Neurotransmission 2: dopamine, serotonin, acetylcholine

Question 1

Primary neurotransmitters and ‘neuromodulators’

Answer 1

Primary neurotransmitters
- Glutamate and GABA - the main workhorses of the brain
- Directly mediate the transmission of information between neurons either via activation (excitation, EPSPs) or inactivation (inhibition, IPSPs) of post-synaptic targets

Some neurotransmitters are ‘Neuromodulators’
- Affect the response properties of a neuron (e.g. release, excitability)
- do not carry primary information themselves.
- e.g. dopamine, serotonin, noradrenaline, acetylcholine (others: histamine, neuropeptides)
- Neuromodulation is a neuron firing. To modulate the firing, you can fine tune it by increasing the firing
- On its own it probably isn’t going to do much

Question 2

The Diffuse Modulatory Systems

Answer 2

Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.

• dopamine in the mid brain
• acetylcholine and serotonin in the brain stem
• noradrenaline in brain stem

They tend to be really widespread- they have massive actions on the brain

Question 3

Dopamine neurons
- where are cell bodies?
- project into where?

Answer 3

• cell bodies in the midbrain
• project into the forebrain

Question 4

What are the three different dopaminergic systems?
- what are the roles of the systems?
- what are their dysfunctions?

Answer 4

Nigrostriatal system (substantia nigra projections to neostriatum (caudate and putamen))
- role in movement
- dysfunction:
—Parkinson’s disease - destruction of DA projections from SN to basal ganglia
—Huntington’s disease - destruction of DA target neurons in striatum

Mesolimbic system (ventral tegmental area projections to nucleus accumbens (NAcc))
- role in reinforcement (reward)
- dysfunction:
— Addiction - most drugs of abuse lead to enhanced DA release in the NAcc

Mesocortical system (VTA projections to prefrontal cortex)
- role in functions such as working memory and planning.
- dysfunction: Schizophrenia

Question 5

Dopamine step 1 and 2

Answer 5

1- Dopamine synthesis
Tyrosine (essential amino acid obtained in diet) →
(catalyzed by tyrosine hydroxylase (TH) (RATE LIMITING STEP/ slowest step)
L-Dopa →
(catalyzed by dopa decarboxylase)
Dopamine

2- Catecholamine storage
Loaded into vesicles

Question 6

Drugs that affect dopamine synthesis and storage modulate behaviour

Answer 6

1) Reserpine
Impairs storage of monoamines in synaptic vesicles. (The vesicles remain empty resulting in no transmitter release upon activation)

2) L-DOPA
The precursor of dopamine, is used as a treatment for Parkinson’s disease. (Bypasses rate-limiting TH step – Dopa decarboxylase converts it into dopamine increases the pool of releasable transmitter)

3) AMPT (a-methyl-p-tyrosine)
- Inactivates TH (used experimentally – not in treatment)
- Allows less dopamine in neurons → less transmission
- Role and importance of neurotransmitter systems in behaviour revealed by drugs. (e.g. Reserpine was used to treat high blood pressure but caused depression)

Question 7

Famous experiment- Reserpine

Answer 7

Rabbits don’t look like they’re alive

Don’t have any dopamine

People thought dopamine wasn’t a neurotransmitter but Carlsson said it is.

After giving reserpine to these rabbits, they gave loads of L-Dopa and then you have lots of dopamine back into vesicles again, dopamine can’t be released and you get these healthy rabbits again.

Important- to this day if you have parkinsons disease, you take L-Dopa and movement improves

However, after a while taking L-dopa when parkinsons progresses, it doesn’t have the same efficacy anymore

Reserpine was recently used to treat high blood pressure but eventually they found out it would cause depression.

Question 8

Dopamine step 3 and 5

Answer 8

3- Dopamine release
- depolarization of presynaptic membrane
- influx of Ca2+ through voltage gated Ca2+
channels
- Ca2+ dependent vesicle docking and
Release
(Ca2+ dependent exocytosis)

4- Dopamine reuptake / metabolism

Signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs))

in the cytoplasm dopamine is:
- reloaded back into vesicles
- enzymatically degraded by Monoamine oxidases (MAOs) or Catechol-O-methyl-transferase (COMT)

Question 9

Drugs that affect dopamine release and reuptake modulate behaviour

Answer 9

1) Cocaine, Amphetamine and Methylphenidate (Ritalin) - psychostimulants

• all block the reuptake of monoamines into terminals. More dopamine in synaptic cleft
• extended action of dopamine on postsynaptic neuron.
• cocaine blocks the dopamine from going back in and you will get dopamine accumulation. This means more action on postsynaptic neuron and increased dopamine transmission.

(Amphetamine reverses transporter so pumps out transmitter - uncontrolled release)

2) Selegiline – Monoamine oxidase B inhibitor

3) Entacapone – COMT inhibitor
- prevent the breakdown of catecholamines,
- increases the releasable pool

These drugs can have antidepressant activity (dopamine levels go up a bit) and can be used for treating Parkinson’s

Question 10

The Serotonergic system:
1- what nuclei?
2- projections?
3- what project throughout the cerebral cortex?
4- raphe neurons?
5- function in?

Answer 10

1- Nine raphe nuclei (in brain stem) with diffuse projections
- each projects to a different part of the brain

2- Descending projections to cerebellum and spinal cord (pain)
Ascending projections (reticular activating system (with Locus Coeruleus))

3- Dorsal and medial raphe project throughout the cerebral cortex

4- raphe neurons
- fire tonically during wakefulness
- quiet during sleep

5- Function in:
- mood
- sleep
- pain
- emotion
- appetite

Question 11

Serotonin step 1

Answer 11

1) Serotonin synthesis
Tryptophan (essential amino acid obtained in diet) RATE LIMITING
(tryptophan hydroxylase) →

5-hydroxytryptophan (5-HTP)
(Aromatic amino acid decarboxylase) →

Serotonin (5-hydroxytryptamine, 5-HT)
Tryptophan and mood:
- depletion diet: method of experimentally inducing a depressive state
- Enrichment: improving mood

Question 12

Serotonin steps 2, 3 and 4

Answer 12

2) Serotonin storage
Loaded into vesicles

3) Serotonin release
Ca2+ dependent exocytosis

5) Serotonin reuptake / metabolism
- signal terminated by reuptake by Serotonin transporters (SERTs) on presynaptic membrane
- degraded by MAOs in the cytoplasm

Question 13

Drugs that affect serotonin release and reuptake modulate behaviour

Answer 13

1- Fluoxetine (Prozac)
Blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) – antidepressant / anti-anxiety

2- Fenfluramine causes the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity)

3- MDMA 3,4-methylenedioxy-methamphetamine (ecstasy)
Causes noradrenaline and serotonin transporters (SERT) to work in reverse releasing neurotransmitter into synapse/ extracellular space
Lets serotonin out of terminal and you get an excessive amount of serotonin in synaptic terminal and this will acutely boost mood.

Monoamine oxidase inhibitors (boost monoamines)

Question 14

The cholinergic system
- in the periphery…
- in the brain…
- what other complex?

Answer 14

In the periphery
Acetylcholine (ACh) at neuromuscular junction (NMJ) and synapses in the autonomic ganglia

In the brain:
Basal forebrain complex
Projections to hippocampus and cortex

Pontomesencephalotegmental complex
cholinergic link between the brain stem and
basal forebrain complex

Question 15

What neuron is in the striatum and the cortex?
What do each interneuron do?

Answer 15

Cholinergic interneurons in the striatum and the cortex

Each interneuron innervates 1000’s of local principal neurons and modulates their activity

Question 16

Acetylcholine steps 1, 2, 3, 5

Answer 16

1) Synthesis:
- made from choline
amount of choline is rate limiting step

2) Storage:
- loaded into vesicles

3) Release:
- Ca2+ dependent exocytosis

5) Metabolism:
- rapidly degraded in synaptic cleft by acetylcholinesterase
- Choline is transported back into the presynaptic terminal and converted to acetylcholine

(acetylcholinesterase is made by the cholinergic neuron, secreted into synaptic cleft and associated with the axonal membrane)

Question 17

Drugs affecting acetylcholine release, storage and degradation modulate behaviour (or neurological function)

Answer 17

Acetylcholinesterase inhibitors

Block the breakdown of ACh thus prolonging its actions in the synaptic cleft

e.g. Physostigmine

treatments for Alzheimer’s disease,

Myasthenia gravis (don’t have that many acetylcholine receptors in some parts of your body- one symptom is dropping of eye lid)

(autoimmune disorder, AchR’s destroyed)

Alzheimer’s disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD.

Question 18

Drugs affecting vesicle docking and release
(3 things)

Answer 18

(ACh release at Neuro-Muscular Junction, NMJ)

Botulinum and tetanus toxins
(from bacteria Clostridium botulinum and tetani respectively)
- blocks the docking of vesicles by attacking SNAREs- no release

Botox
- acts directly at synapse in NMJ
- The muscles lose all input and so become permanently relaxed.
- prevents the blocking and acetylcholine can’t be reduced.

Tetanus toxin
- Retrogradely transported up at NMJ and works at inhibitory (Glycine) synapses on cholinergic motor neurons of spinal cord
- Also attacks SNARE proteins

(Inhibiting the release of Glycine at these sites “disinhibits” the cholinergic neurons so they continuously fire resulting in permanent muscle contraction, ‘lock jaw’)

Question 19

Disorders of the cholinergic system
(related to the peripheral and the brain)

Answer 19

Peripheral
Myasthenia gravis
Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity

Brain
Alzheimer’s disease
Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
→Drugs that increase acetylcholine help
(e.g. donepezil- can alleviate some symptoms)

Addiction
nicotine addiction

Other psychiatric disorders
Schizophrenia (Comorbidity with smoking)