Neurotransmitters and Neuropharmacology

Question 1

Describe the neuronal communication and differences between an electrical and chemical synapse.
- Distance between pre/post synaptic membranes
- Cytoplasmic continuity between pre/post synaptic cells
- Ultrastructural components
- Agent of transmission
- Synaptic delay?
- Direction of transmission?

Answer 1

Question 2

Electrical transmission occurs at a small number of sites in the brain.
Give 3 characteristics of Electrical synapses?

Answer 2

• are not unidirectional in terms of transmission of electrical information;
• do not contain a synaptic cleft;
• do not allow for synaptic integration. (Excitatory/Inhibitory)
• No neurotransmitter

Question 3

Chemical communication in the nervous system depends on?

Answer 3

(1) the nature of the presynaptically released chemical messenger
(2) the type of postsynaptic receptor to which it binds, and
(3) the mechanism that couples receptors to effector systems in the target cell - alteration in the electrical, biochemical, or genetic properties of that neuron.

Question 4

What is the time course for the following neurotransmitters?
- Acetylcholine - nicotinic / AA
- Acetylcholine - muscarinic/ catecholamines
- Peptides

Answer 4

Question 5

What are the 4 synapse locations?

Answer 5

1- Axodendritic or axosomatic synapses: synapses formed by an axon onto the dendrites or soma of a second cell
2- Axoaxonic: axon to axon
3- Dendrodendritic: dendrite to dendrite
4- Dendrosomatic: dendrite to soma

Question 6

How do Ionotropic and metabotropic receptors work?
-Speed?
- What are they?
- What do they do?

Answer 6

> Ionotropic receptors: fast chemical neurotransmission (a) - postsynaptic receptor is ion channel.
* Small molecule neurotransmitters
* Gated ion channels allow passage of specified types of ions
through the membrane

> Metabotropic receptors: slow chemical neurotransmission (b) - signal is transduced by a mechanism involving G protein coupled receptors.
* Activation of “second messenger” that is not an ion channel. Molecule that protrudes into the cell cytoplasm & activates substance(s) inside the postsynaptic neuron
* These second messengers ↑ or ↓ specific cellular functions

Question 7

1. How do auto-receptors work?
2. How does 5HT (serotonin receptor) function as somatodentritic auto receptor?

Answer 7

1- Presynaptic receptor that is stimulated by the same transmitter released by the neuron is known as an autoreceptor.

2- Reside on the cell bodies and dendrites of 5HT neurons > Their activation reduces cell firing and inhibits the synthesis and release of 5HT.

Question 8

What are the different ways a signal can be terminated?

Answer 8

• reuptake of neurotransmitter by the presynaptic terminal
• nearby glial cells
• enzymatic inactivation of neurotransmitter
• uptake by the postsynaptic terminal
• simple diffusion out of the synaptic cleft

Question 9

Define a neurotransmitter.
How many post synaptic neurones can 1 axon affect?

Answer 9

• a chemical substance that is synthesized in a neuron
• released at a synapse following depolarization of the nerve terminal
• which binds to receptors on the postsynaptic cell and/or presynaptic terminal to elicit a specific response

> one axon may contact 1000s of postsynaptic neurons spread widely across the brain

Question 10

How do:
monoamine oxidase (MAO)
& catechol-0-methyltransferase (COMT)
work to inactivate catecholamines (hormones released via adrenal gland)?

Answer 10

• COMT is found both in peripheral tissues & CNS & is the major means of inactivating catecholamines
• MAOs oxidatively deaminate catecholamines to form inactive and unstable derivatives

Question 11

0- What is the function of dopamine?
1- How is domaine synthesised?
2- How is domaine removed?

Answer 11

0- Facilitate the initiation of voluntary movement, (substantial Niagara) reward & addiction (Ventral tegmental area)

1- Dopamine is also synthesised in periphery… No effect on brain tho?

2-
* Inactivated intracellularly by monoamine oxidase (MAO)
* Cleared from the synapse via dopamine reuptake transporters (DAT)

Question 12

Treatments that effect domaine neurotransmitter?

Answer 12

+ COMT-inhibitor > prevent peripheral degradation of levodopa, allowing a higher concentration to cross the blood-brain barrier + prolong action of levodopa. (diminishes motor effects)

+ MAO-B inhibitors prevent breakdown of dopamine

+Dopamine antagonists (Levodopa- L-DOPA)

Question 13

How does dopamine relate to Parkinson’s disease?

Answer 13

• Death of dopamine generating cells in substantial Niagara

Question 14

0- What is the function of norepinephrine?
1- How is norepinephrine synthesised?
2- How is norepinephrine removed?

Answer 14

0- Increases arousal & alertness, promotes vigilance, enhances formation & retrieval of memory, & focuses attention

1-

2- Inactivated intracellularly by monoamine oxidase (MAO) & catechol- 0 -methyltransferase (COMT).

Question 15

Treatments that effect norepinephrine neurotransmitter?

Answer 15

Question 16

Where do norepinephrine neurones project to?

Answer 16

• Thalamus,
• hypothalamus,
• limbic forebrain structures
• cerebral cortex.

Question 17

0- What is the function of Serotonin (5-HT) ?
1- How is Serotonin synthesised?
2- How is Serotonin removed?

Answer 17

0- pain perception & regulation of sleep, appetite, temperature, blood pressure, cognitive functions & mood

1-

2- reuptake (serotonin transporters) + metabolism (MAO)

Question 18

Treatments that effect Serotonin neurotransmitter?

Answer 18

• Selective serotonin reuptake inhibitors act on serotonin transporter (SERT) > prolong its action in the brain.

Question 19

Further treatments that affect serotonin receptors which include ? (4)
1) 1 receptor target is for antipsychotic treatment?
2) 2 receptor target is for migraines
3) 1 receptor is partial agonist
4) 1 receptor is an agonist/ 1 receptor antagonist to suppress nausea and vomiting

Answer 19

• 5HT1B and the 5HT1D receptors – migraine treatment.
• 5-HT3 receptor antagonists, such as ondansetron, and 5-HT4 receptor agonists, such as metoclopramide, have both peripheral and central actions and suppress nausea/vomiting.

Question 20

0- What is the function of Acetylcholine?
1- How is Acetylcholine synthesised?
2- How is Acetylcholine removed?

Answer 20

0-
PNS/CNS : brain functions, such as memory, and body functions, such as muscle contractions to move your muscles.

1-
- Acetyl CoA + Choline by enzyme choline acetyltransferase
- ACh is transported into vesicles via the vesicle-associated transporter (VAT)

2- Degraded by acetylcholinesterase to choline and acetate. Choline is then recycled back into the presynaptic terminal to be used again in the synthesis of ACh.

Question 21

Treatments that effect Acetylcholine neurotransmitter?

Answer 21

1- Cholineesterase inhibitor (reversible+irreversible)

Question 22

Within the brain are two major diffuse modulatory cholinergic systems:
Name and describe these….

Answer 22

• the basal forebrain complex (which innervates the hippocampus and all of the neocortex)
• the dorsolateral tegmental nuclei cholinergic complex (which innervates the dorsal thalamus and parts of the forebrain).

Question 23

0- What is the function of Glutamate ?
1- How is Glutamate synthesised?
2- How is Glutamate removed?

Answer 23

0- Excitatory neurotransmitter of the CNS, Plays role in learning and memory, pain transmission, & some motor functions via influence on dopamine

1-

2- Reuptake into the presynaptic terminal and packaging in synaptic vesicles, through transport into glial cells where breakdown can occur.
- Astrocytes are essential in the synthesis and reuptake of glutamate.

Question 24

Treatments that affect Glutamate neurotransmitter.

Answer 24

Question 25

1- Where are most glutamate pathways found?

2- 3/5 pathways project from the …. and penetrate into deeper brain areas where they exert control over the neuroanatomic structures there.

Answer 25

1- Frontal cortex
2- Neuroanatomic structures there.

Question 26

What is glutamate excitoxicity?
What is it controlled by?

Answer 26

• Excitotoxicity > overactivation of glutamate receptors as a result of increased release and/or decreased uptake of glutamate causing persistent activation of NMDA R → influx of Ca2+ → loss of neuronal function & cell death.
  (stroke TBI, & age-related neurodegenerative disorders such as AD, PD & HD.)

> Controlled by astrocytes

Question 27

How is glutamate related to stroke?

Answer 27

• Ischemic stroke > neuronal death due to dysfunction in homeostasis of glutamate :
  1- Ischemia = ↓ ATP levels as cellular respiration is compromised.
  2- ↓ ATP production impairs glutamate transporters → neuronal depolarization → unregulated accumulation of glutamate in the synaptic cleft → over-activates NMDA R → influx
  of calcium, mitochondrial dysfunction, & generation of ROS → cell death.
• A secondary mechanism is inflammation.
  1. The Reactive oxygen species & cytokines released by dying neurons activate microglia → secrete ROS & other cytotoxic factors that exacerbate neuronal damage.

Question 28

Alzheimers disease is the most common form of dementia. Manifests as a progressive loss of memory, particularly recent memories, & profound alteration of other cognitive functions.

• What are the 2 hypothesis?

Answer 28

1- Cholinergic hypothesis:
ACh is ↓ in both concentration and function & presynaptic cholinergic deficits (including loss of cholinergic neurons & ↓ acetylcholinesterase activity).

2- Glutamatergic hypothesis: excitotoxicity. Activation of NMDA R (NB in learning and memory), may result from deficiencies in glutamate reuptake by astroglial cells in the synaptic cleft. Loss of glutamatergic pathways projecting to and from the hippocampus.

Question 29

Describe the phenomenon called long-term potentiation.

Answer 29

• Memory formation
  > Strengthening of synapses leading to long-lasting increases in signal transmission between neurons.
  > Post-synaptic strengthening via an increased recruitment of AMPA receptors.

Question 30

What does Induction of LTP depends on?

Answer 30

Increase in post synaptic [Ca2+].

1- Postsynaptic [Ca 2+] levels rise during a stimulus because of the activation of NMDA receptors, the only type of glutamate-activated channel that is permeable to Ca2+.
2- Repeated stimulation of presynaptic pathway → Rapid ↑ in number of dendritic spines & synapses on the dendrites of postsynaptic neurons.
3- Changes in the presynaptic nerve terminal may also contribute to LTP.
4- Postsynaptic neuron may release a signal that enhances release of transmitter by the presynaptic nerve terminal.

Question 31

0- What is the function of GABA ?
1- How is GABA synthesised?
2- How is GABA removed?

Answer 31

0- Major neurotransmitter for inhibitory synaptic transmission to control neuronal excitability. Homeostasis between glutamate & GABA works to modulate neuronal excitability & CNS arousal.

1-

2- Reuptake into the presynaptic terminal + into glial cells via GABA transporters.
- In glial cells GABA is converted to glutamate by GABA transaminase

Question 32

Treatments that affect GABA neurotransmitter.

Answer 32

Question 33

GABAergic neurons are located in: (5)

Answer 33

• hippocampus,
• thalamus,
• basal ganglia,
• hypothalamus,
  & brainstem

Question 34

How do GABA and epilepsy relate?
How is it treated?

Answer 34

• Neuronal hyperactivity in epilepsy.
• Epilepsy is excitation going unchecked, producing excitotoxicity that gives rise to seizures.
• Anti- convulsant that inhibits GABA transaminase, which is an enzyme that metabolizes GABA, thus ↑ GABA levels in the brain.

Question 35

How do GABA and Huntingdon’s disease relate?

Answer 35

• Autosomal dominant progressive neurodegenerative condition. Part of the brain most affected by HD are the basal ganglia (responsible for movements).

> Huntingtin protein inhibits transcription & transport of GABA-A receptors, causing neuroinflammation
that weakens the inhibitory response & disrupts astrocytic glutamate transporters.

Question 36

What nerves are first to die as HD progresses?

Answer 36

• Striatum are 1st to die as HD progresses → two different pathways affected:
  1- Indirect pathways – generally affected first → chorea
  2- Direct pathway - produces overall ↓ movement.
• Both pathways controlled by GABAergic neurons.

Question 37

Answer the following about sleep:

1- locus coeruleus activity is low during sleep and virtually none during REM.. What neurons are found here?

2-Cells of Raphe Nuclei fire most rapidly rapid during wakefulness. The neurones are involved in the control of sleep-wake cycle as well as different stages? What neurons are clustered within the nine raphe nuclei?

3- What neurotransmitter is REM sleep turned in by?

4- What neurotransmitters is REM sleep turned off by?

Answer 37

1- Norepinephrine containing neurons are in the tiny locus coeruleus , located bilaterally in the brainstem.

2- Serotonin containing neurons

3- Acetylcholine

4- Norepinephrine + Serotonin (neurones that secrete monoamines)