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Fundamental Neuropharmacology > Acetylcholine and glutamate > Flashcards

Acetylcholine and glutamate Flashcards

1
Q

Myasthenia Gravis

A

Autoimmune disease —> weakness in muscles of the eyes, eyelids and face
- droopy eyelids (in one or both eyes)
- double vision
- difficulty making facial expression
High levels of ACh receptor antibodies in blood
- prescribed cholinestrate inhibitor medication

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2
Q

Choline

A

Found in high concentrations in the presynaptic terminal
Primarily comes from fat in out diet but can also be produced in small amounts by the liver

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3
Q

choline acetyltransferase

A

Enzyme required to combine acetly coenzyme A and choline —> acetylcholine
Only present in cholinergic neurons

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4
Q

What junction in ACh found at?

A

Neuromuscular junction to elicit muscle contractions and act as a neuromodulator in the brain regulating many functions, including memory and sleep

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5
Q

Anatomy of cholinergic pathways

A

Eight small nuclei in the basal for brain and brainstem for cholinergic nucleus supply the cholinergic innervation in the brain.
The basal forebrain cholinergic nuclei are comprised of the medial septal nucleus, the vertical nucleus of the diagonal band, the horizontal limb of the diagonal band and the nucleus basalis of Meynert, the medial habenula and the parabigeminal nucleus
(See notes)

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6
Q

Synthesis degradation of ACh:

A
  1. ACh is synthesised from acetyl CoA and choline
  2. The newly synthesised transmitter is pumped into vesicles
  3. The neurotransmitter is released upon the arrival of an action potential
  4. ACh acts first for a short time on postsynaptic receptors before it is degraded by AChE
  5. Choline is recycled and pumped back into the presynaptic terminal by the choline transporter
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7
Q

Nicotinic and muscarinic ACh receptors:

A

Cholinergic receptors are named after selective agonists which mimic the effects of the endogenous ligand (ACh)
Agonist - nicotine, muscarine
Antagonist - curare, atropine

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8
Q

Nomenclature of ACh units and their subunits

A

-each nicotinic receptor consists of five subunits (α, β, γ, δ, ε)
-There are 10 α and 4 β subunits
- receptors and muscle cells have a different composition than receptors in neurons
- nicotinic receptors are permeable to Na+ and K+ with some subunit combinations also permeable to Ca2+

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9
Q

Myasthesia Gravis testing

A
  1. Antibody testing
  2. Electomyography
  3. Nestagmine (endrophonium) test
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10
Q

Does inhibition of ACh reverse aging?

A

Botox in an injectable form of botulinum toxin.

Wrinkles occur when muscles in the face are
chronically activated. Botox
“erases” these wrinkles by paralysing the wrinkle-causing muscles.

Before Treatment: Note the presence of “unsightly” wrinkles above the brow.
After Treatment: The muscles are now paralysed and remain relaxed

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11
Q

Muscarinic ACh receptors - agonists

A

Carbachol
Arecoline
Pilocarpine
Oxotremorine

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12
Q

Muscarinic ACh receptors - Antagonists

A

Atropine
Scopolamine

( any excess use of antimuscarinic drugs produces cognitive impairment, and at higher doses delirium, along with tachycardia and other dangerous autonomic symptoms)

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13
Q

Ligands affecting cholinergic transmission

A

Botulinis and tetanus toxins inhibit ACh release whereas black widow spider toxin stimulates release

Tacrine and physostigmine inhibits AChE

Curare ad mecamylamine are nicotinic antagonists

Varenicline is a partial agonist at nicotinic receptors

Vesamicol inhibits the vesicular acetylcholine transporter

Hemichollinium inhibits the choline transporter

Arecoline is a muscarinic agonist

Atropine and benztropine are muscarinic antagonists

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14
Q

Alzhiemer’s disease

A

The progressive cognitive decline seen in AD patients is due to neuronal cell death caused by over activation of NMDA receptors and the subsequent pathological increase in intracellular calcium.

Clinical diagnosis: EOAD
Magnetic resonance imagine scan revealed mild generalised cortical atrophy
CT brain imaging revealed additional marked hippocampal atrophy

Symptoms: repetitiveness, memory loss, executive function loss, cognitive decline, difficulty making decisions

Treatment: cholinesterase inhibitor

Autopsy reveal: plaques and tangles with congophilic amyloid angiopathy in addition to prominent Lewy Body pathology noted in the amygdala

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15
Q

Glutamate synthesis

A
  1. In the presynaptic terminals of glutamatergic neurons, glutamine (Gln) is converted to glutamate (glut) by the enzyme glutaminase
  2. Alternatively, glutamate is synthesised by the transmission of aspartate (asp) by transaminase
  3. After it is released from nerve terminals, glutamate is taken up into glial cells
  4. Glutamate is converted into glutamine by glutamine synthetase
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16
Q

Glutamate inactivation

A
  1. Glutamine is pumped out of the glia by SN1
  2. Glutamine is taken up by nerve terminals
  3. Glutamine is converted back to glutamate to replenish the transmitter pool
  4. Uptake of glutamate into glial cells (and, to a lesser extent, neural) compartments; achieved by the glutamate receptors GLT-1, GLAST and EAAC1
17
Q

Glutamate receptor types

A

Described based on different agonists present

Iontropic glutamate receptors (iGluR)
Metabotropic glutamate receptors (mGluR)

18
Q

Iontropic glutamate receptors

A

NMDA

AMPA

KAINATE/KAR

(Agonists, largely expressed on the postsynamptic membrane, some are expressed presynaptically e.g KIANATE on mossy fibres in hippocampus)

19
Q

Metabotropic glutamate receptors

A

GROUP I (mGlu1, mGlu5)

GROUP II (mGlu2, mGlu3)

GROUP III (mGlu4, mGlu6, mGlu7, mGlu8)

(Divided based on signal transduction based on specific agonists)

20
Q

Activation by NMDAR, AMPAR (quisqualate) and Kianate Receptors

A

Kianate —> negative response

Kianate + glycine —> same response as Kianate on its own

Quis —> negative response

Glycine —> no response

NMDA —> no response

NMDA + glycine —> negative response

Glutamate —> negative response

Glutamate + glycine —> elicits greater negative response

21
Q

Why does glutamate give a response but NMDA doesn’t?

A

Due to AMPA and KIANATE receptors
Glutamate activates other iGluR

22
Q

Ketamine

A

Selective antagonist of NMDA receptors
Used in treatment for depression

23
Q

Ketamine and Kianate

A

Ketamine has no effect

24
Q

Ketamine and quisqualate

A

Quisqualate is an AMPAR agonist
Ketamine has no effect

25
Q

Ketamine and NMDA

A

Ketamine inhibits NMDA
Therefore ketamine is a selective NMDA receptor (reduces spiking) —> why I works as an anaesthetic

26
Q

Conventional NMDA receptors

A

Contain 2 GluN1 subunits and 2 GluN2 subunits

Agonists: glutamate and NMDA
Coagonists: glycine and D-serine

27
Q

Unconventional NDMA receptors

A

Incorporate GluN3 subunits in addition to either GluN1 or GluN2

Bind to glycine
They are glutamate receptors but activated by glycine

28
Q

Di-heteromeric NMDARs

A

Incorporate up to 2 types of different subunits

Not activated by glycine by the same extend as tri-heteromeric receptors

29
Q

Tri-heteromeric NMDARs

A

Incorporate 3 types of different subunits

30
Q

Mg2+ Channels in conventional NMDARs

A

Have Mg2+ blockers (open channel) —> open in presence of agonists
In presence of magnesium, wont open
Limiting as it prevents calcium entering cell, can lead to apoptosis

31
Q

Conventional vs. Nonconventional NMDARs

A

Conventional:
(GluN1/2) —> sensitivity to Mg2+ block
Glu, gly, GluN1, Mg2+
-Ca2+

Nonconventioal:
(GluN1/2/3) —> insensitivity to Mg2+ block
Glu, gly, GluN1, GluN2x, GluN3x
-Ca2+

(GluN1/3) —> insensitivity to Mg2+ block
gly, GluN1,
-Ca

32
Q

Assembly of NMDARs

A

GluN3 + GluN1
GluN1 + GluN2/3

33
Q

Pharmacological targeting NMDARs

A

epilepsy, stroke, pain, schizophrenia, psychosis, depression, autism, Alzheimer’s

34
Q

Which compound is a nicotinic receptor agonist?

A

Varenicline

35
Q

Which area of the adult brain shows the highest expression of GluN2C subunits?

A

Hippocampus

Fundamental Neuropharmacology (8 decks)

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