Neurotransmitters Flashcards

1
Q

What makes a neurotransmitter a neurotransmitter?

A

A. The chemical must exist (made and stored) in presynaptic cells (stored in terminals)
B.The chemical must be released from presynaptic terminals on action potential
C. Released chemical must bind to receptors and cause a biological effect
D. There must be a mechanism to inactivate or metabolise the chemical
E. The chemical should have the same biological effect if artificially applied to synapse

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2
Q

Where do neurotransmitters come from?

A

Peptides (made in the soma)
* Precursor peptide (small protein) synthesised in rough ER
* Cleaved in Golgi apparatus to active neurotransmitter
* Secretory vesicles bud off from Golgi apparatus
* Secretory granules (large vesicles, 100 nm) transported to terminal and stored

Monoamines, Amino Acids & Acetylcholine (made in the pre-synaptic terminal) Don’t have to travel
* Precursor molecule (from diet) sythesised to neurotransmitter
* Transported to synaptic vesicle (50 nm) and stored

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3
Q

What is the main Difference between Peptides & Monoamines, Amino Acids or Acetylcholine neurotransmitters?

A
  • Peptide neurotransmitters are made in the soma and transported in secretory granules to the terminal
  • Monoamines, amino acids and acetylcholine are made from precursor molecules in the terminal and are transported into synaptic vesicles
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4
Q

What are the major roles of amino acid neurotransmitters?

A

Glutamate: Major Excitatory NT, Learning & Memory, Neuroplasticity, Excitotoxicity

GABA: Major inhibitory NT, Modulator of many processes

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5
Q

Where are the cell bodies of neurons that release amino acid neurotransmitters and where do they project?

A

Glutamate: thal and subthal, project to various places in cerebral cortex and basal ganglia

GABA: in hippo, accumbens and midbrain and project to cortex and cerebellum and olfact bulb
GABA is also in interneurons

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6
Q

What are interneurons?

A

Interneurons are small neurons retained in the one brain area GABA or Acetylcholine are commonly in interneurons

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7
Q

How are amino acid neurotransmitters metabolised?

A

2 ways (presyn + glial cell) to make sure that the cell env doesnt become too toxic bc of too much NT outside the cell
GABA transaminase breaks down GABA in the presynaptic cell and glial cells
Glutamate is neurotoxic (kills neurons) in high amounts - glial cells work to reduce toxic levels

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8
Q

What are the major roles of ACh? (4)

A

NTs are associated with a wide variety of imp fctions
This is why any NT dysfction can be very problematic
for everyday fction
Memory, Perceptual Learning, Movement and REM Sleep

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9
Q

Where are the Acetylcholine cell bodies and where do they project?

A

Nucleus basalis and project to
frontal and parietal cortex
They’re also in sub nigra and go to thal
Septohippocampal pathway projects
to hippo

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10
Q

How is ACh metabolised?

A

Acetylcholine is broken down by Acetylcholine esterase (AChE) into choline and acetic acid
ACh metabolism occurs in the synaptic cleft
Choline is then transported into the presynaptic cell for re-use
Many insecticides or nerve gases inhibit AChE, enhances ACh transmission at muscle and heart, death usually by respiratory paralysis
Outside agents can interfere with NTs to affect someones fction and overall health

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11
Q

What is ACh’s life cycle?

A

More choline detected in the synaptic cleft = reduces ACh production
Rate limiting step is choline in synapse - inversely related (negative feedback)

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12
Q

What are the major roles of monoamines?

A
  • Dopamine: Short term memory, Strategy & planning, Reward and Movement
  • Serotonin: Cognition, Emotion and Reward
  • Noradrenaline: Attention, Flight/Fight and Sleep
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13
Q

Where are the Dopamine and Noradrenaline cell bodies and where do they project?

A
  • Noradrenaline: In the LC and caudal raphe, project to cerebellum and cortex
  • Dopamine: In SN and VTA, prooject to frontal cortex and midbrain
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14
Q

Where are the Serotonin cell bodies and where do they project?

A

In raphe (rostral, caudal and dorsal) that roject to cortex and cerebellum
NTs are associated with mvmt
and higher cog fctions bc of
where they project

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15
Q

How are monoamines metabolised?

A

Monoamines deactivated by Monoamine Oxidase (MAO) or repackaged into vesicles in the presynaptic cell
MAO inhibitors used as antidepressants

Each monoamine has its OWN transporter (You can selectively target these transporters):
Dopamine = DAT Noradrenaline = NET
Serotonin = SERT
They are each taken up into their own cell and metabolised or repackaged into vesicles

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16
Q

What happens when there’s a monoamine system dysfunction?

A

(Repeated) psychostimulant drug abuse
–> Paranoid psychosis Similar to schizophrenics
–> Depression, Anxiety and Parkinson’s like symptoms
–> Seizures

17
Q

What are the symptoms of Sz?

A
  1. Psychotic ‘positive’ symptoms(episodic) Delusions, hallucinations, thought disorders
  2. Deficit ‘negative’ symptoms(chronic) disturbances in: motivation, experience of pleasure social interactions, spontaneous speech, mood expression
  3. Cognitive impairment(chronic) intellectual, memory, executive function, attention
18
Q

What are the positive psychotic symptoms?

A

Hallucinations - usually auditory (single or multiple)
Delusions (paranoid) - persecution, grandiosity, external control, thoughts inserted or removed, mind read
Thought disorder - tangential, loosening associations
=> Disorganised thinking and behaviour- trouble with simple tasks

19
Q

What is the neurochemistry of Sz?

A

There are 4 main neurotransmitters thought to be involved:
Dopamine (DA)
Serotonin (5-HT)
Glutamate
GABA

20
Q

What is the dopamine hypothesis of Sz?

A

Drugs which increase dopamine levels in the nucleus accumbens exacerbate or produce positive psychotic symptoms
Drugs which block dopamine transmission alleviate some of the symptoms of schizophrenia (dopamine antagonists)
1950s Chlorpromazine (developed as an antihistamine) reduced the positive symptoms of schizophrenia - blocks dopamine receptors
=> Dopamine neurotransmission is involved in psychosis
Schizophrenics have increased dopamine (DA) in the nucleus accumbens and decreased dopamine in the prefrontal cortex (hypofrontality)

21
Q

How does the dopamine hypothesis of Sz explain hypofrontality?

A

PFC Hypofrontality: Cognitive deficits and Negative symptoms
Nucleus Accumbens: Increased dopamine: Positive symptoms (psychoses) and Euphoria at beginning

22
Q

What is the Mesocorticolimbic Dopamine System?

A

The positive psychotic symptoms are produced by increased
Dopamine in the nucleus accumbens (mesolimbic dopamine)
The negative and cognitive symptoms are produced by decreased Dopamine in the prefrontal cortex (mesocortical)
=> Mesocorticolimbic dopamine system is abnormal in schizophrenia

23
Q

What is the mesolimbic dopamine system?

A

The nucleus accumbens (ventral striatum) directly influences the output of the dorsal striatum (Caudate & Putamen) - weakens the ‘filter’
The attentional filter, start focusing on things that arent relevant
Increased numbers of dopamine D2 receptors in mesolimbic system with schizophrenia
Generally considered that enhanced dopamine neurotransmission at Dopamine D2 receptors produces positive symptoms of schizophrenia
=> Use a dopamine D2 receptor antagonist to prevent psychoses

24
Q

What were the First Generation Typical Antipsychotics ‘neuroleptics’?

A

Chlorpromazine, Haloperidol
The ability for these drugs to bind and block dopamine D2 receptors made them more effective at reducing psychotic symptoms
Better binding to D2 receptors = better clinical potency

25
Q

What is the Bad News About Typical Antipsychotics?

A

The first generation typical neuroleptics antagonised both Dopamine D1 and D2 receptors (and many other receptors!!)
- no effect on negative or cognitive symptoms
- ineffective in 30 % patients
- exacerbate symptoms in some
- 20 % relapse rate
- 5-10% have intolerable side effects (due to many receptors involved)
- cardiotoxicity
- Extrapyramidal Side Effects (EPS)

25
Q

What is the Bad News About Typical Antipsychotics?

A

The first generation typical neuroleptics antagonised both Dopamine D1 and D2 receptors (and many other receptors!!)
- no effect on negative or cognitive symptoms
- ineffective in 30 % patients
- exacerbate symptoms in some
- 20 % relapse rate
- 5-10% have intolerable side effects (due to many receptors involved)
- cardiotoxicity
- Extrapyramidal Side Effects (EPS)

26
Q

What is the VTA dopamine involved in?

A

VTA dopamine involved in reward, psychosis and movement
D1 receptor family D1,D5
D2 receptor family D2, D3, D4

Typical neuroleptics block the D1 and D2 family of receptors
D2 receptors in the nucleus accumbens produce positive psychotic symptoms
D1 receptors are very important for normal movement
If also block RD1, affect normal mvmt

27
Q

What is the Substantia Nigra dopamine involved in?

A

Substantia Nigra dopamine involved in movement: Caudate Nucleus
Nigrostriatal DA system Important for movement, Decreased DA in nigrostriatal causes Parkinson’s Symptoms
Blocking D1 andD2 receptors interrupts our ability to move

28
Q

Pyramidal vs Extrapyramidal Movement

A
  • Pyramidal: Primary Motor Cortex M1, Premotor Area and Supplementary Motor Area –> Spinal cord & Muscle for Voluntary Movement

Extrapyramidal: Nigrostriatal dopamine (A9) Substantia Nigra –> Caudate/Basal Ganglia for Rythmic/Phasic Movement, Subconscious: eg. Walking

29
Q

What are extrapyramidal side effects?

A

80% of D2 receptors need to be blocked - antipsychotic
- 80% of D2 receptors blocked also effect D1 receptors
- Extrapyramidal Side Effects (EPS)
Parkinson’s like symptoms (reduced dopamine transmission in Caudate Nucleus), Acute dystonias (involuntary movements) muscle spasms, protruding tongue
May cause development of Tardive Dyskinesia (20-40% over years) = Debilitating movement disorder - involuntary movements: jaw/lips/limbs
- Needed to develop antipsychotics that were specific for D2 subtype
- Needed to discover other neurotransmitter involvement
- Reduce EPS & reduce negative and cognitive symptoms

30
Q

What are the next typical antipsychotics?

A

Drugs that were more selective for D2 receptors were made
Highly selective for D2 receptors
Less Extrapyramidal Side Effects
Still no effect on negative or cognitive symptoms
Need to address prefrontal cortex deficits

Dopamine antagonists will not help a Reduction*of dopamine in prefrontal cortex, Dopamine D2 antagonists do help to reduce the positive symptoms
- Serotonin (at 5HT2 receptors) are thought to mediate the negative and cognitive symptoms
- Glutamate antagonists produce psychosis
- Reduced function of GABA neurons in the prefrontal cortex in schiz.
- Dopamine, Serotonin, Glutamate & GABA are involved in schizophrenia

31
Q

What is the monoamine hypothesis of depression?

A

1950s Iproniazid (Monoamine Oxidase Inhibitor) was shown to elevate mood in tuberculosis patients
Blocking metabolism of the monoamines increases the amount to be repackaged and released and have bio effect on the next cell
The effectiveness of a monoamine oxidase inhibitor to elevate mood in depressed patients indicated that the depletion of monoamines contributed to the pathology of depression
Depletion of dietary tryptophan produces symptoms of depression

32
Q

What is the neuropathology of depression?

A

Depleted monoamines in brain regions produce symptoms of depression

33
Q

How do we enhance monoamine transmission?

A

First Generation Anti-depressants
- Tricyclic Antidepressants (TCAs) Block re-uptake of all monoamines
- Monoamine Oxidase Inhibitors Block the metabolism of active monoamines

34
Q

What are the side effects of TCAs?

A

Side Effects: (sympathetic/antimuscarinic) Dry mouth, impaired vision, increased heart rate, difficult to pee Memory and learning impairments (antihistamine) Sedation (blocks alpha 1 adrenoceptors- periphery) Postural hypotension (low blood pressure on standing)
CARDIOTOXIC (blocks ability for heart to pump) 15 % depressed patients suicide - 25% by TCA overdose

35
Q

What are the side effects of MAOIs?

A

Side Effects: Tremors, excitement, insomnia (CNS overstimulation:convulsions) Food & drug interactions
Foods to avoid: Cheese/Concentrated yeast products/red wine that contain Tyramine Hypertension - headaches or intracranial haemorrhage Cardiotoxic (less than TCA’s)
- Needed to develop better pharmacotherapies
- 40% non-compliance

36
Q

What are selective re-uptake inhibitors?

A

Second Generation Antidepressants
These focus on the re-uptake of serotonin or noradrenaline or both (Reduced Dopamine is not a major problem in depression)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Noradrenaline Reuptake Inhibitors (NRIs)
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
=> More selective = less side effects