Pheromones
This is a name given to communication via chemical signals transmitted through the air or water.
The study of pheromonal communication among insects is the most advanced, and thousands of examples are known: E.g., sex attractant pheromone in moths will attract mates for a distance of miles. The trail pheromone of ants allow others to follow the trail by the odor alone.
Recent reports even indicate that plants may use pheromones. E.g., a tree may release a pheromone when it is being attacked by a particular insect. Other trees receiving the signal will start to increase their chemical defenses against that type of insect.
Here, we will concentrate on animal pheromones.
There are examples where pheromonal communi- cation may occur between members of different species. Here we will concentrate on communication among members of the same species.
One useful categorization of pheromones is that of Releasor vs. Primer. A Releasor pheromone is one that effects a quick, almost instantaneous reaction in the recipient. A Primer pheromone may take a matter of hours or even days before its effect is seen. Primer pheromones often work through the endocrine system.
There are a number of apparent pheromonal effects that have been demonstrated in wild Mus musculus. Some of these have also been demonstrated in certain inbred strains of Mus domesticus, but sometimes it is hard to find an inbred strain that shows the Effect.
Most of these Mus musculus effects are called ' ffects' because the chemical responsible has not been purified. And the 'Effect' is usually named after the person(s) who first published about it.
The Lee-Boot Effect: In 1955, van der Lee and Boot described a condition of spontaneous pseudopregnancy in female mice grouped together. This inhibition of their estrus cycles involves high prolactin levels, as expected. Something about the all-female housing interferes with their normal 4-5 day estrus cycle. It may be a pheromone produced by other females, or it may be due to the lack of a male pheromone that would normally be present in most living conditions.
Interestingly, the Lee-Boot Effect does not occur in rats. However, it is not restricted to mice, as research has shown that deermouse females (Peromyscus maniculatus) also show disruption of cycles when group-housed without males.
Subsequent research has shown that some of the mice in all-female groups are not pseudopregnant, but are simply anestrus. However, the effect is much the same -- disruption of estrus cycles.
Pseudopregnancy resulting from all-female housing has been found in both outbred and inbred mouse stocks. However, the anestrous response has been found only in outbred stocks.
The Lee-Boot Effect does not seem to depend on stress hormones, as the animals do not have increased titers of corticosterone, and do not lose weight or sleekness.
Olfactory manipulations do indicate that the Effect is dependent on odorous chemicals, but the exact chemical or chemicals responsible have not been identified.
Whitten Effect: If a group of female mice undergoing the Lee-Boot Effect is exposed to a male mouse, a majority of them begin cycling again, in about 3 days. And, since they were exposed to the male on the same day, they cycle together, with most of them coming into estrus on the same night, rather that 1/5 on any given night. This part of the Whitten Effect is called estrus synchrony.
Whitten and others have found that an actual male is not necessary to start the Whitten Effect: just the urine from an intact male will start the females cycling together.
Even the soiled cage shavings where a male has been living will start the Whitten Effect.
If the actual male has been castrated, then he does not stimulate the Whitten Effect (nor does his urine). If a female has been androgenized with injections of testosterone, however, she or her urine can stimulate the Whitten Effect.
Thus, the Whitten Effect seems to be androgen-dependent for production in the sender of some sort of chemical signal. And it seems to be a primer pheromone since it takes about 3 days for the receiver's endocrine system to respond, stop PRL, and begin cycles of FSH & LH.
The urine does not have to pass through the penis or clitoris to be capable of stimulating the Whitten Effect. It was thought that perhaps the androgen-dependent preputial gland would be found responsible for adding the signal to the urine. However, urine taken directly from the bladder of intact males or androgenized females can stimulate the Whitten Effect.
Again, the chemical responsible is not known, but the Effect does seem to be due to a chemical signal transmitted through the air, as even air drawn over males and taken to the females will cause the effect.
Most inbred strains show the Whitten Effect, with the exception of BALB/c
Bruce Effect:
In 1955, Bruce observed that if a recently mated female was removed from the stud male and placed with a stranger male, she would tend to return to estrus in about 4 days, and breed again, this time with the stranger male.
Thus, the first pregnancy must have been blocked by something about the stranger male, as otherwise she would be expected to be pregnant from the stud male, and not cycling.
The Bruce Effecrt was demonstrated with wild, outbred mice. However, some inbred strains also show the effect.
But, using both a stud male and a 'stranger' male from the same inbred strain of mice, the Bruce Effect fails. Apparently the males are so close genetically that they do not smell differently enough for the 'stranger' male to stimulate the Bruce Effect.
The Bruce Effect has also been demonstrated with male urine -- if the urine is first stored with antibiotics and an anitoxidant, to keep it fresh.
Castration of the 'stranger' male eliminates his ability to cause the Bruce Effect.
Thus the pheromone appears to be another androgen-dependent chemical secreted into the urine.
WHY? As usual, this is a harder question. Speculation is that these Effects in mice have evolved to maximize their reproductive capacity. This argument sounds pretty good for the Whitten Effect, in that females start cycling a few days after they receive the male pheromone signal.
The argument is harder to bolster for the Lee-Boot Effect, as it is not easy to see why it would help the species for the females to become pseudopregnant or anestrus, when males are absent.
The usual argument for the Bruce Effect is that it maximizes the 'stranger' males reproductive advantage. If a 'stranger' males takes over, then he does not have to wait out a pregnancy before siring his own pups.
Do humans respond to pheromones?
The answer is almost certainly yes. We do have to be careful about generalization, without experiment. But Martha McClintock, with groups of dorm-living young women, has shown that the women tend to synchronize their menstrual cycles. This seems similar to the synchrony of estrus seen with the Whitten effect, although the controls were not as tight.
As humans we usually down-grade our sense of smell. But actually we are fairly acute with smells. This appears to be a wide-open field. Some evidence so far is that we can, e.g., determine the sex of a stranger from breath odors.
Though we are restricting discussion in the main to within species communication, it is obvious that our dogs can sense our individual smells and, perhaps, our emotional state.
Other Examples:
The Vandenbergh Effect - If young female mice are kept isolated from males, their puberty is delayed by several days. If they are exposed to males, or to male urine, then they reach puberty at the usual time.
In a sense, the Vandenberg Effect is a laboratory artifact, in that females would not normally be isolated from male odors. So their usual time of puberty has been computed from the usual, both-sex situation.
The Ropartz Effect:
Male mice and rats apparently produce an androgen-dependent pheromone from the preputial gland of their penis. This is a Releasor pheromone, and stimulates intermale aggression. If a male is castrated, he is usually not attacked. But if a female is covered with penile secretions, she will be attacked even if she is an otherwise gonadally intact female. Urine drawn directly from the bladder does not stimulate the Ropartz Effect. Apparently the urine must pick up secretions from the preputial gland to become effective in stimulating aggression from other males.
Human possiblities: Vaginal secretions Penile and scrotal odors Underarm odors Breath
Most of us minimize body odors. This may be a result of our civilized' state. After all, bathing is a recent development.
12/4/96:
Pineal Gland = Epiphysis cerebri
The pineal gland was first described by Galen, during the 2d Century. He thought it was a supportive element for the brain.
Another interesting speculation for pineal function was given us by Descartes, in 1646. He thought that it was the site where the soul exerted its function.
In humans, the pineal is a small, single organ on top of the mid-brain, near the colliculi, and hidden under the cerebral hemispheres. In animals with less overwhelming cerebral hemispheres, the pineal is near the top of the brain, just under the skull.
Gradually some functions for the pineal have been discovered. There are perhaps three main threads of discovery and research: 1. Pineal effects on the timing of puberty 2. Pineal effects on skin color changes (darkening) 3. Pineal effects on daily cyclicity
There have been sporadic cases of early, or delayed puberty, reported since the middle ages. One conclusion gained from these cases is that many involved a tumor in the vicinity of the pineal. It appears that if a tumor destroys the pineal, then early puberty is likely -- maybe at 5 or 6 years old. On the other hand, if the tumor is of the pineal itself, puberty may be delayed -- perhaps indefinitely. *It appears that normally the pineal is delaying puberty until some set-point for the species.
About 1917, McCord and Allen observed that extracts from the pineal caused blanching of the skin, in amphibians. In 1958, Lerner and co-workers purified the active agent for this blanching effects, and named it melatonin.
Melatonin seems to have hormone-like actions, and may be a neurotransmitter or modulator, as well. The initial substrate for the synthesis of melatonin is the amino acid tryptophan, a component of our diet.
There have been many studies implicating a role for the pineal in cyclicity. Almost every aspect of our physiology shows some evidence of cyclicity of function, certainly including most endocrine gland functions.
A major cycle for life-forms on this, our third rock from the sun, is a daily, 24-hour cycle. This is evidently due to the strong contrast between day and night, as the earth rotates.
When we discern a cycle of 24 hours, or nearly so, we usually refer to it as circadian (about one day). Most of us have circadian sleep-wake cycle, a circadian mood cycle, a circadian temperature cycle, a circadian adrenal hormone cycle, etc.
Some other cycles: crepuscular = twice a day - e.g., tides, twilight monthly or lunar - about 28-30 days (menstruation) circumannular - once per year (breeding season for many animals, including elk, elephant seals, etc.)
It appears that the pineal plays some role in most if not all these cycles.
If people are placed in a deep cave, and insulated from any clues about daylight or the time of day, most go onto a 25-26 hour cycle of activity. This is called a free-running cycle. This kind of experiment must carefully eliminate clues about time-of-day, however. If the experimenters always phone at about breakfast time to see how things are going, the people in the cave might continue showing 24-hour cycles.
The conclusions from this and similar experiments is that we and other organisms have some sort of clock or time keeper in our bodies -- probably in our brain. This is a very imperfect clock, but yet an important one. The clock might consist of a set of interlocking mechanisms that somehow time the speed of a biochemical process. This is the endogenous clock.
Using our endogenous clock, we can usually make a pretty good estimate of the time of day. We somehow feel the passage of hours.
However, the endogenous clock would soon be so inaccurate that it would be almost useless, if it were not re-set often. Apparently, we re-set it every day, using sunlight. If we still lived in the open, we would probably get it re-set quite accurately, at sunrise. The use of a signal to give us the correct time is referred to as a zeitgeber (=time giver, in German).
So, in the course of things, the onset of daylight, acting as a zeitgeber, would reset our internal clock for the day.
Some indicators of zeitgeber/circadian function: 1. 8 o-clock classes -- it appears that most students have enormously important things to do all night, and thus set their desired awakening time well past 8. Then, when they have to take an 8 o'clock class, they are a grouchy bunch.
2. Night shift -- Many businesses and government functions require 24-hour work (King Soopers; factories; police; White House, etc). To accomplish this, people are assigned to work night shift. Often, people rotate shifts, working days for a shile, then swing-shift, then night (graveyard) shift. Most find making the transition from one shift to another somehat difficult. They do not feel well, rested, etc. even if sleeping just as much.
3. Jet Lag -- With the advent of high speed air transport, we can fly across a number of time zones in a few hours. The upshot is, we find ourselves with our (existing) circadian rhythm, but in a country where the circadian activity is offset by several hours. We try to match the local conditions; our bodies rebel; we cite jet-lag'.
All of these cycle difficulties seem to consist of a mismatch between where we are individually on our daily circadian rhythm, and the demands of class, job, shopping, sight-seeing, etc. Our bodies are in one phase (even the sleeping phase), and we are asking them to perform for a different phase.
Manipulations of the pineal, and of melatonin, indicate that this system is somehow a part of the endogenous clock / zeitgeber mechanism.
Sudies of the pineal in amphibians and lizards showed that the pineal in these species can transduce light energy directly, just as our eyes do. That is, the energy in the impinging photons is transduced by cells in the pineal (or retina) to stimulate neural impulses. The brain then interprets these neural impulses as light outside.'
Some species even have a pit or opening just over the pineal, so that light rays can enter more easily. The pineal has thus been referred to as a third eye.'
What about that wonderous animal model, the rat? Well, it turns out that the pineal of the rat can also transduce light directly. The rat does not have a pit or opening over its pineal. But, its pineal is on top of the brain, under a thin, translucent skull. Apparently some light energy makes its way through hair, skull, and into the pineal, and is sensed directly.
What about ye olde human? Can our pineals transduce light directly? Well, maybe yes, maybe no. If we can, it must be a minor amount only. Experiments show that most of the information about ambient light is obtained by our eyes (our lateral eyes), and then this info is transmitted to the pineal.
But: There did not seem to be any nerve tracts between our lateral eyes and our pineal. Yet, our pineal was well aware of light conditions. How could this be?
Anatomist Adrian Kappers figured out how. Nerve collaterals from the superior colliculi, a relay station in the visual system, go from there, down through the mid-brain and hind-brain, and synapse in the first cervical ganglion in the neck. Axons from there then go back up through the hind- and mid-brain, and innervate the pineal. Why this complexity? I'll tell you: I don't know. But it does keep our pineal in contact with light conditions in the outside world. (Named Kapper's loop)
So if our eyes sense light, the pineal is informed. What then? The absence or presence of light changes the speed of biosynthesis within the pineal:
(tryp.hydrolase)
tryptophan ---------------------------> 5-hydroxytryptophan (5HT)
(aromatic amino acid decarboxylase)
5HT -----------------------------------> Serotonin
(N-acetyltransferase = NAT)
Serotonin -----------------------------> n-acetylserotonin
(Hydroxy-Indole-O-Methyl-Transferase = HIOMT)
n-acetylserotonin -------------------> melatonin
Melatonin goes high at night, low in the day. Apparently info about presence/absence of light influences the production of the conversion enzymes above.
Which is "rate-limiting"? -Probably the NAT, though some authorities think that HIOMT is the controlling, or rate-limiting enzyme.
In any case, the production of serotonin and melatonin is up- or down-regulated, depending on the presence of light. Then, this information is used by the brain as part of its endogenous clock from which other body cycles are timed.
Discussions: How does the pineal influence puberty? Well, it delays puberty, until the right' time. How does it do this? Hard to say. There must be some developmental processes that tell the pineal when to stop its inhibition of sex function.
What can we do about jet lag? -Not much, maybe. It's easier flying west, as then our 26 hour cycle doesn't have to be reset to far, to get on local time. It seems to help to go out in the sun when you get to your destination (don't go to bed) -Let your pineal in on the action.
What about seasonal affective disorder? Many people feel somewhat depressed in the winter. It may be severe, for some, with even thoughts of suicide. A promising therapy is to use very bright lights. Put the patient under a battery of very bright lights at the same time each day. This seems to help. It is thought that the person was getting too little info about sunlight, her/his pineal was not keeping good track of time, cycles were mixed up, and the person felt bad. Thus, take care to get info about light to the pineal.
12/6/96: Mellisa Puleo Report
Friday, 12/6 Last Lecture - Outline on Web
Monday, 12/9 - Class evaluation + Review
Wed., 12/11 - EXAM 4 + All term papers due ___________________
Atrial Natriuretic Peptide Hormone = AVP Hormone
So-called "essential hypertension" (High blood pressure) is an odd term still in use by physicians. Basically it means that blood pressure is too high, but we can't see why.
As we know, epinephrine and nor-epi tend to raise blood pressure. Usually, however, persons do not have constant, excessive E or NE.
Another major system for blood pressure control includes the renin- angiotensin system: If blood volume or pressure gets too low, stretch receptors in the kidney sense the low pressure, and cause release of stores of kidney renin. Renin in the blood comes into contact with renin substrate from the liver, and is converted into angiotensin I. Angiotensin I cause NE release from the adrenal medulla, is istself converted by converting enzyme to Angiotensin II. Angiotensin II is a potent vasoconstrictor, and helps to restore blood pressure to normal by decreasing artiole diameter.
It seems clear that malfunctions in the renin-angiotensin system could be a cause of high blood pressure. A direct medical intervention is to prescribe ACE inhibitors, i.e., Angio Tensin Converting Enzyme Inhibitor to decrease the formation of Angiotensin II.
But sometimes this and other interventions have little effect. Blood pressure remains high ("Essential Hypertension")
A 1995 article in Science (John, et al, 3 Feb 95, p.679) may help us understand why.
A 28-amino acid peptide called Atrial Naturetic Peptide (ANP) is produced in the heart muscle in response to atrial distention. The apparent function of ANP is to promote salt loss (natriuresis) in the kidney, and to lower blood pressure by moving fluid from blood to the extracellular space.
After making mutant mice that had different AVP genes, John and colleagues tested them on diets differing in salt.
Mutant mice with no expression of AVP, on an intermediate salt diet had enlarged hearts, but otherwise appeared normal and were fertile. It appeared that their hearts enlarged due to constant pressure. Later tests of their blood pressure showed that it was too high.
But, when they were fed low salt diets, their BP was OK
As dietary salt is increased, BP increases also.
Conclusion: There are known genetic variants in the ANP gene in humans. These variants must result in differing amounts of Atrial Natriuretic Hormone, which in turn, interacts with dietary salt.
For people with a partially defective ANP gene, ANP hormone is inadequate and even a normal amount of dietary salt may be too much, and lead to high blood pressure. Treatment: cut out nearly all salt.
For people with a fully adequate gene for ANP hormone, salt seems not to be harmful, or not seriously harmful.
We need about 1 mg of salt a day. The American average intake of salt is 20 mg ! Try looking at the salt content on some of your food. Try looking at V-8 juice, for instance. ___________
Personality: Type A vs Type B people
For sometime now, a sub-group of hard-working, hard-striving people known as Type A have been known to be prone to atherosclerosis and heart attacks, compared to an easier going group, called Type B.
Type A persons are known to be more responsive to stress (impossible jig-say puzzle; TV ping-pong) with sometimes more E and sometimes more NE.
Williams et al (Science 29 Oct 82, p. 483) evaluated a broad range of cardiovascular and endocrine responses, with Type A and Type B subjects doing mental arithmetic and reaction time tasks.
Type A subjects exhibited hyperresponsivity on certain measures, on certain tasks. Type A subjects tended to have high mean E and NE, cortisol and testosterone, after challenge. But on some measures after some tasks, Type A and Type B did not differ.
As another step, the investigators divided Type A into those with a positive family history for cardiovascular disease (family history positive)
This seemed to magnify the responses: If a Type A from a Cardiovascular-prone family, there were task-related elevations in cortisol and a trend for increase in diastolic BP
The authors conclude that the endocrine hyper-reactivity shown by Type A people under these relatively mild stressors (mental arithmetic or reaction time tests) is likely, over time to cause arterial damage, and scarring. This scarring would reduce the elasticity of the arteries, and lead to high blood pressure and cardiac problems.
They end on a note of optimism about their work leading to useful pharmacologic and behavioral interventions, but they do not outline what these might be.