80-90% of dopamine innervation goes to striatum)

35
Q

biogenic amines as neurotransmitters

A

aminergic neurons project widely in brain and help modulate intensity of more specific neuronal signals

  • used by relatively few neurons in brain, but very important to maintenance of mental health
  • -implicated in a wide range of behaviors
  • -defects in functions implicated in most psychiatric disorders
36
Q

biogenic amines synthesis, packaging, and removal

A

synthesized in nerve terminals

  • packaged in vesicular monoamine transporter (VMAT)
  • removal into nerve terminals (back into same bouton)
37
Q

relationship between biogenic amines and catecholamines

A

catecholamines are dopamine, epinephrine, norepinephrine

biogenic amines are previous 3 + histamine and serotonin

38
Q

biogenic amine receptors

A

metabotropic, but serotonin also has ionotropic

39
Q

synthesis of catecholamines

A
  1. tyrosine –> DOPA (via tyrosine hydroxylase)
  2. DOPA –> dopamine (via DOPA decarboxylase)
  3. dopamine –> norepinephrine (via dopamine hydroxylase)
  4. norepinephrine –> epinephrine (via phenylethanol-amine N-methyl transferase)
40
Q

serotonin synthesis

A
  1. tryptophan –> 5-hydroxytryptophan (via tryptophan-5-hydroxylase)
  2. 5-hydroxytryptophan –> serotonin (via aromatic L-amino acid decarboxylase)
41
Q

distribution of dopamine containing neurons and their projections and function in substantia nigra

A

major; 80% of brain dopamine found in corpus striatum (caudate and putamen), which receives major input from substantia nigra
-function to coordinate body movements

42
Q

what happens to dopamine in Parkinson’s disease? how does treatment work?

A

substantia nigra neurons degenerate, leading to motor dysfunction b/c dopamine input to striatum decreases

  • L-DOPA (precursor) will cross BBB, which increases dopamine levels in the striatum
  • -cells continue to die, though, so only temporary
43
Q

distribution of dopamine containing neurons and their projections and function in midbrain

A

major; project from ventral tegmental area to ventral parts of striatum

  • involved in motivation, reward, and reinforcement
  • addictive drugs raise dopamine levels by interfering with reuptake by dopamine transporters
44
Q

distribution of dopamine containing neurons and their projections and function in cortex

A

minor; involved in emotional behavior

45
Q

distribution of norepinephrine containing neurons and their projections and function in locus coeruleus

A

goes to a variety of forebrain and brainstem targets

  • influence sleep and wakefulness, attention, and feeding behavior
  • for PNS, is prominent in sympathetic ganglion cells as major transmitter of sympathetic motor system
46
Q

dopamine receptors

A

metatropic only

  • act by activating or inhibiting adenylyl cyclase
  • antagonists of receptors in medulla used as anti-emetics to treat nausea and vomiting
47
Q

norepinephrine receptors

A

metatropic only

  • alpha/beta adrenergic receptors (also used by epinephrine)
  • agonists and antagonists used therapeutically for many conditions
  • -cardiac arrhythmias and migraine headaches
  • -most of these effects are mediated by receptors in smooth muscle, not brain
48
Q

catecholamine removal from synaptic cleft and effects of cocaine and amphetamine

A

reuptake into nerve terminals and glia

  • mediated by transmitter-specific plasma membrane transporters
  • -cocaine inhibits dopamine transporter, causing net increase in release of dopamine
  • -amphetamine inhibits both dopamine and norepinephrine transporters, causing net increase in release of transmitters
49
Q

distribution of serotonin containing neurons and their projections in raphe nuclei

A

in upper brainstem; project widely to forebrain and also to brainstem
-implicated in regulation of sleep, eating, arousal, and wakefulness

50
Q

what do drugs to treat depression and anxiety act on?

A

serotonergic neurons

51
Q

what is another name for serotonin?

A

5-hydroxytryptamine (5-HT)

52
Q

serotonin reuptake

A

reuptake into nerve terminal by specific serotonin transporter (SERT)

53
Q

what are serotonin receptors?

A

both metabotropic (majority) and ionotropic (minority)

54
Q

metabotropic serotonin receptors

A

implicated in emotions, circadian rhythms, motor behaviors, and mental arousal

  • impairment implicated in many psychiatric disorders
  • activation mediates satiety and decreased food consumption
55
Q

ionotropic serotonin receptors

A

non-selective excitatory cation channel

-targets for many drugs including some used to prevent nausea

56
Q

why is it hard to disentangle biogenic amine functions from each other?

A

they all impinge on each other

57
Q

how to anti-psychotic drugs work?

A

block dopamine receptors, suggesting excess dopamine release may cause some psychotic illnesses like schizophrenia

58
Q

how do anti-anxiety drugs work?

A

MAO inhibitors block breakdown of biogenic amines

-inhibitors of serotonin receptors

59
Q

what are the 3 classes of anti-depressants and how do they work?

A
  1. MAO inhibitors block breakdown of biogenic amines
  2. tricyclic anti-depressants block reuptake of NE and 5HT
  3. serotonin reuptake inhibitors (Prozac) act specifically on serotonin transporters
60
Q

peptide neurotransmitters overview

A

implicated in modulating emotions, perception of pain, and responses to stress
-biological activity is dependent on their AA sequence

61
Q

5 categories of peptide neurotransmitters

A
  1. brain-gut peptides
  2. opioid peptides
  3. pituitary peptides
  4. hypothalamic-releasing peptides
  5. miscellaneous peptides
62
Q

synthesis and processing of neuropeptides

A
  1. synthesized as pre-propeptides in ER in neuronal cell body
  2. processed into pro-peptides in ER by removal of ER targeting signal
  3. final processing to individual active peptides occurs in vesicles after they bud from trans Golgi
  4. individual pro-peptides can give rise to multiple active peptides w/in a single vesicle
63
Q

peptide neurotransmitter release and removal

A

often co-released with small-molecule neurotransmitters

  • removed from synaptic cleft via degradation by peptidases
  • some peptides are degraded to more active peptides within synaptic cleft by endopeptidases
64
Q

peptide neurotransmitter receptors

A

use metabotropic receptors

  • activated at relatively low peptide concentrations
  • little is known about receptors
65
Q

opioid peptides

A

widely distributed throughout brain

-tend to be depressants, and can act as analgesics (during acupuncture)

66
Q

morphine

A

opioid peptide isolated from poppies

  • one of the most effective analgesics
  • binds to same receptors as opioid peptides