Lecture 14: Depression Flashcards
Which system in the brain controls emotions?
The Limbic System
Which system in the brain controls Motivation?
The Mesocorticolimbic dopamine system
What three elements of behavior does depression distrupt?
- Cognition
- Emotion
- Motivation
What does the motivation system do?
Drives behavior that is purposeful and goal directed
What is the Limbic brain?
A cortical border circling the brainstem
What parts does the limbic brain include?
- Hippocampus
- Amygdala
- Basal Ganglia
- Cingulate Gyrus
What is one of the oldest parts of the cortex?
The limbic brain
How does depression affect the limbic region and striatum?
Major depression causes increased engagement of the limbic regions and decreased engagement of regions involved in motivation (striatum) compared to healthy controls
What is activity in the brain driven by?
Neurotransmitter release or changes in the postsynaptic response
What are the monoaminergic neurotransmitters?
- Dopamine
- Norepinephrine
- Serotonin
What neurotransmitters is the limbic system heavily concentrated with?
Monoamine neurotransmitters
What is the difference between the monoaminergic neurotransmitters and Glutamate and GABA?
The monoamine neurotransmitters are more modulatory as opposed to glutamate and GABA which are more excitatory and inhibitory
What precursor do Adrenaline and Dopamine both start with?
Tyrosine
What does tyrosine hydroxylase (TH) do?
Converterts Tyrosine to L-dopa
What does L-Dopa get converted into?
Dopamine
What does Dopamine B-hydroxylase do?
Converts dopamine into noradrenaline
What is the precursor to Serotonin?
Tryptophan
What does L-amino acid decarboxylase (AADC) do?
Converts L-Dopa to Dopamine and 5-HTP to Serotonin
What does Tryptophan hydroxylase do?
Converts Tryptophan to 5-HTP
What enzyme degrades all three of the monoamine neurotransmitters?
Monoamine Oxidase (MAO)
What kind of behavior is Dopamine important for?
Motivate behavior
What do most of the drugs to treat depression target?
Norepinephrine and the serotonergic system
What does the Amine Hypothesis of Depression state?
That depression results from inadequate monoamine neurotransmission (serotonin and noradrenaline)
What was Reserpine initially used as?
A hypertensive drug used to HBP
How is Reserpine related to depression?
It was found that people who took reserpine developed a syndrome indistinguishable from depression
How does Reserpine cause its depressive effect?
It depletes neurons of dopamine and norepinephrine
What happens to Dopamine after it is synthesized?
It is packaged into vesicles and can either be released as dopamine or it can be converted to norepinephrine by dopamine b-hydroxylase
What is required of dopamine before it can be released in the synapse and bind to receptors?
It must be packaged into vesicles
What does Reserpine block?
The transporter that is necessary for moving dopamine into vesicles
How is Iproniazid related to depression?
Patients who took Iproniazid tended to have their symptoms alleviated
What enzyme does Iproniazid inhibit?
Monoamine Oxidase (MAO), the enzyme responsible for the breakdown of monoamines
What are the problems with the amine hypothesis of depression?
- Drugs that restore monoaminergic levels are only moderately effective in 30-50% of patients
- Inconclusive evidence that serotonin and noradrenergic systems are disrupted in depression
- Antidepressants to several weeks before clinical effect is seen, despite immediate effects on synaptic neurotransmitter levels
What does the Glutamate hypothesis of depression state?
Depression is associated with reduction in glutamatergic signalling in the cortex
What does the loss of Glutamatergic signalling impact?
Excitatory and inhibitory function leading to a reduced signal to noise. It also impacts LTP, neurotrophic production (BDNF), synapse formation and gene transcription
What receptors do inhibitory GABAergic neurons have?
NMDA glutamate receptors
What are the most common antidepressants?
MAO inhibitors
What do MAO inhibitors do?
They increase synaptic levels of monoamine neurotransmitters (norepinephrine and serotonin)
What is an example of an MAO drug?
Iproniazid
What diet must be followed with MAO inhibitors?
A low tyramine diet
What is the tyramine cheese reaction?
When eating a meal rich in tyramine while taking a MAO inhibitor can lead to acute hypertension cause by tyramine binding to adrenergic blood vessels and in the heart
What is Tyramine?
A sympathomimetic monoamine (acts like noradrenaline) and is naturally found in certain foods
What is Tyramine degraded by?
MAO
What does Tyramine bind to?
Alpha and Beta adrenergic receptors in the heart and activates them
What do the selective reuptake inhibitors block?
The serotonin (SET) or noradrenaline transporters (NET)
What do the serotonin (SET) or noradrenaline transporters (NET) do?
Move the neurotransmitters from the synapse to the intracellular space
What happens when serotonin (SET) or noradrenaline transporters (NET) are blocked by Selective Reuptake inhibitors?
They inhibit both NET and SET from removing neurotransmitters from the synapse
What happens when serotonin (SET) or noradrenaline transporters (NET) are blocked by SSRIs or SNRIs?
The increase levels of serotonin or norepinephrine at the synapse
What are the side effects of MAOIs, SSRIs, and SSRIs?
- Nausea
- Indigestion
- Dizziness
- Dry mouth
- Weight loss
Where is 90% of serotonin found?
In the GI tract
What does Ketamine do at the receptor?
It is a noncompetitive NMDA receptor antagonist
What receptor does Ketamine bind to and where does it bind on the receptor?
It binds to glutamate receptors but binds to them inside the pore
What does Ketamine binding to NMDA receptors on GABA interneurons do?
It blocks its ability to open and pass positively charged ions
How does Ketamine work?
It blocks NMDA glutamate receptors on GABA neurons causing a burst in glutamate causing synaptic remodelling and resetting of glutamate and GABA systems because it blocks the inhibition by GABA of glutamate neurons
What is the therapeutic index of Ketamine?
It has a very narrow therapeutic index
