The Rest of the Story

Environmentalists are bothered by the EPA's latest proposed air quality standards:

John Kirkwood, president and CEO of the American Lung Association commented that the EPA plan is "disappointing."

"If EPA adopts the standard as proposed," Kirkwood said, "the agency will have failed the most fundamental task required by the Clean Air Act - to protect public health from one of the major air pollutants."

For the first time, he said, the EPA will have ignored recommendations from its own staff scientists and from its official outside review panel of scientists. Both groups have advised setting a stronger standard than EPA has proposed.

Frank O'Donnell, president of Clean Air Watch, called the proposed standards a giveaway to industry.

One of the standards in question is that which regulates emissions of fine particles, those with a diameter of 2.5 microns or less.  Although very small, they are particularly dangerous.  If you care about the details, here is why (Medscape, free reg. req.):

Environmental exposure to airborne particulate matter of 2.5 microns in diameter or less (PM2.5) has been associated with reductions in HRV, a measure of cardiac autonomic regulation, and increased cardiovascular mortality in the elderly, Dr. Holguin and colleagues explain in the second issue of the December American Journal of Respiratory and Critical Care Medicine.

"We and others theorize that PM2.5-associated reductions in HRV are a potential mechanism by which PM2.5 leads to increased cardiovascular morbidity and mortality," Dr. Holguin said.

By the way, the Medscape article that the excerpt was from, provides 0.25 hrs of CME credit.  The article is a summary of a study done on elderly nursing home residents of Mexico City, to see if fish oil supplements would reduce the cardiac risk caused by air pollution.  The study was too small to be conclusive, but the results suggest that there is a protective effect.  

In case it is not immediately obvious why this would be, here is the mechanism:

The cardiovascular effects associated with particulate air pollution include an increase in systemic inflammation, deregulation of the coagulation system, and impaired endothelial-mediated vasodilatation and microvascular inflammation. These mechanisms may be blocked by omega-3 fatty acids and hence, omega-3 fatty acids may provide a preventative measure to reduce the risk for arrhythmia and sudden death in elderly subjects exposed to air pollution.

Ironically, the (Taiwanese) EPA just issued a report advising people to decrease their intake of fish, because of concerns about mercury pollution.  And the Secretariat of NAFTA has determined that US mercury emissions should be investigated.  And environmental groups are critical of the (US) EPA for not performing routine monitoring of mercury in sea life.  

So, as Tom Lehrer said, don't drink the water, and don't breathe the air.  Whatever.  Nothing new there.  

What might be news to readers is this: essential fatty acids (such as those found in fish oil) are not important only for their anti-inflammatory effects.  There are other kinds of essential fatty acids that are necessary for nerve signals to work properly in the brain.  From the online textbook, Psychopharmacology - The Fourth Generation of Progress, we learn the following:

A schematic picture of the ways in which arachidonic acid and its metabolites may act in regulating neuronal activity is shown in Fig. 1. Arachidonic acid is released from phospholipids in cells stimulated by many first messengers, including neurotransmitters, neuromodulators, and neurohormones. The free fatty acid has, as such, a short lifespan, during which it may interact with and affect the activity of ion channels and protein kinases within the cell. Alternatively, it may be transformed to a family of metabolites—the eicosanoids—which may also produce important effects on intracellular targets. In both cases, the arachidonic acid cascade affects neuronal excitability by fulfilling the primary criteria defining a second messenger system—that is, receptor-dependent formation and intracellular site of action. Where the eicosanoids differ from "classical" second messengers is in their ability to cross the cell membrane, diffuse through the extracellular space, and interact with high-affinity receptors located on neighboring neurons (Fig. 1). Eicosanoid receptors have been characterized in the brain and have been shown to be linked to second messengers, such as cyclic AMP, very much like the receptors recognized by dopamine, noradrenaline, and so on.

Arachidonic acid is an essential fatty acid, like those in fish oil, in that the human body cannot produce it.  In order to have it, you must get it by putting it in your mouth and swallowing it.  It and its derivatives are then incorporated into the cell membrane, and do interesting things.

I mention this because the model of neurotransmitter action that is commonly presented in the media is grossly oversimplified.  Often, one will see a simple diagram that shows how serotonin, for example, is released by one cell and interacts with a receptor on the next cell.  This completely ignores what happens after the transmitter binds to the receptor.  After the transmitter binds to the receptor, a whole series of events is created by what are called second-messenger systems.  There are several second messengers, and all interact in complex systems.  The arachidonic acid cascade happens to be one of the most complex:  

The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with. Not only can it generate multiple messenger molecules (at least 16, according to a conservative estimate limited to the brain), but these molecules may act both within and without the neuron, bringing into play intracellular as well as extracellular targets.

Furthermore, simplified models of neurotransmission do not account for the many factors that regulate the release of the first messenger:

A novel arachidonic acid derivative was recently isolated from brain and was identified as the ethanolamide of arachidonic acid (Fig. 4). This compound was shown to (a) inhibit the specific binding of a radiolabeled agonist to the cannabinoid receptor and (b) produce inhibition of the twitch response in mouse vas deferens, a typical response to cannabinoids. These properties have led to the suggestion that arachidonoylethanolamide (dubbed "anandamide" after the sanskrit word for bliss, "ananda") may act as the endogenous ligand for brain cannabinoid receptors (13). The pathways leading to the biosynthesis and the degradation of anandamide in the CNS are not known.

In order to understand  how complicated this makes things, consider the following:

Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis

Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of {Delta}9- tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.

Thus the release of serotonin is regulated, in part, by anandamide, a derivative of arachidonic acid.  And when serotonin is released, it regulates the release of other arachidonic acid derivatives.

I guess the real reason I wrote this is, in part, a response to a comment left on one of my prior posts about antidepressants.    

Your understanding is nearly as superficial as Mr. Cruise's. While the data do show that neurotransmitter concentration seem to be a function of depressed state, correlation is not causation. The full data, which do not show up in a blithe web search, also show that "fixing" the neurotransmitter levels has zero immediate effect on depression. This is in stark contrast to a true chemical imbalance disorder, such as loss of the sense of smell due to zinc deficiency, where administration of zinc fixes the problem quickly and dramatically.

In general, the therapeutic effects of antidepressants (as well as their side effects) take weeks or months to show up. That shows rather conclusively that depression involves large multi-part control systems that are slow to change. The best current guess is that it results from the absence of entire nerve cells in a part of the brain called the hippocampus, and that antidepressants trick the cells into being born more rapidly. Conversely, destroying those cells with x-rays in mice causes the mouse version of depression regardless of neurotransmitter levels.

Furthermore, Mr. Cruise is absolutely right that vitamins are an antidepressant drug. That's because of the placebo effect: if a depressed person believes that something might help them, there is a substantial chance that it will.

The person who left the comment was pointing out that "correlation is not causation," and implies that my post was superficial because there is a lot more to the chemical imbalance in depression than merely the regulation of serotonin.  Well, duh!, no kidding: it is a lot more complex.  More that you probably imagined.  More than anyone can hope to understand, at this point in time.  I know this.  That is why I base treatment decision upon empirical evidence, not poorly-delineated hypotheses such as the serotonin hypothesis of depression.  It is also why I ignore -- and everyone else should ignore -- those cute little drug company ads with the cartoon neurons and neurotransmitters.  They don't really tell you anything interesting.  They are true, to the extent that science permits, but they are so oversimplified as to be meaningless.  

Another interesting point, illustrated by the arachidonic acid story, is that all parts of a biological system are dynamic.  Nothing just sits there.  Simplified descriptions of cell biology often portray the cell membrane as just sitting there, being a membrane.  Nothing could be further from the truth.  The cell membrane is an active part of the cell, interacting with the cell's interior, the cell's environment, and nearby cells in an eloquent dance of incredible subtlety and complexity.  

So what can we conclude from all this?  The EPA is useless, anatomy and physiology are really complex, don't drink the water and don't breathe the air, don't pay attention to drug company ads (except for their entertainment value), and be careful leaving snarky comments on blogs where the blogger actually knows something about the subject.  Oh...and Tom Cruise is better at jumping on sofas than sniping at scientists.