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Medical Negative feedback in the dopaminergic system

  1. Nov 17, 2005 #1
    Does anyone know what sort of negative feedback there is to a state of dopamine surplus?
    I always assumed it involved some kind of downregulation, thinking along the lines of receptor downregulation, and maybe reuptake channel/MAO-A/catechol-o-methyl transferase upregulation. But I just saw a mechanism of neurotransm. desensitization mentioned that I hadn't seen before, on a page discussing MDMA:
    "A few hours later, there is a decrease in serotonin levels, amplified by the reduced activity of tryptophane[sic] hydroxylase, the enzyme responsible for synthesizing serotonin."
    Could there be an analogous system for dopamine? Is tyrosine hydroxylase deactivated by dopaminergic overstimulation? I can't find any literature on the subject. I'm damned curious as to how it the feedback works*, if it does, and if a chemical can be designed/found that can inhibit this inhibition, mitigating the nasty rebound from dopaminergics might be possible. Something which could have application in those who take methylphenidate (ritalin) for half the day and become increasingly dysfunctional in the evenings.

    lates,
    cotarded.
    *p.s. I'm guessing it's a presynaptic receptor that initiates a second messenger response... but I still can't find information.

    edit: had accidentally said mao-a/catechol... etc. downregulation when I meant upregulation.
     
    Last edited: Nov 18, 2005
  2. jcsd
  3. Nov 18, 2005 #2

    DocToxyn

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    Yes, but there's more. Tyrosine hydroxylase is the main enzyme responsible for the synthesis of dopamine (aromatic amino acid decarboxylase is also involved but is not rate-limiting). It is regulated by just about every mechanism possible. End-product inhibition occurs when dopamine feeds back on the enzyme an inhibits the binding of the necessary cofactor tetrahydrobiopterin (BH-4). Another method of feedback inhibition comes from the stimulation of presynaptic autoreceptors that will down-regulate TH activity and/or reduce release of already synthesized and packaged dopamine. The autoreceptors can work through pathways involving adenylate cylase and others to inhibit TH activity. Impulse flow can also stimulate TH activity, so if the nerve is experiencing increased activity, kinetic activation of TH can occur by increasing the affinity for the BH-4 cofactor and decreasing affinity for dopmaine feedback inhibition. Phosphorylation of TH by various kinases also positively regulates TH activity, however many of the triggers/players involved in this process are still unknown.

    These previously mentioned mechanisms are generally for rapid alterations but sometimes for long-term changes, genetic control of TH content can be initiated through down/up regulation of TH production. This may occur in a disease state (Parkinson's) where loss of neurons leads to an overall reduction in dopamine thus the remaining neurons ramp-up dopamine production to compensate.

    As you can see there are numerous sites for regulation of TH/dopamine and this makes it particularly difficult to pharmacologically target one specific effect such as the one you mention. Plus you also have the influence of other neuronal pathways (GABAergic inibition for one), that also influence the system you are trying to manipulate. It's an incredibly complex system and one we are still learning about making it doubly difficult to produce effective drugs to treat specific conditions without unwanted side effects.
     
  4. Nov 18, 2005 #3

    Moonbear

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    Do you by any chance know of a good reference (original research paper, not a textbook) that shows TH is the rate-limiting enzyme in dopamine synthesis? This is commonly stated as "fact" without any reference to support it, I guess because it's assumed to be so commonly accepted nobody bothers to challenge it. I'm asking, because sometimes these things are carried through as "dogma" from old studies (and I have yet to dig up the relevant study) which were the best information available at the time, but may not be the best information we have now...and, well, I'm now wondering if AADC might (and I emphasize very strongly might) be playing a more important role in the neuronal population I'm studying. They don't contain DBH or PNMT, but have only very light AADC immunoreactivity (though, this could be an antibody issue...but that's what I'm questioning, if it's the antibody or if there really is very little AADC in these cells that have very robust TH-ir).

    Also, I'm trying to catch up on the literature on this because it hasn't been directly relevant to what I've been doing in a while, but is becoming more important now. There seem to be quite a few studies out now suggesting there are neurons that are TH-positive, but AADC-, DBH-, and PNMT-negative, so they likely only produce L-DOPA. The prevailing idea seems to be that the L-DOPA is then converted to dopamine in the post-synaptic neuron that contains AADC (possibly even serotonergic neurons), or even via axo-axonal contacts. What I'm wondering, but haven't found anything that directly answers this: is there any evidence at all that L-DOPA is capable of acting on any of the dopamine receptors, or for that matter, any receptor, directly, without being converted further to another neurotransmitter? In other words, can L-DOPA act as a neurotransmitter by itself? I don't care in what system or what neuronal population. Or, is there any pharmacological evidence to suggest it has absolutely no affinity whatsoever to the receptors? The lab I'm in has always dismissed this idea based on the assumption that L-DOPA doesn't do anything itself, but requires conversion to other neurotransmitters to have any effect, but I'm trying to determine if this is based on any evidence, or just old "dogma" of sorts that has since been overturned.
     
    Last edited: Nov 18, 2005
  5. Nov 18, 2005 #4
    Many thanks DocToxyn for upping the resolution of my still grainy understanding on these matters.

    Questions persist, as always, though, and hopefully you won't construe them as dissatisfaction, and will be able to help when you've got time.

    Let me interrupt myself though, to note I'd appreciate it if you have any general molecular biology reference recommendations that you could pass along (links online would be superb for rapid stopgap, and books are great for the longer haul - my broke a** will have to save up a bit first). More specifically I'm still intensely curious about the tyrosine hydroxylase regulation systems; any links discussing that would be treasured most of all.

    Round two:
    How does cAMP manage to be an integral part of so many distinct second messenging systems? (glucose detection in beta cells; adrenaline response; bone cells absorbing calcium in response to parathyroid hormones; etc..) The only explanation I can imagine is unlikely: That each cell limits itself to one implementation of a cAMP system, which is specific to its function. I don't have an example offhand but I'm sure there are cells that simutaneously use cAMP in different systems (those same beta cells probably respond to adrenaline, reducing insulin secretions - although I can't be sure of this). So yeah, what's going on here?

    The next question pertains to something moonbear said that seemed outside the paradigm that I've learned from my elementary level textbooks (it always gets stranger and stranger, and the notion of a steady rule more and more becomes a fairy tale)
    "The prevailing idea seems to be that the L-DOPA is then converted to dopamine in the post-synaptic neuron that contains AADC (possibly even serotonergic neurons), or even via axo-axonal contacts."
    I've never heard of NT intermediates being conveyed from one neuron to another so the latter can assemble the final product. (Also subscribed to the probably naive understanding that serotonergic neurons were just that, and didn't dabble in other types of transmission). Anyone up for a little clairification?

    Also - axo-axonal contacts? Is an action potential started along the post-synaptic neuron's axon by opening an ion channel along its length?

    thanks & lates,
    cotarded.
     
    Last edited: Nov 18, 2005
  6. Dec 1, 2005 #5

    DocToxyn

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    Sorry I haven't gotten back to this sooner. We closed on and moved into our new house, so that set me back a bit, plus catching up with work and everyone in my family getting sick hasn't given me much spare time.
    I found a review by Udenfriend that has the information you're looking for. I know it's not the actual original research article, but they reference it, (it's his work) as well as several other experiments that lead to the conclusion that TH is the rate-limiting enzyme, so I figured you could chase down the desired articles. Of course this was done in 1966 and he was more specifically concerned about norepinephrine (NE) synthesis, so maybe it could be challenged, but I think it would hold up. Plus there is I I remember my parkinson's lessons from classes, they were not able to alter the disease state with exogenous tyrosine (the initial precursor to dopamine/NE/epinephrine), but l-dopa worked, again suggesting that TH is the bottleneck.
    As far as l-dopa being a neurotransmitter, I found this article from TiPS 1993. You probably found it also, and it seems to present a fairly convincing case for l-dopa as a neurotransmitter or neuromodulator, and their recent work looks to have targeted some of the brain regions/functions that are mediated by this compound. Of related interest to your work, they mention in the first paper about a cells which posess a strong TH signal but no detectable AADC staining. Let me know how these papers are recieved by your lab group. It's always interesting to see how researchers react to ideas that challenge the dogma you bring up.:devil:
     
  7. Dec 1, 2005 #6

    DocToxyn

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    You're welcome, it's fun to get back to this since my current work isn't centered in the brain at the moment.

    As far as references/places to go for information, I have to tell you that I mainly seek out refereed articles or go to text books. Links/web pages are sometimes hard to judge for accuracy of content, especially if one is new to the subject. Your best bet is gain access to a good university library and use their resources (not just the electronic ones, but the people too!). Sorry I can't help you out further on this, but please come here with questions about what you do find and what you want clarification on.

    To your cAMP question, yes it is a very "promiscuous" second messenger and indeed it does play multiple roles in cells, although there may be examples of very specific cells that it has only one role in (doubtful), but I am not familiar with any. This article gives a nice intro into cyclic nucleotides, even though it's main focus is on their relationhship to plant biochemistry. One telling quote from this article follows:
    To give you an actual example along similar lines, calcium as a second messenger in neuronal cells acts simultaneously to stimulate release of neurotransmitter (exocytosis), upregulate NT synthetic activity (previoulsy discussed), alter other enzyme systems via interactions with calmodulin, calcineurin to result in things like phosphorylation of synapsin I to release vesicles from the cytoskeleton and it surely does even more.

    The l-dopa issue and conveyance of said compound from one neuron to another may not actually be a major route of precursor collection via the neuron, it may simply be adjacent to the releasing neuron and pick up diffused l-dopa, which it then converts to DA if it has the proper enzymes. Maybe Moonbear has more on this since she brought up the subject?

    Axo-axonal contact are classically defined as a way for the pre-synaptic neuron to modulate the postsynaptic cell's activity. They can inhibit or facilitate the postsynatic cells function, generally by a calcium-mediated process.
     
  8. Dec 1, 2005 #7

    Moonbear

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    Thanks. I hadn't come across any of those references previously (probably would have never found that 1966 review since there's no abstract online).

    Sounds like you have a personal opinion on that one. :wink:
     
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