Antidepressants - MA Theory

Question 1

List the monoamines (MAs) involved in mood.

Answer 1

Serotonin (5-HT), Norepinephrine (NE), and Dopamine (DA) may play a role as well.

Question 2

Where do the MA NTs have centres in the brain? Where are their fibers sent to?

Answer 2

MA centres in midbrain and upper brainstem, they send projections forward to various parts of the limbic system and the forebrain through the medial forebrain bundle.

Question 3

Where is the centre for NE?

Answer 3

Fibers arise from locus coeruleus in the midbrain.

Question 4

Where is the centre for 5-HT?

Answer 4

Originate in the areas of the Raphe System.

Question 5

Where is the centre for DA?

Answer 5

Fibers of the Mesocorticolimbic system that originate in the ventral tegmental area (VTA).

Question 6

According to the MA theory of depression, depression was a result of what?

Answer 6

Reduced levels of activity in these monoamine systems.

Question 7

How was this theory supported?

Answer 7

Observations that changing mono-amine activity levels affected mood.

Question 8

What are examples of drugs that increased MA activity, and what was their effect?

Answer 8

Cocaine and amphetamine increase MA activity by enhancing MA neurotransmission, this make people feel good.

Question 9

Give an example of a condition related to depression, and how this supports MA theory of depression.

Answer 9

Parkinsons disease is associated with decreased transmission at MA synapses, and has a high co-morbidity with depression.

Question 10

Give an example of a drug that decreases MA activity, and its effect.

Answer 10

Reserpine (formerly used to treat high blood pressure) depletes MAs by blocking the activity of vesicular transporter proteins that reside in the axon terminals where they fill synaptic vesicles with MAs. Patients prescribed with Reserpine developed severe depression.

Question 11

In a nut shell, describe MA theory of depression.

Answer 11

• MAs are associated with mood (5-HT, NE, & DA - but primarily 5-HT).
• Increased MA levels associated with feeling good.
• Decreased levels of MA associated with depression.

Question 12

Describe “lag time” as it relates to anti-depressants and MA theory.

Answer 12

When antidepressants are taken, they immediately affect MA levels at synapses (i.e. have an immediate physiological effect), but their therapeutic effect for treating depression is not seen for 4-6 weeks (even up to 12 weeks for their full effect).
Therefore the neurophysiology of depression is more complex than MA theory states.

Changing MA levels likely causes a cascade effect that eventually reaches the mechanism that underlies depression.

Question 13

Explain how tryptophan shows further evidence against MA theory in its simple form.

Answer 13

Depleting tryptophan levels (the amino acid precurser to 5-HT) does not cause depression in everyone. When no family history of depression is present, depleting tryptophan levels does not cause depression.

Question 14

Describe serotonin (5-HT)’s role in depression based on specific evidence.

Answer 14

• 5-HT likely not the sole cause of depression, but plays a role in vulnerability.
• Individuals diagnosed with depression have low cerebrospinal (CSF) levels of 5-HT, tryptophan, and its major metabolite 5-HTAA.
• Low levels of 5-HTAA correspond with fivefold increase in suicide risk.
• Treatments that are effective at treating depression ultimately increase transmission at 5-HT synapses.

Question 15

Explain the role of 5-HT reuptake transporters and depression.

Answer 15

• Depressed individuals exhibit decreased numbers of 5-HT reuptake transporter proteins in the brainstem.

Question 16

Depressed individuals exhibit decreased numbers of 5-HT reuptake transporter proteins in the brainstem, what does this indicate?

Answer 16

• This indicates a pathalogical reduction in the sheer number of serotonin neurons.
• Could also be an indication of a widespread dysregulation of 5-HT system function.

Question 17

What does a pathalogical reduction in the sheer number of serotonin neurons translate to?

Answer 17

Even a slight reduction in the sheer number of raphe serotonergic neurons would translate into an exponentially greater loss of 5-HT release in projection areas, such as the cortex.

Question 18

Which chromosome and gene has genetic research found to be responsible for 5-HT transporter protein production? What does this regulate?

Answer 18

Chromosome 17, portion of the gene: promotor region.

Regulates the number of 5-HT transporter proteins that get made.

Question 19

What are the two forms that this gene (promotor region on chromosome 17) come in?

Answer 19

Long form and short form.

Question 20

What is possessing the short form of the promotor region gene’s effect?

Answer 20

Associated having significantly fewer 5-HT transporter proteins and a heightened risk of developing depression.

Question 21

What is possessing the long form of the promotor region gene’s effect?

Answer 21

Creates a protective effect against depression (have more 5-HT transporter proteins).

Question 22

What could lack of 5-HT reuptake transporter proteins also indicate?

Answer 22

A compensatory mechanism, an attempt by neurons to overcome a preexisting state of synaptic 5-HT hypoactivity by reducing 5-HT reuptake activity.

Question 23

What 5-HT receptor is associated with depression? What abnormalities are found in depressed individuals?

Answer 23

The 5-HTA1 receptor subtype has abnormalities in quantity and function.

Question 24

What functional abnormalities of the 5-HTA1 receptor subtype are associated with depression?

Answer 24

Differences in receptor binding potential which could indicate an upregulation or downregulation in the density of receptors present on neurons, a change in the sensitivity of the receptors to neurotransmitter molecules, or it could indicate an increase or decrease in the presence of neurons containing those receptors.
Hotly debated whether binding potential increases or decreases.

Question 25

Where are 5-HTA1 receptors found?

Answer 25

As autoreceptors in the raphe nuclei (presynaptic) - thus inhibiting further release of 5-HT when activated.
Postsynaptic receptors in hippocampus, hypothalamus, amygdala and cortex - thus stimulating further release of 5-HT when activated.

Question 26

What might cause changes in the sensitivity or number of 5–HTA1 receptors?

Answer 26

• Genetic makeup, rendering the individual more or less vulnerable to depression.
  Or
• Might represent an adaptive response to depression - a way for the brain to compensate for abnormal levels of serotonin activity, perhaps triggered by some physiological or environmental event.

Difficult to see cause and effect relationship between 5-HT and depression.

Question 27

Is an increase in 5-HT transmission produced by antidepressant medications necessary or sufficient for relieving depressive symptoms?

Answer 27

Necessary, but not sufficient.

Question 28

Does an increase in 5-HT in the synapse increase postsynaptic cell firing?

Answer 28

No, presynaptic 5-HT autoreceptors detect the increase and inhibit further 5-HT release. Thus, it takes a few weeks of taking an antidepressant in order for the autoreceptors to habituate to the increase in 5-HT. with chronic treatment, antidepressants are able to enhance the sensitivity and function of 5-HTA1 postsynaptic receptors, leading to increased monoamine activity.

Question 29

What happens to 5-HTA1 autoreceptors as a result of antidepressant use?

Answer 29

Over time, downregulation and desensitization of 5-HTA1 autoreceptors. This acts to decrease cell inhibition resulting from the antidepressant-induced rise in MA levels and thereby enhance MA neurotransmission. The delay may result from adjustment mechanisms.

Question 30

What is the 5-HT system comprised of?

Answer 30

Runs from the raphe nuclei through the medial forebrain bundle to the forebrain.