Monday, April 18, 2011

Omega 3s, Mice, and Receptors for Funny Cigarettes

Jamie (who has a fabulous post up now about Survival of the Fittest) sent me a link to a new paper this morning.  Or possibly last night.  The mound of papers is starting to slide, and sometimes I lose track.  In any case the paper is from Nature Neuroscience, and that always makes me flinch a bit, because Nature Neuroscience is rather advanced.  In most papers, every other word is an abbreviation for some sort of obscure brain chemical or neurologic process, which makes for a lot of blinking and re-reading.  Fortunately, for the same reason, most Nature Neuroscience papers are very short.

Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

Endocannabinoids!  I know!  Those are our innate chemicals that stimulate the endocannabinoid receptors, which happen to also be stimulated by the merry-making chemical known as THC in marijuana.  I am not, personally, a marijuana fan, having seen too many psychotic young people brought in by parents after a summer of six bowls a day, and also seeing a few too many older folks who could barely put a sentence together after four decades or more of heavy use.    And of course the innumerable people with lack of motivation, weight gain, and rebound anxiety "but I just smoke one or two puffs a day, doctor."  And I'm sorry, you really aren't as interesting as you think you are when you are high.  It's just cold hard fact.  It is especially uninteresting in the emergency room at 3am.  Trust me.

But, as with anything in nature, we have our little endocannabinoids (anandamide and 2-arachidonoylglyceral (2-AG)) that stimulate our endocannabinoid receptors which serve a very useful purpose in the brain.  In fact, there was a great hub-bub a few years back about a potential new weight loss drug, rimonabant.  This drug blocked the cannabis receptors, leading to weight loss.  (Actually, leptin will short-circuit the binding of endocannabinoids in the hypothalamus, also decreasing appetite and resulting in weight loss (1)) I believe rimonabant was approved in Europe and may be in use there.  However, it was never FDA approved in the US due to some unfortunate side effects such as anxiety, depression, insomnia, mood swings, and even aggression (2).  The longer you were on rimonabant, the worse the side effects became.  In fact, a doctor in Texas had his license suspended after prescribing himself rimonabant for weight loss, and then becoming erratic and aggressive at his place of work.

So what on earth is going on with those endocannabinoid receptors, and what does that have to do with omega 3s and mice?  Back to the paper, which I have obviously been avoiding for a couple of paragraphs now.  These researchers had two groups of mice, one born after a pregnancy of omega 3 supplementation (for some reason, the researchers used ALA, but I honestly have no clue as to the conversion to DHA in mice) and then continued on supplementation.  The other group was fed a diet rich in peanut oil (mostly linoleic acid - omega 6) without omega 3s.  Then the researchers used some very sophisticated machinery and lots of abbreviations to prove that "dietary PUFAs influence eCB-mediated synaptic plasticity… in PFC slices prepared from mice that had received an n-3 diet, tetanic stimulation induced a robust eCB-LTD of excitatory synapses onto layer V/VI pyramidal neurons in the PrPFC."

Roughly translated, our brain has off switches if we get too much stimulation in one area.  For example, have a buddy poke you in the forehead between your eyes repeatedly.  At first you won't be able to stop blinking when the finger comes close, but after a while, you can keep your eyes open.  This is a process called stimulus "extinguishment." There is a lot of evidence that problems such as psychosis and even depression develop because certain signals just keep going and going and going and getting through, without extinguishing.   In the brain, a signal that goes on too strong for too long will result in a process called "long term depression" (LTD).  Simply stated, a repeated signal ad nauseum or a signal that is too much will result in the synapse being modulated to reduce the signal strength.  This process is an important part of "synaptic plasticity."  And it turns out this process is modulated in the mouse prefrontal cortex by the endocannabinoid system.  And in mice raised on a lifelong diet deficient of omega 3 fatty acids, the long term depression did not occur in the prefrontal cortex.  This means the omega 3 deficient mice had decreased neuronal plasticity.  Their brains were, essentially, more brittle, less flexible in responding to different stimuli.

The researchers used excessive abbreviations to prove that it was the endocannabinoid systems affected in the mouse, not a myriad of other systems, including our old frenemy the NMDA receptor.

There is an interesting wrinkle.  PUFAs happen to be the precursors to our own natural funny cigarette compounds, anandamide and 2-AG.  It is possible that a high level of PUFAs result in an excess of natural funny cigarette compounds (OMG, that soybean oil ranch dressing was like, so totally amazing man) which then saturate and perhaps desensitize our endocannabinoid receptors.  In this mouse paper groups of lifetime n-3 deficient and n-3 replete mice had equal circulating levels of natural endocannabinoids in their little mouse brains.  In other papers, there were differences, suggesting that there may be compensatory mechanisms for endocannabinoid levels.

So, what are the effects of omega 3 deficiency on mouse behavior again?  They are more depressed, are less motivated and explore their environments less.  They scratch more, indicating anxiety.  They also avoid open spaces and like to remain close to walls, also thought to be a sign of mouse anxiety.  The researchers then gave the sad and nervous mice of control and omega 3 deficient groups some cannabinoid agonists (not puff the magic dragon, but another one hilariously called WIN), and the mice perked up and started hanging out in the middle of open space again, and presumably began planning trips to the minimart for twinkies and bugles.  The omega 3 deficient mice were less responsive to WIN than the regular mice, consistent with the theory that cannabis receptor functioning was a bit shorted out in the deficient mice.

There is a lot to like about this paper.  It doesn't answer all questions, to be sure, but it brings up plausible links between industrial diets, depression, anxiety, and even possible connections to hypothalamic dysfunction, leptin, and obesity.  It plugs some missing links in the overall picture of mood and appetite regulation.  Word.


  1. I literally laughed out loud a couple times while reading this- thanks for a great post!

    If I were going to stick with this whole research thing, I'd love to do a postdoc somewhere with an O3:O6 model and go play with rat livers from such a paradigm... That, or I'd like to be the person that gets to name newly synthesized agonists... WIN!

  2. I used to have somewhat of a funny cigarette habit but since learning about PUFAs and getting enough omega 3s I haven't felt like doing any of that, or other addictive things for that matter.

    Paleo party! BYOF (bring your own fish)

  3. Never has reading about stuff I have no hope of ever understanding been so fun. WIN!

  4. Another important paper for my files. And thanks for translating all of the goobldygook terminology. The only correction I have is that the effect you called "extinction" seems more like habituation to me. Habituation is the waning of an unconditioned reflex (e.g., blinking to a looming stimulus) over repeated presentations, whereas extinction is the waning of a conditioned reflex (i.e., a Pavlovian CR) over repeated presentations.

  5. Hi Aaron - I'm sure you are right, though extinction of the reflex is the term we used in neurology - they were likely being imprecise.

  6. Dr. Deans, thank you for another fascinating and delightful post.

    If the mice which had had the lifelong Omega-3 deficiency were put on a mouse version of an evolutionary diet, and given the best possible Omega-3 for mice, would the brittleness and shorted-out receptors be healed?

    I'm with Stabby, this post is motivation for more salmon for breakfast, sardines for lunch, cod liver oil at bedtime, etc.

    Thank you for making learning so enjoyable.

  7. Hi H. Thanks for all your nice comments! The lack of DHA seems to screw up the g protein coupling in the cannabis receptor complex - I'm guessing this is something that should be reversed with repletion, but the long term consequences of brain development lacking major neuroplasticity systems are unknown, and that part might be irreversible.

  8. So,if I understand this post,"baked salmon",could be looked at as a potential treatment for lethargy and depression?

  9. Dr. Deans, thank you very much for the explanation. I appreciate your help.

    Here's hoping that making the best choices we can will do more for us than improving a mouse's diet would for the mouse. Being able to make choices is the grandest thing.

    Wild salmon, pastured butter and coconut oil for breakfast this morning. :) And, Assam tea.

  10. Olddude - In a large Finnish epidemiological study, women who eat more fish had less depression. In a hot-off-the-presses Nurses Health (epidemiological) study, fish intake had no relation to depression, but an increase in ALA did decrease depression (riddle me that one, Denise Minger!) Some O3 supplement randomized controlled trials showed little to no benefit for depression - the largest one to date, from Canada last year, showed an effect in depression without complicating anxiety equal to an antidepressant. No one has done a randomized controlled trial of wild caught salmon for depression, however :)

    I tend to err on the side of 1) common sense, 2) biologic plausibility, and 3) real food and 4) with a dash of "do no harm." Therefore, I do recommend (wild caught) salmon for everyone - and I can't really see why it wouldn't stack the deck a bit in your favor if you have tendencies toward depression. There are so many variables that just adjusting the omega 3 might not make an overall difference, I'm fully ready to admit.

  11. Aaron - now that I think on it, we often used the term "extinguished" rather than extinction, so I'm probably the one who is being imprecise. Maybe I'll change it. Hmm.

    H - no prob! Sounds like a yummy breakfast.

    Production - just because you didn't like physics doesn't mean biochem is hard to understand ;-)

  12. Hi Dr. Deans,

    This is off-topic, but I noticed the title of your blog in my RSS reader now reads "Drink Milk" instead of "Evolutionary Psychology". I have nothing against milk (but I prefer real cream), but it does seem strange to me!

  13. Frank - that I cannot explain! I do like whole milk in my scrambled eggs, and my kids sure drink a lot of it, but I haven't changed anything with my blog...

  14. If I am correct, then endocannabinoids anandamide and 2-arachidonoylglyceral are both derived from Omega-6 fatty acids (check the metabolism pathways). I'll be damned if there aren't endocannabinoids derived from omega-3 fatty acids. And I'll be damned if both n-3 and n-6 compete for the same enzymes. Just like the inflammatory series-2 (omega-6) prostaglandins and the less-inflammantory series-3 (omega-3) prostaglandins. Now, if too much omega-6 and too little omega-3 can drive inflammation, can it drive addiction too? By simply clogging the metabolism pathways?

    Tony Mach

  15. Tony, 2-AG is the major EC in the brain and both 2-AG and anandamide are derived from arachidonic acid (derived obviously from LA) There are a million other ECs and I'm not sure their metabolic pathways. The researchers were looking for a difference in those two levels in the paper between the mouse groups and didn't find any - but other researchers did find different levels among groups without the lifelong depletion of these mice, apparently. ECs act locally so you need a constant supply. I don't know if it drives addiction but it certainly could be possible.

  16. Avoiding open spaces and staying close to walls is a completely normal mouse behavior that greatly reduces the risk of death. It is definitely not a sign of "depression". Wild mice are extremely cautious and exceptionally timid.

    An anxious mouse gets to reproduce.

    A confident mouse is a dead mouse.

  17. Hi blogblog - I've never done any mouse research myself, but my understanding is these standard tests are used as objective measures - mice are videotaped and literally the amount of time they spend in the center is catalogued, or how long it takes them to start exploring, etc. There are several variations - and mice in certain stress paradigms (after restraint, for example, or being confined with an aggressive mouse) exhibit more anxious and nervous behaviors and are less likely to go to the center of the room, and are less likely to explore a maze, things like that. They will also tend to have different postures and scratch more, depending on the species. Whether or not this is a good model for anxiety is certainly up for debate - though it would fit with the human stress diathesis model of depression and anxiety. There are obviously levels of confidence - a mouse who won't explore might not find the cheese. A mouse who will stick his neck out too much will get its head lopped off.

  18. Dude, I've searched long and hard for a crunchy, salty munchie that is relatively low in n-6, so I like reeely don't appreciate the reference to bugles. They're just corn (no gliadins), salt, and palm oil.

    Have come to love your blog.

  19. Jim - I'm all for mice gorging on bugles rather than twinkies if palm oil, salt, and corn are the primary ingredients. In fact, I might seek them out as a candy cigarette sort of snack myself… thanks for the heads up :-)

  20. According to Yahoo answers, Bugles is made from the following

    "Ingredients: Degermed Yellow Corn Meal, Coconut Oil, Sugar, Salt, Baking Soda, Nonfat Milk, Wheat Flour. Freshness preserved by BHT.

  21. Not sure where they fall on the n-6 scale, but if you want a crunchy munchie that's healthier than bugles, I recommend Kale Chips. A Google search will turn up plenty of recipes. (I make mine with my Pizzazz Pizza cooker, takes about 5 min.)

  22. WIN is the profile of developmental chemicals from Winthrop Grumann, not a particular agonist

    There are a number of cannabinoid agonists from Winthrop, and many other researchers, in fact you could buy many of them online for the past few years until the DEA recently took action...


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