Dopamine deficiency, Parkinson's, and CIS

I have been reading the 23andme forums quite a bit, on the lookout for things related to the whole cholinesterase inhibitor sensitivity issue. 23andme is working with the Michael J. Fox foundation to make it easy for Parkinson's sufferers to use the service in return for their participation on surveys (see article here). As a result, a lot of people with Parkinson's Disease are active participants. One such participant asked about excess salivation, which I recognized as a symptom of cholinergic excess. So, off I went on a new research tangent... It turns out that there is a significant overlap between the symptoms of Parkinson's and the symptoms of cholinergic excess. According to the book "Handbook of Parkinson's Disease" (see Fifth Edition, p. 383, "Mechanisms of Action" section), decrease in the level of dopamine, as is seen in Parkinson's, can cause the symptoms of cholinergic excess. It says this happens because it's the ratio of acetylcholine activity relative to dopamine activity that's significant. So, I went out and read about dopamine, and dopamine deficiency. I found all sorts of exciting stuff in that quest -- enough to fill a huge number of future blog posts, so watch out. Click here for a good web page describing the basic neurophysiology of dopamine, and here for a list of the effects of dopamine deficiency. Here are some highlights:

• High/increasing dopamine levels make you feel good: the "high" caused by many drugs of abuse like cocaine, heroin, and amphetamines work by temporarily greatly increasing dopamine release
• Low/decreasing dopamine levels make you feel bad: the "low" after such drugs wear off, the plunging feeling when something you did that you expected to be praised for instead results in scorn or abuse, etc. are caused by your dopamine levels decreasing
• People feel motivated to seek experiences which are expected to increase dopamine, and to avoid experiences which are expected to decrease dopamine.
• Dopamine is involved in reinforcement training: if you expect a positive outcome of an intended action, you get an increase in dopamine. If you get a positive outcome, you get even more dopamine. If you get a negative outcome, your dopamine drops precipitously.
• Dopamine is involved in social dominance: successful assertion of social dominance increases dopamine; being the target of someone else's assertion of social dominance decreases dopamine
• Dopamine is involved in behaviors related to food: eating increases dopamine; chronic overeating decreases dopamine receptors so you have to eat more to get the same "high" (see article on role in obesity here); but, paradoxically, low dopamine decreases motivation for and willingness to expend effort to gt food (in a paper on Regulation of Effort in Food-Seeking Behavior rats are less inclined to press a lever to get food if you suppress their dopamine).
• Dopamine is involved in sexual behavior: a good description of this role of dopamine is here.
• Dopamine is related to motivation and perception of one's ability to effect change (empowerment) in general: many of the symptoms of dopamine deficiency relate to lack of motivation and enthusiasm; high dopamine leads to a feeling of "social potency" and the feeling that you can take action that leads to success (and higher dopamine); success at such attempts leads to even more dopamine; failure leads to less dopamine, and makes it harder to try again.
• Dopamine may be related to subjective experience of temperature: high dopamine makes you feel warmer, low dopamine makes you feel colder. I need to research this more, but I certainly notice this effect correlating with other indicators of dopamine level. I have found some other places that mention this, for example this paper abstract says increased dopamine increases heat dissipation (skin is hotter, but core gets colder).

Anyway, reading about all this I realized that the state I have been in after getting the cholinesterase inhibitors far enough out of my system looked just like what I'd learned about dopamine deficiency. Sure enough, dopamine reuptake inhibitors, which increase the effect of dopamine by making it spend more time in the synapse, had a huge impact. I've been feeling a strange inability to initiate action, even for stuff I wanted to do, like make dinner, or start this blog. I could eat plenty if it were put in front of me, but seldom ever felt hungry, and had difficulty making myself prepare food -- particularly anything at all complicated -- even though I know how important it is to eat. (In the old days, I would have just grabbed a snack or microwavable convenience food, but that's incompatible with my efforts to avoid cholinesterase inhibitors, so it's a lot more of a problem now.) I didn't really feel enthusiastic about anything, even stuff I know I would normally be excited about, like the Yuri's Night celebration or seeing old friends I hadn't seen in a long time. Dopamine reuptake inhibitors, specifically bupropion, made all these effects go away within a few hours. Now, the typical way this would be interpreted in our culture is "oh, that's an antidepressant, so if it helped it means you must have been depressed." I could get into a semantic argument about this, and maybe I should in a future post. (Interestingly, it's also used to relieve smoking addiction -- another condition relating to dopamine and cholinergic receptors.) For now, leave that aside and consider this as a Human System Debugging experiment which confirms that dopamine is likely playing a role here. The fact that the success of that experiment allows me to finally get on with writing this stuff down is a happy side effect. :) So, putting all that together with the insights from the Parkinson's book leads to an interesting hypothesis: maybe low dopamine increases sensitivity to the effects of cholinesterase inhibitors. If so, then people with conditions which cause low dopamine, such as Parkinson's, or who are deficient in dopamine either by genetic predisposition, current circumstance, or nutritional insufficiency of dopamine precursors may be at greater risk for suffering symptoms of cholinergic excess from ingestion of cholinesterase inhibitors. If they also have a compromised ability to detoxify cholinesterase inhibitors, such as the BCHE, ACHE, and PON1 SNPs described by Dr. Soreq, this could be a bad combination. This is my current favorite hypothesis for conditions which could lead to what I'm calling Cholinesterase Inhibitor Sensitivity (CIS).

AChE-R and Mass Spectroscopy

Dr. Hermona Soreq and her colleagues have published several papers and a book chapter which talk about various forms of cholinesterase, how they're regulated, and what they do. In particular, they talk about a form called readthrough acetylcholinesterase, or AChE-R, that the body produces in response to acute stress and exposure to cholinesterase inhibitors (CIs).

Apparently AChE-R is not fun stuff. It's pro-inflammatory, may cause neural damage, and may somehow make you more prone to other bad stuff. It hangs around for a long time after the stressful event/CI exposure too.

I want to be able to measure AChE-R, AChE, BChE (butyrylcholinesterase), and PON1 levels. I've got so many ideas for experiments I could run if only I could measure these things. Among other things, I hope it would let me test whether or not strawberries are really cholinesterase inhibitors or not. I really hope not, but a book from 1985 says they are, so I'm avoiding eating them until I can find or perform an independent verification or refutation that finding.

Unfortunately, I don't know how to accomplish measuring these things. I haven't seen anyone other than Dr. Soreq and her collaborators even talk about AChE-R, which is the most interesting one of all. They're mostly in Israel and I'm in the US. Even if they were optimally interested in working with me on this, I doubt samples would make it through customs.

My husband is suggesting we learn how to use a mass spectrometer so we can measure these things ourself. He's doing things like finding online courses and books at amazon and searching eBay for used mass spectrometers.

My idea is to try to find a lab in Pittsburgh (where we'll be for the rest of the year) with appropriate equipment and someone who is willing to help with this. I figure I could barter one-on-one tutoring with lab personnel. I can help them learn how to do various forms of automation to make their jobs easier in return for training and time on their equipment so I can do my cholinesterase inhibitor experiments.

I don't know how to find and set up something like this with an appropriate lab, but this really seems like the best option if I could pull it off. Any leads anyone?

Leaky Gut Syndrome

Another condition that could potentially be related to cholinesterase inhibitor sensitivity is Leaky Gut Syndrome, aka Intestinal Permeability.

The best info I've found on this is in the book Digestive Wellness by Elizabeth Lipski. I stumbled across a web site today that also looks potentially good on this topic, though I haven't read it carefully: http://www.ei-resource.org/illness-information/environmental-illnesses/leaky-gut-syndrome-(lgs)/

The idea is that if you have compromised intestinal permeability, things like cholinesterase inhibitors could enter your system more freely without being broken down properly while within the intestines. Also, solanaceous glycoalkaloids, the cholinesterase inhibitors in nightshade foods, can apparently cause membrane disruption that can lead to and/or exacerbate leaky gut syndrome.

So, you can easily imagine that once this process got started it could form a positive feedback loop and get progressively worse until you stopped eating nightshade, taking NSAIDs, and eating whatever else your gut associated lymphatic tissue had gotten upset about so you could heal.

I've finally started writing up info on avoiding nightshades and other cholinesterase inhibitors at http://sites.google.com/site/annerwright/avoiding-cholinesterase-inhibitors

SNPs for cholinesterase inhibitor sensitivity

I've been trying to understand the potential causes of cholinesterase inhibitor sensitivity. My leading theory at this point relates to single nucleotide polymorphisms (SNPs) affecting the genes for encoding and promotion of acetylcholinesterase (ACHE), butyrylcholinesterase (BCHE), and paraoxonase 1 (PON1).

I've found several papers and a couple of books that relate to these genes and talk about polymorphisms which can result in being more susceptible to cholinesterase inhibitors. I've also signed up for 23andMe which hopefully in 8 more weeks or so will allow me to see which version I have of many of them. If, that is, I can figure out the mapping...

First off, it turns out that there are two ways of reporting the alleles for a given SNP: A=T; C=G. SNPedia uses one way, and 23andMe uses the opposite way. A partial explanation of this is at
http://www.snpedia.com/index.php/Talk:Rs4420638. This isn't complicated, but it does make your head hurt more when trying to compare them.

Secondly, the various sources aren't using a consistent naming scheme. I've tried to start making a table to cross reference the names I've found in the papers to the "rs" codes that 23andMe and SNPedia both use (see http://sites.google.com/site/annerwright/snps). It's a clunky way to do it, and I'm fantasizing about making something with django to do the job better. So, I'm kinda stuck on that project until I either bite the bullet and do it clunky way, or learn enough django to do it the fancy way and possibly enter a bottomless development hole...

Finally, three SNPs into the project I ran into a possible numbering discrepancy. The paper lists the SNP as position -162 on the PON1 gene. SNPedia doesn't list a SNP there, but lists Rs705381 at position -161. Is it the same one?

How many more of these things are going to almost but not quite line up? Aaaahhhh!

It begins

I've decided to start a blog on the general topic of "Human System Debugging."

I call it that because I used to work as a systems engineer for one-off robot systems, and then I got too sick to do that, and nobody could figure out what was wrong. I started applying the techniques of debugging one-off robot systems to figure out what was wrong with myself. The theories I've come up with are rather unconventional in places, but seem to be helping. I hope that that some of the things I'm learning along the way may be of use to others. Hence this blog.

Here are some things I've got so far that may be of interest to someone:

• Slides from my first "Human System Debugging" presentation in October, 2008 at a conference in Atlanta: http://docs.google.com/Presentation?id=dc438rq4_39f33nfrcm
• A Google Site I'm starting to work on on the topic of cholinesterase inhibitors: http://sites.google.com/site/annerwright/cholinesterase-inhibitors