July 2015 Blog with Durk and Sandy

by

APPETIZERS

America can cease to be the wealthiest nation on Earth and remain America. It can cease to be the most powerful nation on Earth and remain America. It cannot cease to be the land of the free and remain America.

—Charles Murray,
Rebuilding Liberty Without Permission, 
CATO’S LETTER (CATO Institute)
Vol. 13 No. 2 Spring 2015

The physician can bury his mistakes, but the architect can only advise his client to plant vines.

—Frank Lloyd Wright, New York Times 4 Oct. 1953

The Puritan hated bear-baiting, not because it gave pain to the bear, but because it gave pleasure to the spectators.

—Lord Macauley, A History of England Vol. Ch. 2 (1849)

If you’re in Amish country and you see a man with his hand buried in a horse’s ass, remember he’s just a mechanic.

—Robin Williams, 2003

Well, he thought, you can fool some of the people all the time, and all the people some of the time, which is just long enough to be President of the United States.

—Spike Milligan, 1963

Take the hair, it is well written
Of the dog by which you are bitten
Work off one wine by his brother
One labour with another.

—Antiphanes (400 BC), hangover cure

(D&S comment: a combination of Vitamin B1, the amino acid cysteine, and Vitamin C—as in Party Pill—is a better remedy, we think. Even back then, they may have heard of drinking orange juice (vitamin C) with a raw egg (cysteine) for hangover.)

Whilst Titian was mixing rose madder,
His model posed nude on a ladder,
Her position to Titian
Suggested coition,
So he climbed up the ladder and had ’er.

—Anon.

 

THE MYSTERY OF THE RISING IQS MAY BE SOLVED

Sandy has a hypothesis (though it is entirely possible that others have also suggested this) to explain the widely discussed fact of a rising IQ over six countries in the past 100 years that has been getting a lot of press. See, for example, the Sat./Sun. May 30-31 2015 The Wall Street Journal, pg. C2.

You will have noticed if you’ve read about this—and this has been discussed—that the greatest increase in IQs has taken place during periods of prosperity. Right now, the IQs are still increasing but only slowly. Consistent with the trend, the present economy is not a very prosperous one.

Sandy proposes that the rising IQs are occurring as a result of ENVIRONMENTAL ENRICHMENT, which has been studied extensively in the scientific literature using both animals and humans as subjects. Environmental enrichment is robustly linked to an increase in neurogenesis. It appears to explain quite nicely how, during periods of prosperity characterized by the availability of many opportunities (like putting lots of toys and things to do in an animal’s cage), an increase in neurogenesis is likely to be taking place with IQs being a rough indicator of that.

How Much of the Obesity Epidemic Is Real?
The Bad News and the Worse News

The bad news is that there is certainly a lot of obesity around. You can see it by looking at people in shopping centers or schools or anywhere there are large numbers of people.

But what do official counts of the rising number of obese Americans really mean? Consider: Durk points out that the new medical coding that requires doctors to assign numbers to patients that represent their medical condition is behind a phenomenon called “overcoding” where it is to the advantage of the doctor or hospital to code a patient as “obese” even if he or she is merely overweight to allow for increased reimbursement through government health “insurance” schemes or even private insurance. And perhaps the scariest part of this is that those designations follow the patient all the way from the doctor’s records for that patient to scientific research on obesity as a public health problem to government health surveys, with the designation “obese” being used to describe somebody only overweight making it appear that there is an epidemic of obesity.

We’re still waiting to hear about disappearing bedbugs

EPA RELEASES DRAFT PLAN TO CONTROL BEDBUGS
FOLLOWING THE FIRST NATIONAL BED BUG SUMMIT

As reported in the Sept. 9, 2013 Chemical & Engineering News. As of that date, the article says, the federal government announced a draft plan putting itself on top of the bed bug problem, so relax, we can assume that by now everything is under control. Everything except that taxes keep going up because, hey, Bed Bug Summits cost money, don’t you know.

Admitting from the start that bedbugs can be a health problem, carrying allergens for example, one wonders whether the federals simply have too much money to spend when they are developing a national plan to control bedbugs that included representatives from EPA, the Centers for Disease Control & Prevention, and the Departments of Defense, Housing & Urban Development, and Agriculture. The Department of Defense?? Oh, don’t they have something more important to spend their budget on than fighting bedbugs? Have the bedbugs developed weapons of mass destruction or something? Can’t the military use good old DDT on infected beds? We wonder how the Department of Homeland Security feels about being left out of this proposed spendfest.

We note, first, that there is nothing in the Constitution authorizing the federals to do anything about bedbugs, though the States are not prohibited therein from doing so and presumably could, if they wanted to and had the money, do something about bedbugs and it would be Constitutional, though almost certainly expensive and ineffective.

The federals are way beyond having any concern about being authorized in the Constitution to do anything, so now we have a national plan putting a bureaucracy together for dealing with the bedbug disaster, which we imagine would be far more dangerous than bedbugs themselves, leading us to conclude that: “We have nothing to fear but the bureaucracy set up to ensure that we have nothing to fear.”

We wonder whether the group did a comprehensive survey of the hotels that participated in the national summit of bedbugs to determine how many bedbugs had also attended the summit. Did they have a representative from an ethics advisory group on whether it would be ethical to kill bedbugs with chemical weapons? Extinction is forever; therefore, consistent with the precautionary principle, we had better not take the chance that bedbugs being eliminated from the ecosystem is of no consequence.

Is There a Real Bedbug Problem and, If So, What Is It?

There IS an actual problem, however. What this is all about is that hotels are now having a serious problem with bedbugs driving away customers precisely because the EPA itself has banned nearly any insecticide that could be used to kill bedbugs. The military has the same problem because even though the military could actually tell the EPA to take their insecticide ban and shove it, the Prez won’t let them do that. No doubt he has a reason for forcing the military to comply with the EPA’s rules on the use of insecticides for killing bedbugs, but we doubt that national defense played any part in his analysis.

COMPLAINTS FROM THE PAST
ANYTHING ABOUT THIS SOUND FAMILIAR?

If anybody is interested, the historical course of the Roman Empire looks almost exactly in its declining years like what is going on now in the U.S. and the modern world, with our advanced technologies mostly speeding up the changes but otherwise things look almost the same. Remember it was the collapse of the plumbing, e.g., the Roman water supply and sewage systems, that ultimately (as the proximal cause) depopulated the city by killing people with repeated plagues of diseases resulting from the poorly maintained fresh water and sewage systems. And, of course, it was Benjamin Franklin who has been given credit for saying, as he left the Constitutional Convention of 1789, “you have a Republic … if you can keep it.” Well, so did the Roman Empire and they failed to keep it. The [Roman] Republic entered the dustbin of history and it was followed by …. well …

Here’s the complaint. The poet Virgil narrowly avoided losing his estates during the period when Octavian took over Spain, Sardinia, and Africa, and undertook to put down Sextus Pompeius (the son of Pompey). Virgil alluded to this in his first Eclogue:

“To think of some godless soldier owning my well-farmed fallow, A foreigner reaping these crops!

“To such a pass has civil Dissension brought us; for people like these we have sown our fields.”1

Reference

  1. Virgil’s The Eclogues 1.70 ff, trans. C. Day Lewis, in The Eclogues, Georgics and Aeneidof Virgil, Oxford Univ. Press (1966), cited in Stephen Kershaw, A Brief Guide to Classical Civilization (Running Press, 2010).

Letter to Virgil

Dear Virgil,

We were sorry to hear of your problems with various military invaders from the Roman Empire. We do hate to tell you this but even if you could get to our time via time travel, it would do you no good as the situation hasn’t improved at all. They do it (sow crops in your field) with regulations rather than (usually) outright invasion, but the result is the same: your crops disappear and you don’t get to eat or sell them. Of course, there are a lot of interesting new things (such as telephones, the Internet, jet planes, etc.) available nowadays, so you still might like to make the trip. We just thought you ought to know that your crops will not be any safer from state predators today than they were then. See the US Supreme Court decision called KELO.

If you do decide to take the trip, available at your local time travel provider, please come and visit us. One caution, though, governments and predators (though sometimes in disguise) are everywhere and at all times.

We had a Republic, Virgil, but we couldn’t keep it.

Sorry about that.

SURPRISE! KAPPA OPIOID RECEPTORS MEDIATE THE ANTIDEPRESSANT-LIKE ACTIVITY OF HESPERIDIN IN MICE

Who would have thought it? That hesperidin could exhibit anti-depressant effects in mice subjected to the forced swim test and do so by interacting with the kappa opioid receptor. But that’s one thing about biomedical science—there are always lots of surprises.

The kappa opioid receptor is one of the three currently known opioid receptors, that also includes mu and delta opioid receptors. Hesperidin, a naturally occurring flavonone glycoside, is found in rich quantities in citrus fruits and has been reported to have antioxidant, neuroprotective, and anticancer effects. An earlier paper2 reported that in traditional Mexican medicine, infusion of flowers of the Citrus genera are used as a sedative to treat insomnia. That paper explored this interesting property of Citrus; the authors reported that, in an earlier study, hesperidin in the methanol extract of Citrus sinensis was identified as the sedative active principle of the plant. Others had described the involvement of opioid receptors to the behavioral and antinociceptive (anti-pain) effects of hesperidin.

The immobility period of the mice subjected to the forced swim test (freezing as a result of fear) was significantly reduced by treatment with hesperidin at doses of 0.1, 0.3, and 1 mg/kg. Pretreatment with naloxone (a nonselective opioid receptor antagonist) reversed the antidepressant-like effect of hesperidin, evidence that that effect of hesperidin was mediated by an opioid receptor.

Because of scientific evidence supporting hesperidin’s neuroprotective effects (such as its antidepressant activity in mice subjected to a severe stress), we included hesperidin at a dose of 100 mg per capsule in our special lithium formulation, same as the lowest dose of hesperidin that had antidepressant effects in the mice in this study. If you are a mouse, we suggest you consider the secure feeling you’ll get by taking a hesperidin supplement. If you are a human, we don’t know exactly what dose is going to provide the exact same effects as in the mice, but that hesperidin will activate the kappa opioid receptor seems very likely as there is no evidence to our knowledge that mice and humans differ in this particular respect.

There is much scientific evidence for beneficial effects of hesperidin, such as providing protection against amyloid beta induced neurotoxiciy (as occurs in Alzheimer’s disease),3 reducing neuroinflammation in an animal model of stroke,4 protecting against ischemia-reperfusion injury in rats,5 as just a few examples.

YOU CAN GET HESPERIDIN FROM ORANGE JUICE, BUT …

To get the amount of hesperidin contained in a single capsule of our lithium formulation would require drinking 400 ml of raw orange juice. Delicious, but there is a very large amount of natural sugars and calories in all that OJ. Besides, it is a lot more expensive than our lithium formulation. [See “Announcing Durk & Sandy’s New Lithium Formulation” in the May 2014 issue.]

  1. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol.698:286-91 (2013).
  2. Guzman-Gutierrez and Navarrete. Pharmacological exploration of the sedative mechanism of hesperidin identified as the active principle of Citrus sinensis flowers. Planta Med.75:295-301 (2009).
  3. Wang et al. Protective effects of hesperidin against amyloid-beta induced neurotoxicity through the voltage dependent anion channel 1 (VDAC-1)-mediated mitochondrial apoptotic pathway in PC-12 cells. Neurochem Res.38:1034-44 (2013).
  4. Raza et al. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res.1420:93-105 (2011).
  5. Gaur and Kumar. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep.62:635-48 (2010).

 

THE DIFFERENCE BETWEEN MODERN MEN AND THOSE THAT PRECEDED THEM

A philosophical speculation

by Sandy Shaw

An interesting thing to think about is: when were men smart enough to realize that everything might be explainable as the result of a natural process? You go back to Benjamin Franklin (not so long ago) and if you showed him, say, an iPOD, he would not know how it worked but he would be quite sure that there was a natural explanation for what it did, that it was not MAGIC.

Then go back to Leonardo da Vinci (1459-1512?), if you showed him an iPOD, he too wouldn’t have any idea how it worked, but we are sure (though we can’t prove it) that he would believe it to be a device explainable by natural processes, not MAGIC. You can go back pretty far in recorded history and there were men of genius who would be capable of such a distinction, natural processes explained how things worked, MAGIC was not needed. An example was very early astronomical theorists who thought that stars in the sky were probably natural bodies much like our sun or perhaps like planetary bodies. These men had little actual data but were using a large brain capable of very sophisticated thoughts to imagine what might explain lights they saw in the sky. So how far back would you have to go to reach a point where some humans had just begun to think that natural processes could explain everything and you didn’t need to invoke MAGIC. I think that was when you could say that modern man had arrived.

DO YOU INGEST ENOUGH CHOLINE?

Are You One of the 92% of the Population That Does Not Consume the Adequate Intake of Choline Recommended by the Institute of Medicine?

Why Getting Enough Choline is Vitally Important—
It Is An Essential Nutrient—
And Why Your Health, Quality of Life, and Probably
Your Lifespan Depends on Getting Enough of It

POSTOPERATIVE COGNITIVE DECLINE

Postoperative Cognitive Decline and Infections Prevented by Stimulation of the Cholinergic Antiinflammatory Pathway in Mice

Another 2014 paper5 reported on research attempting to determine how to prevent the all too common cognitive deficits that occur following surgery after acute illness and hospitalization. Mice were subject to tibia fracture (surgery) and infection (postoperative administration of lipopolysaccharide (LPS) to induce inflammation as occurs in a natural infection). The results of these procedures were, indeed, increases in measures of inflammation. However, in those mice that were treated with a selective activator of the n-7 nicotinic cholinergic receptor, which activates the cholinergic antiinflammatory pathway, 2 hours after the administration of LPS, resulted in significant improvement of the neuroinflammation in the hippocampus of the mice compared to mice receiving surgery or LPS alone.

The authors conclude that “[o]verall these results suggest that it may be conceivable to limit and possibly prevent postoperative complications including cognitive decline and/or infections, through stimulation of the cholinergic antiinflammatory pathway.”

  1. Terrando, Yang, Ryu, et al. Stimulation of the alpha7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice.Mol Med. 20:667-75 (2014).

NOTE that the galantamine in our galantamine formulation is a selective activator of the alpha-7-nicotinic cholinergic receptor, [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.]

OBESITY

Dysregulation of Metabolism and Immune Function in Obesity Points to Novel Therapeutic Approaches Involving the Cholinergic Antiinflammatory Pathway

A 2012 review paper6 describes how “cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.”

As the authors note, “[d]ecreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.” Later in the paper, the authors describe how the cholinergic antiinflammatory pathway suppresses the production of major inflammatory cytokines such as TNF-alpha, via the administration of alpha-7-nicotinic acetylcholine receptor agonists (which includes the nutrient choline6B) or a centrally-acting acetylcholinesterase inhibitor, such as galantamine. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.] The authors describe how galantamine treatment of mice with high-fat induced obesity and hyperglycemia had reduced plasma levels of IL-6, CCL2, leptin, and resistin levels to levels detected in lean control mice.7 They further explain that cholinergic signaling, such as that of alpha-7-nicotinic acetylcholine receptor agonists in brain regions such as the lateral hypothalamus, implicated as part of the brain’s control system for appetite and feeding behavior, can suppress food intake.

  1. Pavlov and Tracey. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol.8(12):743-54 (2012).
    Mike, Castro, Albuquerque. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res. 882:155-68 (2000).
    7. Satapathy, Ochani, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 17(7-8): 599-606 (2011).

 

OBESITY

Dysregulation of Metabolism and Immune Function in Obesity Points to Novel Therapeutic Approaches Involving the Cholinergic Antiinflammatory Pathway

A 2012 review paper6 describes how “cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.”

As the authors note, “[d]ecreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.” Later in the paper, the authors describe how the cholinergic antiinflammatory pathway suppresses the production of major inflammatory cytokines such as TNF-alpha, via the administration of alpha-7-nicotinic acetylcholine receptor agonists (which includes the nutrient choline6B) or a centrally-acting acetylcholinesterase inhibitor, such as galantamine. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.] The authors describe how galantamine treatment of mice with high-fat induced obesity and hyperglycemia had reduced plasma levels of IL-6, CCL2, leptin, and resistin levels to levels detected in lean control mice.7 They further explain that cholinergic signaling, such as that of alpha-7-nicotinic acetylcholine receptor agonists in brain regions such as the lateral hypothalamus, implicated as part of the brain’s control system for appetite and feeding behavior, can suppress food intake.

  1. Pavlov and Tracey. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol.8(12):743-54 (2012).
    6B. Mike, Castro, Albuquerque. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res.882:155-68 (2000).
    7. Satapathy, Ochani, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 17(7-8): 599-606 (2011).

CHOLINE COADMINISTERED WITH ASPIRIN HAS SYNERGISTIC EFFECT ON PAIN RELIEF: HIGHER POTENCY, LONGER DURATION, FEWER SIDE EFFECTS

The results published in a new paper1 will likely be of interest to anybody taking regular NSAID (nonsteroidal antiinflammatory drugs, such as aspirin, Naproxen, or ibuprofen) pain killers, particularly for chronic inflammatory conditions such as arthritis. The researchers report that choline, an alpha7 nicotinic receptor agonist (a natural endogenous activator of this particular type of cholinergic receptor) has anti-nociceptive (anti-pain) effects of its own in a variety of pain models. They were, therefore, interested in a possible positive interaction between choline and aspirin in the treatment of pain and thus carried out experiments with two inflammatory pain models in mice. One of the models they studied was the writhing test, where acetic acid is injected into the lower left quadrant of the abdomen of mice causing what must be excruciating pain as the pain behavior is manifest by writhing and evaluated by the number of writhes. We have chosen not to discuss this gruesome model as the results in terms of the observed pain relief to treatment with choline, aspirin, and a combination of the two were similar to the results of the inflamed paw test, described below.

The other model of pain studied was that caused by subcutaneous carrageenan injection into the paw of a mouse, which caused pain behavior assessed by how long it took the mouse to withdraw its injected paw (the Pain Withdrawal Latency, or PWL) in response to the application of heat; the heat would cause pain to the inflamed paw. The results showed that the administration of a single dose of choline (48 mg/kg, i.v., 1 hour after carrageenan injection) or a single dose of aspirin (30 mg/kg i.v., 1 hour after carrageenan injection) significantly suppressed the carrageenan-produced reduction in PWT only at 2 hours post carrageenan; thus, this time point was used as the test time in the remaining tests. (This is equivalent to less than one serving of our Memory Upgrade III.™) [See https://www.life-enhancement.com/shop/product/mu3-memory-upgrade-iii.]

“Choline (4–48 mg/kg, i.v.) produced a dose-dependent inhibition of carragennan-induced thermal hyperalgesia [pain], which was significant at doses of 16, 24, and 48 mg/kg (F(6,68)=10.8; P<0.01)). Aspirin (0.3125-30 mg/kg) also produced a dose-related inhibition of the carrageenan-induced thermal hyperalgesia, with significant effects at doses of 1.25, 2.5, 10, and 30 mg./kg. (F(5,54)=6.6; P<0.01)).

At low doses, choline (4 and 8 mg/kg, i.v.) or aspirin (0.3125 and 0.625 mg/kg, i.v.) administered alone were reported to have no effect on the carageenan-produced reduction in PWT, but when choline (8 mg/kg) was coadministered with aspirin at 0.6125 mg/kg or choline at 4 mg/kg + aspirin at 0.3125 mg/kg, the combination of drugs significantly reversed the carrageenan reduction of PWT. The effects were observed at 2 hours after carrageenan injection, but also at 3 hours and 4 hours after injection. Hence, the anti-pain effects of the coadministered choline and aspirin was prolonged. (If you wake up with aches in the morning, this mouse dose is equivalent for a human to about one serving of SleepScape™). [https://www.life-enhancement.com/shop/product/sls45-sleepscape]

Attempts to Find Mechanisms for the Observed Synergy Between Choline and Aspirin

The authors attempted to identify mechanisms that could help explain the interaction between choline and aspirin (and other NSAIDS).1

Curiously, pretreatment with one alpha 7 nicotinic cholinergic antagonist, MLA, blocked the anti-pain effects of choline, while a different antagonist, alpha-bungarotoxin, enhanced the choline-induced anti-pain effect.1 The researchers propose that the carrageenan-induced hind paw edema in mice is a biphasic event, with an early phase of inflammation resulting from the release of histamine, serotonin, and similar substances, while a later phase is associated with the activation of kinin-like substances. This biphasic behavior may result in different responses to the two alpha-7-nicotinic cholinergic antagonists. Another complication they point out is that choline is a partial agonist of alpha-9 alpha-10 nicotinic cholinergic receptors. “Taken together, the antinociceptive effect of systemic choline seems to be dependent upon the presence of inflammation and its activity may be mainly via attenuating the release of inflammation cytokines through activation with peripheral macrophages and monocytes through alpha-7-nicotinic receptors, but this needs further studies in more pain models.”1

The researchers also note that in their study1 the analgesic effect of choline was inhibited by naloxone, which suggests that opioid receptors are involved in choline’s anti-pain behavior, but that the data from some other studies (for which they provide references) are not consistent with this.

“These results provide support for further study of the synergistic antinociceptive mechanisms of coadministration of choline and NSAIDS such as aspirin, and they provide a basis for exploiting new analgesic treatments using low antinociceptive dose, long antinociceptive course, and reduced side effects.”1

Cholinergic Control of Inflammation May Be a Mechanism for Its Effects on Pain

There has been a considerable amount of research supporting an antiinflammatory function of the cholinergic nervous system.2 One paper3 reported that choline itself, by its signaling via the alpha-7 subunit nicotinic acetylcholine receptor, modulates the release of tumor necrosis factor (TNF), a major proinflammatory cytokine. TNF synthesis and release has been identified in various types of pain.4,5 Blocking TNF-alpha has been very effective in the treatment of rheumatoid arthritis, with sometimes dramatic reductions in both the pain and tissue damage resulting from the disease.6

In a study of the antiinflammatory effects of choline (50 mg/kg, intraperitoneally (i.p.) in mice, this treatment prior to endotoxin (a bacterial cell wall constituent that activates the immune system) administration significantly reduced systemic TNF levels. In the same study, though, mice that did not have alpha-7-nicotinic acetylcholine receptors (knockout mice) did not have reduced systemic TNF levels in response to the same dose of choline, showing that these receptors were required for the reduced TNF (anti-inflammatory) effect of choline. In cells studied by the researchers,3 choline incubation prior to exposure to endotoxin suppressed both TNF and NFkappaB, another major regulatory molecule in inflammation. Choline also suppressed TNF production from endotoxin-stimulated human whole blood and cultured macrophages. As the researchers3 noted, “[t]he effective doses of choline used in the present study (25-50 mg/kg, i.p.) are within the dose range used in [] other studies. It is important to note that we did not observe any adverse neurobehavioral effects of these choline doses, which are comparable with the recommended tolerable upper limit of dietary choline intake in humans.”

Finally, one more curiosity: A paper on the effect of aspirin and opioids on pain was published in the 11 Dec. 1997 Nature;7 the accompanying commentary8 described the findings of the study that the combination of aspirin and opioids is more analgesic than the summed effect of each drug separately with an attempt to identify mechanisms. Here is another example of the difficulty of identifying the pathways of pain regulation. It could link to the choline-aspirin work described above if the analgesic effect of choline is actually inhibited by naloxone (an opioid antagonist).

References

  1. Yong-Ping et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain.15:858-65 (2011).
  2. Rosas-Ballina and Tracey. Cholinergic control of inflammation.J Intern Med.265:663-79 (2009).
  3. Parrish et al. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling.  Med.14(9-10):567-74 (2008).
  4. Richter et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum.62(12):3806-14 (2010).
  5. Xu et al. The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg.105:1838-44 (2007).
  6. Basbaum et al. Cellular and molecular mechanisms of pain. CELL 139:pg. 275 (2009).
  7. Vaughan et al. How opioids inhibit GABA-mediated neurotransmission. 390:611-4 (1997).
  8. The painless synergism of aspirin and opium. Nature.390:557-9 (1997).

 

SATIETY SIGNALING AT THE END OF A MEAL MAY BE DUE TO ACTIVATION OF THE CHOLINERGIC NERVOUS SYSTEM—AN EXPLORATION OF POSSIBLE MECHANISMS REGULATING INGESTION

This article will be of interest only to the highly technically inclined, especially if they are overweight.

Hypothesis:

Activation of Cholinergic Nervous System May Promote Satiety by Signaling the End of a Meal Could the Widespread—92% Deficiency of Choline Ingestion Be Contributing to the Obesity Epidemic?

A new paper1 propose that activation of cholinergic interneurons in the nucleus accumbens (NAc) and cholinergic projections to the ventral tegmetal area affect feeding behavior. “In vivo microdialysis studies in rats have revealed that the cessation of a meal is associated with a rise in acetylcholine (ACh) levels in the NAc.” Moreover, the researchers note, “ACh activation will suppress feeding, and this is also associated with an increase in synaptic accumulation of ACh.”1

The paper also discusses the relationship between cholinergic activity and drug addiction and withdrawal. “Studies reveal that accumbens ACh is increased during withdrawal from several different drugs of abuse (including cocaine, nicotine and morphine). This rise in extracellular ACh, coupled with a decrease in extracellular levels of DA [dopamine] is believed to contribute to an aversive state, which can manifest as behaviors associated with drug withdrawal.” The authors suggest that these changes, observed both in the cessation of feeding and in drug withdrawal, may point to a form of “food addiction” and “withdrawal” from overeating.1

Acetylcholine participates in the regulatory pathways of many behaviors, including (for example) learning and memory and muscular contraction. Particularly interesting is, as the authors explain, that, “two major ACh projections innervate key components of the reward system.” The authors then propose that these projections may play a key role in the reward of drug addiction as well as in the promotion of either satiety or appetite, depending upon their specific co-transmitters.

As explained above, the rise in extracellular ACh, coupled with a decrease in extracellular levels of dopamine (DA) are part of the regulatory pathway that is observed both in the cessation of feeding and in drug withdrawal. The rewarding signal at the start of a meal that stimulates eating includes increased DA: “The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity.”2The researchers found in their study2 that there was a blunted dopaminergic response to food which, they surmise, “implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.” Unfortunately, the latter study did not include examining the effects of acetylcholine.

In another paper,3 researchers reported that “[o]ur recent data suggest that one such interaction is the regulation of ACh of DA synapse signalling of reward-related activity.” This comment was in relation to interactions between ACh and DA in the striatum in motor response selection, particularly in reward-related learning of stimulus-response associations or habits, acquired through positive reinforcement. “… striatal ACh neuron activity and ACh release are inhibited by DA.”3 This cross-talk between striatal ACh and DA in reward-related motor activity would be consistent with another appetitive activity (meal cessation) associated with ACh increase and DA decrease in the striatum.

As noted earlier, microdialysis studies have shown that there is an increase in extracellular ACh in the NAc at the end of a meal.1 “Further support for the theory that increased extracellular levels of accumbens ACh are associated with the cessation of feeding comes from data showing that when rats binge eat sugar while at a reduced body weight, or when they are sham fed(*) sucrose using a gastric cannula, accumbens ACh is blunted.”1

“Other studies suggest that food intake can be promoted by depleting ACh via local injection of the selective cholinergic neurotoxin ethylcholine azirdinium mustard (AF64A) into the NAc. In an acute (1 wk) feeding test, rats that were given this lesion showed a 2-fold increase in food intake.”1 (There was, however, a significant and lasting lag in body weight gain in these animals, which the authors of paper#1 suggest may point to a compensatory mechanism when cholinergic function is ablated.)

Nicotine-induced decreases in eating by mice may be, as suggested by recent studies, due to the activation of cholinergic nicotinic receptors in the hypothalamus, which activates pro-opiomelanocorin neurons leading to the activation of melanocortin 4 receptors critical for nicotine-induced decreases in food intake in mice.1

In comparing the biochemical pathways that involve the cholinergic nervous system in both drug or food withdrawal, the authors suggest: “Thus, rats in withdrawal from palatable food appear to show the profile of ACh in the NAc that has been seen in withdrawal from drugs of abuse.”1

The researchers conclude that “increased levels of ACh in the NAc act to promote satiety.”1 Also, another paper1B reports that cholinergic interneurons in the brain’s accumbens play a role in the regulation of body weight and metabolism.

In a 2011 paper,4 researchers examined cholinergic function in the regulation of reward, noting that “[m]ore than three decades of research into the neurobiological substrates of reward have focused attention on the nucleus accumbens (NAc)…” “The preponderance of this research effort has centered on dopamine (DA) as the primary neurotransmitter in this regard.” “Studies by Hoebel and colleagues have demonstrated increases in the release of DA in the NAc as a function of a variety of behaviors including feeding, rehydration, models of binge eating, and hypothalamic stimulation.” The authors4 then point to the work of Hoebel and other scientists for contributing work that has brought about an increasing appreciation of the importance of the role of acetylcholine in the brain reward circuit.

Interestingly, older people and animals have been found to drink less water in response to thirst as compared to younger individuals, thus being at increased risk of dehydration under hot, dry conditions.4B The above suggests that it might be a deficiency in the release of DA in the NAc during rehydration that is involved.

The RATIO of the Release of Dopamine to Acetylcholine May Regulate Ingestive Behavior

Eating Too Much? Choline to the Rescue?

As the authors of paper #4 indicate, the fact that dopamine (DA) plays a major role in the modulation of ingestive behavior is now well documented. They describe studies in hungry rats showing that “hungry rats stop feeding if the DA/ACh balance in the NAc is tilted in favor of excess cholinergic tone.” In the rat study, rats were implanted with bilateral microdialysis probes in the NAc and allowed to eat ad lib during their active period (night). When the probes implanted in the animals were perfused with an acetylcholinesterase inhibitor (which increases cholinergic activation), neostigmine, there was an almost complete discontinuation of eating, which did not happen in the control animals that received perfusion of standard Ringer’s solution. The animals treated with neostigmine continued to drink water, though, showing that the discontinuation of eating was not caused by malaise or immobility.

A 1998 paper5 was an early paper describing increased dopamine release combined with reduced acetylcholine release as a possible mechanism for hypothalamic initiation of feeding behavior. Using adult male Sprague-Dawley rats as subjects, animals received microinjections of the hormone galanin, neuropeptide Y, or saline into the hypothalamic paraventricular nucleus (PVN). The results showed that the injection of galanin in the PVN induced eating, causing the release of dopamine in the NAc and decreasing the release of ACh in the NAc. (The injection of neuropeptide Y also induced eating, but had no effect on either dopamine or acetylcholine.)

In a 2007 paper,6 researchers reviewed studies on the effects of the ACh/DA ratio on approach and avoidance. They examine several animal models of human behavior on meal satiation, taste aversion, escape from aversive brain stimulation, depression, drug withdrawal, and sugar withdrawal (following binge eating of sugar). They explain that in their own work, they tested the opposite effects of DA and ACh in the accumbens loop controlling motivation and some aspects of learning by injecting neurotransmitter agonists and antagonists into the NAc to reveal their effects on ACh/DA balance and observing animal behaviors. They also observed avoidance behaviors to see whether ACh is released in the NAc. “The evidence suggests that ACh inhibits the approach system via muscarinic M1 [cholinergic] receptors, and thereby counteracts the effects of DA at the D1 [dopaminergic] receptors.”6

One study they reviewed, for example, showed the effect of a mildly distasteful (bitter) solution that, when drunk, triggered injection of a nutritious ingredient into the stomachs of the subject rats. Ordinarily, rats avoid bitter tasting substances, but in this case, as compared to a bitter tasting solution that triggered only a water injection into the stomach, the animals soon developed a preference for the bitter tasting solution that delivered nutrition. The researchers found that squirting the (mildly) bitter flavor into an animal’s mouth (after it had developed a preference for its taste) resulted in the release of DA in the NAc, to which the authors attribute the approach behavior (the desire to eat). On the other hand, rats generally like sweet tastes, including that of sugar or saccharin. In a study where rats have developed an aversion to saccharin (because of pairing the saccharin with nausea) the taste significantly increases ACh release in the NAc, with the induction of avoidance (not wanting to eat).

The implications of these observations, that feeding behavior may be initiated by increased dopamine accompanied by decreased acetylcholine in the NAc and that feeding behavior may be terminated by decreased dopamine release accompanied by increased acetylcholine release, should they be affirmed in further studies (especially ones with human subjects), is that one may be able to induce the cessation of feeding by taking a cholinergic agonist (a substance like choline itself that increases acetylcholine production and release) at an appropriate time at the start of a meal or slightly before starting the meal. Another possible way to get the increased cholinergic activity in the NAc is to take a cholinesterase inhibitor such as galantamine, that increases cholinergic activity by causing acetylcholine to remain in the neuronal synapse for a longer period of time.

A couple of things to keep in mind: (1) the timing of the increase in cholinergic neuronal activity in relation to the cessation of eating is going to be important. That information may not yet be available; hence, some experimentation using safe ways to increase cholinergic activity (such as supplemental choline or the cholinesterase inhibitor galantamine) will be required. (2) A cholinergic agonist such as choline is going to be used throughout the body and brain, not just in the NAc, for the synthesis of acetylcholine, hence, side effects of excessive cholinergic activity, such as headache caused by increased muscle tone, could occur that have nothing to do with the desired effect on eating and, indeed, nothing to do with the NAc, another reason that some experimentation would be required.

References

  1. Avena and Rada. Cholinergic modulation of food and drug satiety and withdrawal.Physiol Behav.106:332-6 (2012).
    (*) The sham feeding of sucrose through a gastric cannula means the animals are fitted with a gastric cannula, but do not receive sucrose. That way, there is no confounding effect in the interpretation of the effects of sucrose feeding as compared to placebo by possible effects induced by receiving—or not receiving—a gastric cannula. The goal in experiments is to change only the variable you are studying and to keep everything else the same.
    1B. Hajnal, Szekely, et al. Accumbens cholinergic interneurons play a role in the regulation of body weight and metabolism. Physiol Behav.70:95-103 (2000).
    2. Stice et al. Relation between obesity and blunted striatal response to food is moderated by TaqlA A1 allele. Science. 322:449-52 (2008).
    3. Cragg et al. Striatal acetylcholine control of reward-related dopamine signaling. In The Basal Ganglia VIII, eds Bolam JP, Ingham CA, Magill PJ. New York: Springer;99–108 (2005).
    4. Mark et al. Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav. 104:76-81 (2011).
    4B. Mack et al. Body fluid balance in dehydrated healthy older men; thirst and renal osmoregulation. J Appl Physiol (1985). 76(4):1615-23 (1994).
    5. Rada et al. Galanin in the hypothalamus raises dopamine and lowers acetylcholine release in the nucleus accumbens: a possible mechanism for hypothalamic initiation of feeding behavior. Brain Res. 798:1-6 (1998).
    6. Hoebel et al. Accumbens dopamine-acetylcholine balance in approach and avoidance. Curr Opin Pharmacol. 7:617-27 (2007).

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