Is Dopamine produced, stored and then depleted or just produced and used at same time?

[marnegro]

Is dopamine produced, stored and then depleted or just produced and used as needed ( no storing or accumulated )? I have been looking for that answer for a while.... I’m wondering why do I wake up at morning at my best well being feeling of the day I mean minimum symptoms no dizzy no diskinesya minor shaking, free walking ( my last medication dose is about 3:00 to 5:00 pm previous day) then before going better from that point, I got worsen just after 30-45 minutes of my first c/l doses to the point I get almost immobile, shuffling, freezing, rigid then after hitting the bottom I start to improve mobility and stability about 30-45 additional minutes.

[johntPM]

Good question. I too wake up with few symptoms (1), and can go several hours with no meds, then once I take a dose I begin to feel worse for about 30 minutes, or so, until the meds kick in (2).

(1) - There are two ways that dopamine can be produced: endogenously (naturally) and exogenously (artificially, from the levodopa that we take). Depending on the progression of the disease you can still be producing some dopamine naturally. This is produced by the remaining dopaminergic neurons. These contain vesicles (small bags) that act as reservoirs of dopamine. It seems reasonable that these fill up during sleep. The neurons in the substantia nigra project into the striatum, and deliver the dopamine there, where it is needed.

(2) Levodopa levels take about a hour from taking the dose to reach their maximum. So, some delay in symptom relief is to be expected but, I think, the post morning dose downturn is worse than that. I speculate that the cause of this is that the exogenous dopamine floods the whole brain. I suspect that the brain detects this excess and turns down the natural production leaving you worse off, until enough levodopa is absorbed to lead to a net improvement.

[marnegro in reply to johntPM]

Thanks for taking your time to share your excellent research. Appreciate it so much.....

[Astra7]

A very good question. I go from 5 on to 6am with nothing, but during the day I want more (another quarter madapor) every 3 to 4 hours.

I think it can build up a bit then gets used up with activity. I find I need an extra dose if I’m going to play tennis.

I’ll ask my neuro when I see him next month.

[marnegro in reply to Astra7]

Thanks for sharing your experiences.

[jeffreyn]

If it was me, I would try experimenting a little. For example, reducing the size of my first dose of the day, just to see what difference that made.

[marnegro in reply to jeffreyn]

Thanks. I’ll do

[MBAnderson in reply to jeffreyn]

ditto

[Hidden]

A tidbit suggesting that there is some dopamine storage (key part starts at "indicating that...").

ncbi.nlm.nih.gov/pmc/articl...

"Mounting evidence now suggests that levodopa-associated motor complications are a result of high dosage and the non-continuous delivery of levodopa to the brain. Conventional levodopa/DDCI is rapidly metabolized in the periphery, resulting in a short plasma half-life of ~60–90 minutes (Nutt and Fellman 1984). In the early stages of PD, this short plasma half-life is discordant with the clinical effect of the drug, which may persist for many hours, indicating that surviving dopaminergic neurons are able to store the exogenous dopamine generated from levodopa and so buffer variations in levodopa availability. However, with progression and further neuronal degeneration, the levodopa-buffering capacity is lost and deep troughs in plasma levodopa levels correspond with deep troughs in dopamine within the striatum, resulting in pulsatile stimulation of striatal dopaminergic receptors (de la Fuente-Fernandez et al 2001). Under these circumstances, patients experience a predictable pattern of symptom re-emergence that corresponds with these low troughs. Sustained pulsatile stimulation of dopaminergic receptors is also thought to underlie the pathogenesis of dyskinesia (Olanow et al 2006). Continuous enteral infusion of levodopa has been shown to significantly increase the bioavailability of levodopa and prevent low troughs in plasma levodopa levels (Stocchi 2005). The improved plasma profile achieved with infusion is associated with dramatic improvements in OFF-time and dyskinesia (Stocchi 2005). Such data support the theory that motor complications result from deficiencies in the delivery of levodopa due to the poor pharmacokinetic profile of conventional oral formulations."

[parkie13 in reply to Hidden]

That must be why we do better with sinemet CR, which is released over time. I have been using the generic form for a while now and it works out great for me.

[Beverly2017 in reply to parkie13]

Hi Parkie I was wondering what your dosage is and how often do you take the sinemet cr? I take sinamet cr 100/25 at 2 am to sleep, I've tried taking it in the day and it doesn't seem to work very well. Right now I take macuna powder inbetween regular sinamet 100/25 of which I take half at 11 am and half at 5 pm I use macuna capsules by Now and also use the amazon macuna powder. It seems that I need something every 90 min. I'm trying hard not to over do it as my theory is that if I can take small doses of levadopa then my brain will keep manufacturing some of its own. If I over dose my self with too much levadopa, it descourages my brain from making its own. What do you think? Thanks for your input, Beverly

[parkie13 in reply to Beverly2017]

I was diagnosed in 2013. Had many symptoms before that. I take 3.5 pills in 24 hours. It's generic 25 / 100 CR. I take my first dose at 6 a.m., 11:30 a.m., 5 p.m., and then just before bed I take a half a pill. I was hoping to maybe make my own so I was hoping that during the night I did make my own. I had to resort to half a pill before going to bed since I had so much tremor and could not sleep. That scheduling seems to be working out really well for me so far. Last time when I went to see my neurologist he wanted to up my dose but I was not receptive to that. He told me since we are taking Carbidopa , mucuna pruriens powder, standardized, works a lot better and he said if I needed to I could always take some of that. Which of course you're taking the same kind of drug especially if it is standardized. I have noticed too that first thing in the morning I feel pretty good so I'm sure that some of it dopamine has been made by my brain and it has been stored. Mary

[Beverly2017 in reply to parkie13]

Thankyou, I'll try my sinamet cr in the day time. The macuna seems to be very good and has enabled me to keep my sinamet dosage down to 2 pills 25/ 100 per day but I'm needing more macuna now and take a tablespoon of the macuna powder twice a day. It's a juggle. I've been unable to keep up my excercise due to appendicitis and then appendectomy 2 wks ago. Feeling pretty good. I'm also on thiamine hcl 3000 mgs. Good luck to everyone and thanks for your tips. Great!!! Bev

[Goldencbc in reply to Beverly2017]

Beverly, your post is helpful to me. When I switched to c/l cr, the nausea really went away and I was doing well. Recently my tremor has been worse and I have had bad headaches. I have decided to try half of the c/l cr 25/100 morning and afternoon to see if that helps. I like your theory. Does the mucuna make you nauseated at all? Thanks, Carol

[Hikoi in reply to Goldencbc]

Hi Goldencbc

Long acting drugs work by the outer layer breaking down more slowly than that on the short acting meds. In general if a long acting med is broken it becomes like a short acting med.

[Goldencbc in reply to Hikoi]

Thanks for the information. I was pretty sure that may be the case but my neurologist told me I could go ahead and split them if I needed to. I’ll see how it goes.

[PDGal4 in reply to Hidden]

Interesting. Could not follow all the medical/scientific terms, but gather the goal is more even delivery of meds. This parallels what my neurologist has said, that the current thinking is dyskinesia and other med-related symptoms are attributable to rise and fall of dopamine levels. Rytary aims to smooth that delivery out.

parkie13 are you in the US? I recently read (it's on MJF site) that the manufacturer of sinemet CR is discontinuing. I hope this doesn't affect you as you seem to be doing so well on it.

[Hidden in reply to PDGal4]

Thanks for the tip. Good news is that:

"...generic alternatives to Sinemet CR, and Sinemet (levodopa/carbidopa) remains on the market."

michaeljfox.org/news/sineme...

[parkie13 in reply to PDGal4]

I'm using the generic kind. Yes I'm in USA. I'm just hoping they're not going to switch generic brands, since I heard on this site some feedback that some of the generics are inferior. Before I got the extended version I kept on throwing up on the immediate release sinemet.

[PDGal4 in reply to parkie13]

egads, I hope the generic company continues to manufacture. (Just backpedaled and read pdinva's post that they will.)

I had a generic brand sinemet that didn't really work. Doctor said it has something to do with fillers, although I've since read some not-so-hygienic stories about manufacturing facilities overseas. Mylar generic sinemet worked best for me. Due to insurance (they wouldn't pay) my doctor couldn't write for name brand, but he did write prescription for this brand generic. I'm in the US too.

[parkie13 in reply to PDGal4]

Recently, high blood pressure drugs have been contaminated with cancer-causing chemicals. That happened to be drugs from China. I know it's kind of luck of the draw. Mary

[marnegro in reply to Hidden]

Thanks for the information. Very helpful

[Hikoi]

Good question marnegro

Wish I knew!