When dopamine is taken up back into the neuron, why does it need to be broken down?

[aced126]

When dopamine is taken up back into the neuron, why does it need to be broken down by MAO-a and MAO-b? Surely just being taken up back into a vesicle would be more effective?

 

[serotonin2A]

Most of the dopamine taken up IS recycled into vesicles. Only a small amount is broken down.

Dopamine is metabolized by MAO-B. MAO-A degrades serotonin. The thinking used to be that MAO-A was primarily in dopaminergic cells, and MAO-B was primarily in serotonergic cells, to prevent the monoamines from being taken up by the wrong neuron and released as false transmitters. I'm not sure if that expression profile has been confirmed using modern biochemical tools, but you get the point that MAO-B may not just exist to break down transmitters in their own neurons.

 

[aced126]

Most of the dopamine taken up IS recycled into vesicles. Only a small amount is broken down.

Dopamine is metabolized by MAO-B. MAO-A degrades serotonin. The thinking used to be that MAO-A was primarily in dopaminergic cells, and MAO-B was primarily in serotonergic cells, to prevent the monoamines from being taken up by the wrong neuron and released as false transmitters. I'm not sure if that expression profile has been confirmed using modern biochemical tools, but you get the point that MAO-B may not just exist to break down transmitters in their own neurons.

If this is so then why are MAO inhibitors effective in the treatment of e.g depression? If say MAO-B was only mainly expressed in 5HT neurons, then blocking this enzyme would lead to more dopamine in the 5HT neuron (rather than more serotonin) thus potentially being neurotoxic to the neuron.

Also why then are selective MAO-B inhibitors like selegiline effective in treatment of Parkinson's (if barely any MAO-B is expressed in DA neurons at all)?

 

[Cotcha Yankinov]

If say MAO-B was only mainly expressed in 5HT neurons, then blocking this enzyme would lead to more dopamine in the 5HT neuron (rather than more serotonin) thus potentially being neurotoxic to the neuron.

MAO-B inhibition greatly reduces serotonin neurotoxicity concerning MDMA, this would make me think that its not necessarily the dopamine itself that is harmful to a serotonin nerve terminal (even though I have heard that even dopamine entering a serotonin nerve terminal is harmful) but rather it is the breakdown and formation of damaging metabolites of dopamine that is harmful.

But it sounds like the whole "dopamine in the serotonin nerve terminal" thing is mostly concerning when MDMA has removed some of the natural defenses against this form of damage. But you asked this a while ago and I'm still curious:

Why isn't dopamine harmful to dopamine neurons? Is it just a matter of increased anti-oxidant defenses? Or is it harmful (just slightly) to dopamine neurons and maybe this explains the constant degeneration of dopamine neurons throughout life?

 

[serotonin2A]

If this is so then why are MAO inhibitors effective in the treatment of e.g depression? If say MAO-B was only mainly expressed in 5HT neurons, then blocking this enzyme would lead to more dopamine in the 5HT neuron (rather than more serotonin) thus potentially being neurotoxic to the neuron.

Also why then are selective MAO-B inhibitors like selegiline effective in treatment of Parkinson's (if barely any MAO-B is expressed in DA neurons at all)?

Re-read over what I wrote -- I said the thinking "used to be". There is almost certainly some MAO-B expressed in catecholaminergic neurons, but that isn't necessarily where most of it is expressed. Likewise, there is almost certainly some MAO-A expressed in serotonergic neurons. The point of my post was not to argue that dopamine isn't broken down by MAO-B in dopaminergic neurons, but rather to point out that breaking down transported dopamine may not be the primary function of MAO-B.

But you asked this a while ago and I'm still curious:

Why isn't dopamine harmful to dopamine neurons? Is it just a matter of increased anti-oxidant defenses? Or is it harmful (just slightly) to dopamine neurons and maybe this explains the constant degeneration of dopamine neurons throughout life?

Dopamine can be harmful to dopaminergic neurons. There is evidence that dopaminergic neurons are more susceptible to oxidative stress than other cell types.

This question came up in the context of MDMA. You have to remember that the situation occurring with MDMA is not a normal physiological situation. Serotonergic cells normally tolerate some dopamine in the cytoplasm because they use multiple detoxification mechanisms to deal with dopamine. They can break the dopamine down with MAO-B (and they have detoxification mechanisms to deal with the resulting peroxide and other free radicals) or sequester it in vesicles (which keeps it out of the cytoplasm). But MDMA produces several effects that act in concert to overwhelm the defenses of serotonergic neurons. The degeneration seems to depend on hyperthermia and may require the presence of neurotoxic MDMA metabolites that are taken up by SERT. So it isn't just the presence of dopamine in the terminal that causes toxicity.

 

[Cotcha Yankinov]

Do you think that dopamine's metabolism is what is causing the apparent age related decline in dopaminergic cells in all humans regardless of Parkinson's, and that MAO-B inhibition will be protective in this regard?

 

[serotonin2A]

Do you think that dopamine's metabolism is what is causing the apparent age related decline in dopaminergic cells in all humans regardless of Parkinson's, and that MAO-B inhibition will be protective in this regard?

Yup, thats what a lot of studies suggest.

 

[aced126]

Yup, thats what a lot of studies suggest.

It seems very "unevolutionary" that the above would take place. If MAO-B had to fulfill another role, then why does it 1) "by chance" have the ability to metabolise dopamine and why 2) is it even expressed in dopaminergic neurons at all. If other roles could be filled, why hasn't an enzyme evolved to serve for that function but not interfere with dopamine?

 

[serotonin2A]

It seems very "unevolutionary" that the above would take place. If MAO-B had to fulfill another role, then why does it 1) "by chance" have the ability to metabolise dopamine and why 2) is it even expressed in dopaminergic neurons at all. If other roles could be filled, why hasn't an enzyme evolved to serve for that function but not interfere with dopamine?

You are missing my point. I never said that MAO-B does not exist to metabolize dopamine. My point is that it metabolizes dopamine, but the metabolism does not occur primarily in dopamine neurons. I mentioned serotonergic neurons as one location. There is also a large amount of MAO-B in astocytes. They basically "mop up" excess dopamine that escapes from dopaminergic synapses.

http://www.ncbi.nlm.nih.gov/pubmed/8406673

EDIT: I looked over what I wrote again to see if I had written something confusing. My previous post stated:

"The point of my post was not to argue that dopamine isn't broken down by MAO-B in dopaminergic neurons, but rather to point out that breaking down transported dopamine may not be the primary function of MAO-B."

In that sentence, I was specifically referring to transported dopamine, meaning dopamine that has been taken up by DAT into dopaminergic neurons. I wasn't trying to say that dopamine degredation is not a primary function of MAO-B. I guess maybe I used have gone into more detail about what I was talking about.