Sunday, September 12, 2004

Neuropeptide S and Me

This is a story of a medical career and a molecule, neuropeptide S. The stories are interwoven in order to illustrate some points about neuroscience and bioethics, with a couple of political jabs thrown in just for kicks.

Eocene mammal fossilThe story begins in 1980. That summer, I was in Wyoming, collecting Eocene vertebrate fossils for Dr. Philip Gingrich's team of paleontologists from the University of Michigan. I was just along for the ride, really, but I did find a lot of fossils. My new wife was a graduate student in physical anthropology at the time, and had to do some fieldwork. Living in a tent in the Wyoming badlands is not the usual idea of a great honeymoon -- unless you're a scientist.

I had a great time.

The year before, I had decided to go to medical school. My other career choice had been bioengineering, but I chose medicine because it is the more portable of the two professions. One of us had to do something practical, as anyone married to a grad student knows. I knew I was about to spend eight years with my nose in a book. A summer in Wyoming was the perfect experience to prepare for the grind.

While I was in Wyoming, a country singer named Merle Haggard had a hit song: Big City.

I'm tired of this dirty old city.Wyoming badlands
Entirely too much work and never enough play.
And I'm tired of these dirty old sidewalks.
Think I'll walk off my steady job today.

Turn me loose, set me free, somewhere in the middle of Montana.
And gimme all I got comin' to me,
And keep your retirement and your so called social security.
Big City turn me loose and set me free.

Been working everyday since I was twenty.
Haven't got a thing to show for anything I've done.
There's folks who never work and they've got plenty.
Think it's time some guys like me had some fun.

Turn me loose, set me free, somewhere in the middle of Montana.
And gimme all I got comin' to me,
And keep your retirement and your so called social security.
Big City turn me loose and set me free.

That sort of sums up how I felt.

Neuroscience was in an early stage of development. For example, the dopamine hypothesis of schizophrenia was just being established, and there were two competing hypotheses to explain major depression. Some thought is was primarily a deficiency of norepinepherine in the brain; others thought that serotonin was the culprit. We had just learned about neurotransmitters and receptors, and it was becoming possible to do quantitative assays of neuroreceptors. Because of these and other related discoveries, it seemed that we were on the verge of resolving the scourge of mental illness. Since that time, we indeed have made some major advances, but the field of neuroscience has turned out to be much more complex than anyone imaging at the time.

Being a bit of an idealist, once I got to medical school, I thought I would end up as a family practitioner or a pediatrician. However, as I got more clinical experience in the third and fourth years, I developed the impression that I did not want to spend every day seeing one ear infection after another. That is an unfair characterization of primary care, but it's what I was thinking at the time. I had learned about the dopamine hypothesis and receptors and all that, and I knew that psychiatry was about to undergo a major transformation. Not wanting to be stuck in a boring profession, I decided to go into psychiatry.

You see, at the time, it seemed to me that being a pediatrician would be like having a job in a big city. Just one little problem after another, never really getting anywhere. Psychiatry, on the other hand, offered the lure of being "somewhere in the middle of Montana:" wide open horizons, a new discovery everywhere you look.

Of course, I was right about a couple of things. Psychiatry -- which is really the applied branch of neuroscience -- is undergoing a major transformation. It is not boring. Every time I think to myself, "now I've seen everything,' someone with something new comes into the clinic. There is no end to human variation. Having the time to really get to know patients, seeing all the little details that make up a complex life story; these factors lead to endless fascination.

In contrast, I was wrong about a couple of things. We were not on the verge of eliminating the scourge of mental illness. We were not close to finding some kind of ultimate truth about the causes and cures. Instead, what has happened, is that every question that gets answered, merely leads to more questions.

In the time since 1980, we have discovered many "new" neurotransmitters. We have learned that each transmitter acts on a variety of different receptors, and that these receptors are made and regulated in complex, mysterious ways. For example, the GABA type A receptor is made of five protein subunits. Each person has multiple slightly different genes that code for the subunits. If you calculate all the possible permutations, it turns out that there are over 1000,000 different ways to make that one receptor. Complexity always has purpose in biology, so there must be a reason for that complexity to exist. It's just that we have only the vaguest notion why.

Each discovery leads to speculation and hope about possible clinical applications. Neuropeptide S (NPS) is a good example. The August 19, 2004 issue of the journal Neuron has an article about NPS. I can't legally reproduce the whole thing here, but here is the abstract:

Copyright © 2004 Cell Press.
Neuron, Vol 43, 487-497, 19 August 2004

Neuropeptide S: A Neuropeptide Promoting Arousal and Anxiolytic-like Effects

Yan-Ling Xu 16 , Rainer K. Reinscheid 16 , Salvador Huitron-Resendiz 4, Stewart D. Clark 1, Zhiwei Wang 1, Steven H. Lin 1, Fernando A. Brucher 2, Joanne Zeng 1, Nga K. Ly 1, Steven J. Henriksen 4, Luis de Lecea 5, and Olivier Civelli 1,3

1Department of Pharmacology, University of California Irvine, Irvine, CA 92697 USA
2Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92697 USA
3Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697 USA
4Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037 USA
5Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037 USA
Rainer K. Reinscheid
(949) 824-9228 (phone)
(949) 824-4855 (fax)

Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.

For those without a subscription to Neuron, there are summaries posted elsewhere (1 2 3 4). The company that makes NPS (for research, not clinical use) has information about the experiments here.

Already, this has made it to the Blogosphere; Blogpulse lists four references (1 2 3 4). The sentiment expressed in these is illustrated by the following quotes:

  • Cool beans, I want my new study drugs!!!
  • Personally, I think that Olivier's newest paper (Xu et al., 2004, Neuron 43:487-497) on the discovery of a putative role for Neuropeptide S in arousal is a highly significant and exciting development.
  • All I want to know is, when can I get some?
  • Brain Protein Turns on Calm Alertness:
    Finding could lead to treatments for sleep disorders and anxiety.

In 1980, I might have said something like "cool beans!" Now, I have a more reserved, stoical, skeptical response...not! It is really cool to think that we might be able to use this discovery to develop a drug that would simultaneously lower anxiety AND increase alertness. For example,. it might allow our military pilots to fly all night and not drop bombs on Canadian troops.

One interesting thing about finding is that it illustrates the falsity of a common misconception about psychiatric medication. It is believed commonly that such drugs are either "uppers" or "downers." Although that was true until the mid-1950's, in 2004 it is a gross oversimplification. So much so, that it is more misleading than useful.

The therapeutic applications for drugs that affect the NPS system could include: Attention Deficit Hyperactivity Disorder, sleep disorders, and anxiety disorders. Currently, the most effective drugs for these conditions all have some addictive potential. It is possible that an NPS receptor agonist could treat these conditions without the potential for drug dependence.

There are many hurdles to get over before anything clinically useful comes of this. First, since NPS is a peptide; therefore, it cannot be given orally. Even a peripheral injection probably would not get into the brain. The rats in the Xu study got NPS via intracerebroventricular (ICV) injection: it was injected into the cerebrospinal fluid; this is not acceptable for routine use by patients. What is needed is a chemical that can be given in pill form, get absorbed, make it through the hepatic portal system without all of it getting enzymatically degraded, pass the blood brain barrier, and get to the correct receptors -- all without killing the patient. Plus, there is no guarantee that the drug would do the same thing in humans that it does it rats.
New Yorker cartoon
Such concerns will not stop pharmaceutical companies from trying. Especially since this research could be used to produce a drug that could enhance the productivity of its own employees. Talk about return on investment!

Seriously, a medication that enhances alertness and decreases anxiety would raise some ethical issues. Some bioethicists, such as those on the President's Council on Bioethics, would suggest that the concept of "human dignity" precludes the use of drugs that enhance performance without actually treating a disease. Even if the drug turns out to have a useful purpose in the treatment of disease -- such as Narcolepsy -- the would argue that it should be used only to treat that disease. That is only one view espoused by conservatives. The opposite view is expressed by the National Center for Policy Analysis and the American Enterprise Institute:

Like cosmetic surgery, the use of these drugs may not be medically necessary for some patients who would benefit. However, they are available only by prescription and require otherwise mentally well people to fit themselves into a diagnostic category in order to gain access. This encourages patients and doctors to expand the universe of the diseased.

Patients with genuine psychiatric problems that affect behavior should certainly have access to medications and third party coverage for their care, says Sally Satel.

Additionally, responsible adults who could benefit from these drugs should have access at their own expense.

They argue that such drugs should be available to anyone who wants them -- and who chooses to pay for them. Their only concern is that insurance companies should not have to pay, if it is not a "genuine" disease that is being treated. They do not address the question: Who gets to decide what constitutes a real disease? My answer, after 14 years of medical practice, is that the people who get to decide should be the doctors and their patients.

Even within the medical profession, this is a topic of some debate. For example, see the Medical Crossfire article about Cosmetic Psychopharmacology.

See what I mean? There is a new discovery everywhere you look, but every answer just brings more questions. And they are not always the questions that you would expect.

(Note: The Rest of the Story/Corpus Callosum has moved. Visit the new site here.)
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