Deep South: A Social Anthropolical Study of Caste and Class: A Brief Summary

A group of social anthropologists directed by Allison Davis of the University of Chicago went to Old City and Old County Mississippi during the Great Depression to study the amount of racial prejudice existent in the Deep South of the United States. Old County and Old City were selected because the economy is based on the old cotton plantation system. Old City contains a population of roughly 50% black, 50% white, Old County contains a population of 80% black, 20% white. Apparently, two types of social order exists within the Deep South. A class system based on sociological factors, status or income, and a caste system based primarily on race.

"A caste may be defined as a endogamous and hereditary sub-division of a ethnic unit occupying a position of superior or inferior rank or social esteem in comparison with other sub-divisions."* This clearly does not denote a class system which contains upward or downward social mobility. A caste system allows for no such mobility because members of different castes cannot intermarry. Therefore, competition exists between castes for control of power. One caste will assume a superordinate role, another a subordinate role. In our present discussion the white race is disproportionately dominant and "all social institutions in the South including family, school, association, clique, church, and so on, are formed to fit the dominant caste social situation."**

In this paper the situation will be viewed as the social order existed during the study and as a afterthought speculate about what kind of conditions might be evident to change the social pattern.

The White Ideology: Keeping the Black Man in his Place.

It is a prominent belief along whites that blacks are a illiterate group, incapable of learning, child-like in their behavior, unmanageable people. This belief is demonstrated through caste sanctions and behavior. Blacks are expected to pay deference to whites. If a black and white person meet on the street, the black person is expected to give way. When addressing a white man, a black man must use the adjective "Sir," to denote respect, while a white man must never show respect to the black man. Violations of this caste sanction is considered "rebellion." After a series of minor infractions of the caste regulations, "whipping parties," or in some extreme cases "public hangings" are initiated to demonstrate to other would be offenders the "correctness" of the white cast ideology.

Endogamy and the Caste Sexual Taboos

Sexual taboos exist in the caste system to support the law of endogamous marriage but they vary depending upon the sex and color of the person involved. Due to the notion of white female purity, any acts of sexual intercourse between white females and black males violates the strongest sexual taboo and warrants a terrible punishment. If discovered, white females will either be publicly whipped, hanged, or "put on a train.". Sexual intercourse between white men and black women is permitted, if the relationship is conducted covertly. Most sexual encounters of this sort are for profit,  the black female is paid a wage. But in some cases white men actually have black mistresses and families they support for life.

The implications of sexual intermingled  castes is clear. If the white man could incorporate his children into the white caste group the caste distinction based upon race would disappear. But caste endogamy extends also to children. Children born miscegenation are always placed into the mothers caste group. The effects of this law are discussed more thoroughly in the section on black social class groups.

The White Social Class System

The white class system is rooted in ideological differences. The white upper-class group pay deference to "old wealth," or the amount of time money has existed in the family. Middle-class groups base their ideology in morals, middle-class people place a high value on wealth, and emphasize the "need to improve." Poor whites distinguish themselves on the basis of "consistency of a job," for a great many lower-class families are either unemployed or are working on work relief programs. Class differences are rooted in antagonisms. A sociological death and re-birth is needed to leave one social class and enter another. This involves severing old ties, abandoning old modes of behavior, and incorporating new ones.

The base of class, then, is to distinguish who does and who does not belong. A person trying to enter the middle-class may be excluded due to lack of demonstrated middle-class qualities. A person wishing to climb from middle-class to upper-class may be excluded for lack of "old wealth."

The Effect of Miscegenation on the Black Class System

The black caste base class antagonisms primarily upon three factors; income, occupation, and race. Because black elites have no clearly defined occupation or income guidelines, to identify with, blacks often turn to race as a qualification for higher status. The degree of a persons skin color as a value is the result of two basic problems. Blacks are discriminated against in the labor market, and for psychological reasons. "The effort of black upper and middle-class individuals to maintain or to increase their class status appears to be equated psychologically with a attempt to acquire the traits of the white caste. The distinguishing traits of the white caste are skin color and hair type, so it is to be expected that whiteness of skin and straightness of hair will have value as a class sanction in the black group."*** Black upper-class members designate commonness to lower-class blacks partly on the possession or lack of these white characteristics. Also, a notion exists in black groups that blacks with a more  pronounced negroid tint are regarded as unclean.  Black nurses with more pronounced white attributes were found to be washing their hands quite frequently and expressing disgust when handling darker black patients. A white doctor exclaimed, "Why they abhor those people worse than I do!"

The Changing Economy

Old County's economy depends on cotton. Cotton cultivation requires a long growing season, (210+ days) and a large group of skilled and unskilled workers.

When a tenant rents from a landlord in Old County he or she either pays a fixed cash or lint payment. This is largely dependent upon two factors,  The number of people in the tenants "squad," or the number of people in the tenants family, or whether a tenant has his or her own implements or farm stock. This is fundamentally important when viewed in context with uncontrollable changes in Old County's economy.  During 1934-35, a large boll weevil infestation destroyed a majority of the crop. That year the harvest was so low as to force a large number of tenants into the newly developed industrial firms in Old City. The entire economy suffered from deflated cotton prices as a result of the Great Depression.  The Federal  Government began the cotton reduction program.***** This caused a labor shortage. Landlords soon found themselves competing for labor. The tactics landlords used to keep labor on the farm and still maintain profit included economic or physical intimidation, or violence upon the tenants to keep them in a perpetual state of peonage.

Literate tenants cannot challenge the plantation system for several reasons. (1) Blacks are excluded from holding political office and in most cases are excluded from the polls. (2) Blacks are excluded from buying land. (3) Blacks cannot sue landlords for theft. (4) Black testimony is considered invalid in criminal cases. (5) The police ignore black civil or criminal complaints. Whites exclude black participation in the most fundamental and basic institutions in the United States. Therefore, all law, legislation, political platform, and judicial decisions favor the white caste.

Conclusion: Death of the Plantation System

The plantation system cannot endure.  Old County is no longer isolated from the world of technology and industrialization.  When the system of agriculture changes planting more acres of land by share croppers to tractors and fertilizer, a great number of farm workers will no longer be necessary.  Migration from Old County into Old Town will change demographics and culture as well.  The standard of living will improve.  This will prompt educational opportunities and stimulate class awareness. The result is certain, the entire cultural restructure of the Deep South.


Footnotes

*Please refer to page 3 for more details.
**Please refer to Chapter 1.
***Page 235
****The Federal Government placed a limit
on the number of acres a planter could grow in cotton to stabilize cotton prices. Those acres not grown in cotton were compensated for in subsidiary payments.

William S. Burroughs: Drug Dependency Versus Drug Addiction

William S. Burroughs in Junkie wrote the best definition of drug dependency versus drug addiction I have ever seen.  Burroughs points out that opium derivatives cause physical addiction.  Marijuana causes psychological dependency but no addiction because if you run out of the pot and cannot secure more the body does not go through physical opium-based withdrawal symptoms.*  William S. Burroughs also noted that even though cocaine increases dopamine levels in the brain, and despite the fact that pigeons will peck a lever for a dopamine reinforcement to the exclusion of all else until they drop dead, these facts have no relevance, if the stimulus is withdrawn and the behavior ceases without the physical distress associated with opium withdrawal syndromes.  Thus by strict definition behavior associated with cocaine use is driven by dependency, not addiction.

I have had discussions with potheads who insist they are addicted to marijuana.  But potheads function in a fog of altered perceptual awareness.  True some potheads will spend days running around town looking for an elusive lid, waiting around in cars for hours, while friends look for contacts.  Most times they come up empty-handed.  But this behavior to secure more dope is not driven by physical distress that requires "the cure" at Lexington's Narcotic Farm.

Marijuana as a gateway drug has never been established.**  However, marijuana dependency has some adverse consequences.  I knew a woman who would steal items from her family members and run off to a pawn shop.  While stoned, she would craft a masterful plan to steal without being caught.  This woman had a very reduced mental capacity, an intelligence quotient of 70, but when she was stoned she thought she was an exalted princess of a higher dimension.  Of course, when challenged, she resorted to habitual lies and denials a narcissistic psychopath would envy.  Her denials were so transparent a three-year-old child could have seen through them, and when confronted with absolute facts as to her culpability, she would explode into childish temper tantrums intended to intimidate you into backing down.  The old biker gang momma bitch act.  I always thought she was nothing more than a second rate con-artist.  If she had been a little smarter, she would have run a Ponzi scheme like Bernard Madoff, living like a queen in a mansion, with high priced cars, a yacht, dining at the finest restaurants, swindling other people like a bloated parasite until she was arrested.  Later on, she would act all innocent and friendly like nothing happened.  Anti-social personalities have a lack of impulse control, they take things without permission based upon immediate need, rush off to the pawnshop, pocket the money, then congratulate themselves on a job well done.  Anti-social personalities have no morality, no conscious, they are indifferent to the damage they do to other people.  People exist to be used as pawns.  Why does she do these things?  She needs to get stoned!  Marijuana dependency mixed with anti-social traits is as damaging as a heroin addict committing burglary to support a habit.

Update

*Police officers, prosecutors, and judges all make the same mistake when classifying marijuana as a "narcotic".  Opium based derivatives such as heroin are narcotics.  Marijuana is a hallucinogen, not a narcotic.  Hunter S. Thompson in Fear and Loathing in Las Vegas, correctly points out that a "roach is not called a roach because it resembles a cockroach".  This idiotic idea was presented to a gullible law enforcement audience by some quack "drug expert" psychiatrist during a "police anti-drug convention".  In the same vein a prosecuting attorney who calls marijuana a "addicting narcotic" is doing nothing more than demonstrating his or her ignorance of the facts at hand.  Unfortunately, some judges have been brainwashed into believing that marijuana is a "dangerous drug" with no "medicinal value," and that use of marijuana constitutes a "clear and present danger" to society.  An argument straight out of 1965.  Of course, the cannabis prohibition law was formulated by ignorant legislators who were probably indoctrinated by the clergy, or by anti-drug propaganda films written by Nancy Reagan and shown in high schools, or by watching cheap camp movies like Reefer Madness.  Marinol (dronabinol) is a synthetic form of delta-9 tetrahydrocannabinol (THC), the psychoactive component of cannabis.  THC fits into cannabinoid receptor sites in the brain.  Marinol is prescribed to patients as an appetite stimulant, antiemetic, and sleep apnea reliever.  Marijuana has medical efficacy for cancer and AIDS patients.

**Whoever invented the notion that marijuana is a dangerous gateway "narcotic" needs to have his or her brains tested.  52% of Americans over 18 have smoked marijuana at some point in their lives.  According to the pot gateway theory logic, there should be 171.6 million deranged "addicted dope fiends" running amok terrorizing suburban neighborhoods.  Science calls the weak "correlation" between pot smokers and heroin users a spurious relationship.  The appearance of a comet did not cause a plague, even if a plague occurred shortly after the appearance of the comet.  People who blamed the comet for the plague reached a spurious conclusion based on superstition, not on scientific facts.  Much like the advocates of the theory cannabis is a "gateway" to more destructive drug abuse.

I am not an advocate of cannabis recreational use.  Actually, I think potheads are some of the stupidest people I have ever met.

Dr. Rachel McKinnon: Women's Cycling Fraud

Women's cycling has gone off the rails.  A Transgender "woman" Dr. Rachel McKinnon, won the women's 35-39 UCI masters track sprint world championship.  Dr. McKinnon edged out two biological females, Carolien van Herrikuyzen of the Netherlands, and Jennifer Wagner of the United States.

Social media went crazy.  Comments ranged from gender fluidity to political correctness, to the death of women's sport.  I questioned the sanity of the UCI who allowed a biological male to compete with females, apparently with the acquiescence of USA Cycling, when cycling boasted a mantra of "fair play."

When Chris Froome tested positive for salbutamol no one cared.  When Floyd Landis had a 4.1/1 testosterone/ epitestosterone ratio the UCI raced to fire up the carbon isotope ratio test.  But, now the newly crowned Transgender women's track sprint master, Dr. Rachel McKinnon, is complaining about a dangerously low endogenous testosterone level, "below a woman" that is impeding her performance. Dr. McKinnon is demanding an exemption from taking testosterone suppression drugs as a human right.  Apparently, her fast twitch fibers were inhibited somehow and she wants to build a little extra muscle mass from the testosterone produced by the gonadal Leydig cells women do not possess.  Dr. McKinnon wants total domination of female sport thanks to unnatural biological advantages Transgender athletes have acquired as men.  This domination must be embraced by all female cyclists and cycling fanatics.  Of course, the fact that biological women will suffer a penalty from this unnatural arrangement is of no concern to Dr. McKinnon.  Perhaps, all future female cycling races will evolve into exclusive Transgender "women," athletic events.

Poor women's cycling.  Hanging by a thread.  In local criteriums, class 1, 2, and 3 women all raced together in a single race.  The men had multiple teams in multiple races. The women's Tour de France has generated marginal interest.  Now we have a man winning a woman's masters sprint world championship jersey.  I am so sickened by this folly I could almost puke.  How do we endear women to our sport if men are allowed to win every women's race?  Who wants to watch a group of men masquerading as women in criterium races?

Women of the cycling world hear my plea: if a man enters your race, strike!  Lay down your bicycles and leave the velodrome.  Bernard Hinault would not have tolerated this bullshit for one instant!  Women!  You are being cheated.  Refuse to ride!  If the UCI doesn't like it tell them to pound sand!

The UCI should know better than to inflame women's passions.  This is a mistake.  The women cyclists on social media are angry!  There is no reason to train for an important race if a man is going to participate and win.  Women are not going to put up with this nonsense for long.  Then, beware!

Carolien Herrikuyzen is the true world champion.  Dr. McKinnon is a fraud, she should have never been allowed to participate.  The master races are being trivialized, cycling will be mocked and ridiculed.  Regain sanity, gender fluidity has no place in cycling!

UPDATE

Dr. Jennifer Wagner has tweeted that the UCI was wrong to allow a biological male to compete against women. Dr. McKinnon called Dr. Wagner a "transphobic bigot," a standard cliche and label Transgenders use when anyone is critical of their viewpoints. Carolien Herrikuyzen stated that the race was conducted under UCI rules and if anyone disagreed with the rules they need not race. Therefore, the race was "fair." Dr. Wagner is correct, the race was not fair, the UCI needs to change the rules, and women cyclists need to boycott races until the UCI makes the necessary modifications in the rules. Women's races are to include biological females only. Allowing men to race in women's races is cheating and far worse than doping.

2018 Tour de France Bedlam

Geraint Thomas and Team SKY wins another Tour de France!  Break out the champagne!  Whew!  The international cycling fanatics were outraged.  (An aside to David Brailsford, cycling fanatics attend the Tour de France from all over the world, you dolt! )  Along the course international cycling fanatics pelted team SKY cars with eggs, people attempted to leap over barriers to knock team SKY riders off their bicycles!  People spit in the faces of team SKY riders! It has been alleged that people threw urine bombs at team SKY!  Totally dangerous bedlam.

Chris Froome, four time winner of the Tour de France, had to settle for a podium third place.  Chris Froome and team SKY were lucky to get invited to race the Tour de France.  ASO did not want Chris Froome or SKY, after the UCI mysteriously dropped the salbutamol adverse analytical finding Chris Froome was charged with.  Chris Froome tested positive after Stage 18 of the 2017 Tour of Spain for salbutamol, a beta-2 agonist bronchial dilator.  The WADA threshold for salbutamol is 1,000 nanograms/milliliter. Chris Froome tested 2,000 nanograms/ milliliter.  Since salbutamol is not an endogenous substance produced by the body, the only source is an external application, like an inhaler.

Never, to my memory, has an adverse analytical finding been so thoroughly debated among the worthies at the UCI and WADA.  Dick Pound the former president of WADA, amazed me when he stated that Chris Froome may have innocently snorted too much salbutamol!  What turnabout is this?  In every other case on record riders were banned for the mere presence of a prohibited substance, regardless of circumstances.

I am simply astounded at the myriad of excuses WADA and the UCI are dishing out to explain away this innocent snorting of salbutamol.  Usually, excuses to explain away positive tests fall under the purview of the riders.  Unique physiology, specific gravity, they actually proposed doing a longitudinal study to determine if Chris Froome could keep his values constant.  Constantly above threshold?  What manner of insanity is this?  WADA standards are so variable! WADA standards should be discarded as useless rubbish!  The goal posts change either in favor of, or against, athletes depending upon the person being considered.  If you are going to use a set of standards as a bludgeon, at least be consistent, or exit the field.

Unbelievable.  Dick Pound says WADA only try cases, or spend money on cases,  prosecutors expect to win.  Really?  Floyd Landis was prosecuted with zeal based upon a single metabolite above threshold, WADA spent millions to support weak evidence, no concern for unique physiology then!  At the point of being sarcastic, Mr. Pound, your long drawn out charade proved nothing except WADA laboratory incompetence.  However,  Chris Froome is an open and shut case.  But WADA declines to appeal the UCI decision to drop the case, even though Mr. Froome would likely be banned with overwhelming evidence.  Mr. Froome was double the threshold limit on both samples.  Mr. Froome has no credible excuse to explain away these test results.  Any credible prosecutor would rip Mr. Froome to shreds.

I remember when Dick Pound wanted to throw the entire peloton in jail, suspecting everyone of doping.  Now he is acting as a apologist for the dopers, accepting every half baked spin job in existence.  Dick Pound has gone mad.  Mr Pound should refrain from adding future senile commentary until he consults with his doctor.

In 2013, I warned people about SKY and David Brailsford .  Nobody listened.  Now their biggest star Chris Froome has tested positive for salbutamol.   Nobody cares.  The indifference by the regulatory agencies almost started a riot at the Tour de France. People may get hurt next time.  David Brailsford did not improve relations when he called the people of France xenophobic hillbillies.  Next year, David Brailsford may be the spark that blows up the whole Tour.

Finger Frostbite Amputation Photographs

I lived on the street for twenty-five years and never had a serious health issue, even though I slept outdoors under a tarp through every imaginable weather.  But, I got caught in a canyon downslope wind storm that resembled wind storms recorded in the death zone on K2.*  My hands turned blue, but I thought if I warmed them up, they would recover.  Next morning I had blisters, I thought I had second-degree frostbite.  Instead of recovering from a moderate frostbite, my hands died from blood clots.  Apparently, the body will reduce the blood flow to the extremities in order to protect the vital organs in the core during life-threatening wind chill events.  I should have gone straight to the hospital.  Maybe Dr. Amalia Cochran could have saved my digits.  After all, Dr. Amalia Cochran pioneered the use of blood thinners in severe frostbite cases to save fingers and toes with remarkable success rates.  I was blessed with one of the best frostbite experts in the country as my doctor, and all she could do was cut off all of my fingers.

The dynamic duo.

Amalia Cochran MD 

Katherine Elizabeth Smiley MD

If you need an excellent surgeon, (or two) look no further than this blog post.  Fortunately for me, both of these accomplished ladies were working together at the University of Utah hospital intensive care burn unit.

This is no longer the case, however.  Dr. Cochran is now off to Bozeman, Montana!   Dr. Smiley has a private practice as an allopathic trauma surgeon in Bloomington, Indiana.

Ha!  Look at your flowery hat, Amalia!  But because I am a sixties counterculture guy, you can wear tye-dye day glow in surgery for all I care!  I don't place a priority on being a misogynist when facing certain death.  I can't understand gifted feminists and their persecution complexes.

I don't think these ladies are iron maidens who have to maintain a facade of inflexible super-rationality because some idiot invented a notion that women go mad every twenty-eight days.  Therefore, women can't be trusted with the nuclear football.  But we don't live in the world of Betty Friedan and the Feminine Mystique, or in the world of Father Knows Best anymore.  1950's retro thinking is so cliche.  I was so thankful for these women surgeons, and for my free clinic doctor Tanya Williams MD who got me admitted into the hospital.  Superior intelligence, skills, and empathy.  Who cares what sex they are, or what they wear at work.

I needed great surgeons, not a militant Gloria Steinem manning the barricades.  I was lucky to receive such awesome care at the University of Utah burn center.  Amalia Cochran is a universally recognized expert in frostbite, with a slew of medical journal publications. And Dr. Amalia Cochran has published a book on introductory surgery.  Dr. Kate Smiley graduated from medical school with honors! and she has a very successful practice that is based upon a diversity of medical experiences!

I may be thick, but I know good health care professionals when I see them.


* When the Wasatch mountains experience conditions that generate easterly winds, gravity straight line winds may occur with speeds exceeding 100mph.  These straight line winds historically have caused considerable personal and property damage.

Post Traumatic Stress Disorder: Random Thoughts

Living a life of chronic pain is something I never imagined.  One becomes hyper-aware of environmental inputs to the point of morbid intensity.  The stress is unendurable.  The realization that this condition will never improve inspires fatalistic thoughts and deranged conjectures.   For example, when I die will I awake in some religious purgatory with this infernal misery as punishment.  I was indoctrinated as a child and have lasting scars.

I understand the reasoning of our wounded warriors who return from a valorous fight maimed for life and who have been changed forever.  I empathize with these brave patriots who after experiencing unimaginable trauma, can no longer maintain their former personalities.  Brave soldiers who have become so physically and mentally dysfunctional they no longer fit properly in the context of our society, or in the context of their own families.  This may explain the huge number of homeless veterans who sleep on American streets daily, forsaken and cast aside by the most giving of all nations.  This abandonment of our veterans is a national disgrace.

I knew homeless veterans personally, not as a detached social worker, but as a homeless bum.  Our group did not drink alcohol or use drugs.  We did not fly signs, pester people for handouts, receive food stamps, or receive cash assistance.  Some of my old friends were pensioners who actually contributed years of work to society.  Yet these gentlemen preferred to dine at soup kitchens and live under tarps under trees through every type of imaginable weather, exposed, harassed, fearful, hungry, dirty, and insane.  Why am I telling you this?  Stereotypes, as conceived from afar by ivory tower talking heads, don't apply to everyone who lives on the street.  They are not all lazy people either.  Some take day jobs desperately wanting to escape their plight.  The rent-a-bum industry makes a fortune off of down and out hard luck people.  Some even gain long term employment through temporary services, but most aimlessly drift from job to job, from town to town, accomplishing nothing.

When I was in the University of Utah burn unit (costing the taxpayers God knows how many thousands of dollars) I asked to be released before the doctor even considered it.  I had nowhere to go except for the shelter medical bed.  When I was being discharged from the hospital I had a chance encounter with a homeless liaison social worker.  She shamelessly shouted at me in the hallway from afar, that I could not continue to mooch off the hospital forever.  I was never so offended in my life.  Did she think that I was using the hospital as a sort of vacation retreat and that the hospital staff had to force me from my bed?  If that cunt had expended five minutes of her time familiarizing herself with "my case" she would have never been so rude and insulting.  Social workers have no business among poor people.  Her behavior typifies the prevailing response you can expect from these social justice warriors who claim to have a monopoly on compassion for the sick and injured in this world.  Snide condescending jeers and sneers.  Mangled veterans suffering from post-traumatic stress disorder probably run the same gauntlet when dealing with professional psychiatrists who consult their diagnostic manuals, and like pontificating gods, espouse factitious disorder or malingering.  Meanwhile, people are left to dangle in the wind to deal with a constellation of mental horrors alone and unaided.  Have no doubt, people derive a great deal of sadistic satisfaction from the misery of other people.  But when the laughter subsides, when fatigue of supporting a chronically debilitated person takes over, people do get bored with the plight of disability and frustrated being around people who cannot control their moods and who involuntarily express discomfort, sometimes irrationally.  I have been guilty of irrationality on many occasions.  This has lowered my self-esteem, damaged my interpersonal relationships with family members, and has filled me with remorse.

There is a distinction, however.  I am entirely responsible for my folly.  I had a choice to behave like a fool.  I was not serving my country as a loyal patriot.  I was not ordered into battle.  I deserve my misery.  I understand that some injuries change people forever.  I understand why so many people consider suicide.  The country can do better to help people who are not at fault and who served with distinction.

I used to spend days in the library researching depression.  I thought I had rewired my neurons, a firm believer in plasticity.  That was a voluntary effort, but this chronic pain is beyond conscious control due to the sheer number of damaged pain receptors in my bones and skin.  Extinction is impossible.  Recently, I have been fighting suicidal ideation.  There is a concept in psychology known as learned helplessness.  A rat is placed on an electric grid and shocked.  No matter what kind of behavior the rat engages in, it cannot escape the shock.  There is no avoidance response to learn.  So the rat cowers in the corner doing nothing.  The rat has an instinct to survive, but the rat has no language skills to communicate the trauma the rat is experiencing.  Human beings have the ability to conceptualize uncontrollable suffering, even rate pain intensity on a theoretical scale, but there are limited behavioral strategies available to reduce the perceived stimulus.  There are certain pharmaceutical interdiction available, opioid or anticonvulsant remedies, that can be ingested to reduce chronic pain.  Drugs could be considered a behavioral strategy, which produces fleeting medical efficacy.  The effect of pharmaceutical interventions is temporary and implies negative secondary psychoactive side-effects such as increased suicidal ideation.  Pharmaceutical behavior designed to reduce pain is directly contravened with increases in distorted perceptual sensory input; into the association cortex, pre-frontal cortex, and limbic systems; the centers of long term memory assimilation, executive planning, conceptual thought, and emotion.  Gabapentin causes mood swings, and has a high suicide incident rate.  Opioid derivatives have high overdose rates.

Pharmaceutical interventions have a transitory effect, high tolerance, and short half-lives.  Dependency on pharmaceutical drugs becomes a huge problem.  Delta-9-tetrahydrocannabinol (THC), the psycoactive component of cannabis, and similar holistic remedies have theoretical pain relieving medicinal properties.  However, delta-9-tetrahydrocannabinol (THC) is a hallucinogen that fits into the cannabinoid receptor active sites within the brain.*  Delta-9-tetrahydrocannabinol (THC) like opioid compounds alter perceptual awareness, creating transitory euphoric effects.  Endorphins and enkephalins can be theoretically generated by and reinforce euphoria.  Endorphins and enkephalins may be referred to as endogenous opioids.  But altered perceptual awareness is no panacea.  Chronic pain though suppressed below threshold briefly, always returns to remind you that the situation is hopeless.

It is inhumane to force people to suffer, but millions do every day without any possible respite.  We as a nation can do better to help those who cannot help themselves.

A physiological experiment worthy of Sigmund Freud

*I have considered experimenting with delta-9-tetrahydrocannabinol (THC) like the intrepid researchers of yore, to find out if medical marijuana is real or a hoax.  But I don't want to sit around like a stoned zombie all day long.  And I can't stand the stink of Mexican skunk weed.  But there are synthetic variations of THC, dronabinol or marinol, that would be very effective research tools sans the stink.  I have talked to people who smoke marijuana and have asked for their opinions on the painkiller properties of marijuana.  One person said marijuana alters pain awareness, you feel pain, but don't care.  This indifference to pain, under the influence of cannabis, intrigues me. Maybe, even though the brain percieves pain, the brain through some unknown mechanism considers the pain a trivial concern.  Maybe, the solution to the problem can be found in trait-state pain perceptual thresholds.  The pain threshold in the trait mode has value x.  Pain threshold in the stoned state mode has value y.  This idea is most intriguing as a hypothetical construct and should be explored scientifically in controlled experimentation.  However, formulating a measurement tool for threshold would be a daunting task, as all responses to be measured would be subjective opinions of the person being measured.  But pain is measured by opinion now.  Walk into a clinic or hospital and notice the row of cartoon faces.  The faces change from happy to angry, each face is assigned a number.  Zero is assigned a happy face with a broad smile, indicating little pain.  Ten is assigned to a angry frowning face, indicating severe pain.  You ask the person sober to indicate a face that reflects his opinion of his or her pain at the moment.  Then after taking a dose of marinol you repeat the question, which face represents your current opinion of the pain you are experiencing at the moment?  Then measure the difference.  Crude, primitive, unreliable, with very little validity, but what else is there?  You might increase the dose of marinol, or reduce the dose of marinol, or vary the time scale, or monkey around with a million other variables until you establish some approximation to scientific truth.

Controlled medical experimentation is a much better idea than relying upon the hysterical debate of people who are either in favor of, or against, the notion of medical marijuana use.

Eugene Onegin: Alexander Pushkin

Dover Publications 

Eugene Onegin is an epic poem written by Russian poet Alexander Sergeyevich Pushkin.  The poem published in 1833 profoundly depicts Russian culture of that period.  Eugene Onegin is considered by Russian literary scholars as the first epic poem written in the Russian language since The Lay of the Host of Igor, (1185).*  Eugene Onegin served as a template for future Russian literary works.  In 1833 books written in Russian were rare, or of poor quality, or the product of the sentimentalists.  Suddenly, Russian genius blossomed.  Nikolai Vasilievich Gogol wrote, The Inspector General, (1836) a classic Russian comedy and play.  The plot of The Inspector General was originally suggested to Nikolai Gogol by Alexander Pushkin.  Mikhail Yuryevich Lermontov, a great Russian poet, wrote the prose classic,  A Hero Of Our Time, (1839).  Ironically, Alexander Pushkin and Mikhail Lermontov were both killed in duels, although Mikhail Lermontov was allegedly shot in the back by a solider with a carbine rifle, during the duel, under the direct orders of Czar Nicholas.  Czar Nicholas was a particularly spiteful man who crushed the Decembrists, exiled Alexander Pushkin, murdered Mikhail Lermontov, and exiled Fyodor Dostoevsky to Siberia.  Nevertheless, in spite of the heavy handed censorship, the 1830 publications would spawn the Russian literary Rennisance, which reigned supreme until the Boleshivek revolution reduced Russian letters to petty partisan formulaic gibberish.  After the publication of Eugene Onegin, during the Rennisance, the Russian people would be blessed to read and enjoy literary classics written in Russian.  Everything from romance to the seminarists.  The years of literature imported from Europe, and read mostly by aristocratic families, had come to an end.

N.B.  French, the universal language, was taught to children by tutors in wealthy Russian homes.  Speaking French coveyed aristocratic status upon the speaker.  Alexander Pushkin spoke, read, and thought in French, not in Russian.  Eugene Onegin changed the Russian literary landscape forever.  Simply put, Alexander Pushkin wrote a poetic masterpiece in the neglected Russian language.  Alexander Pushkin demolished the idea that Russian language and culture was barbaric and offered no artistic merit.  Alexander Pushkin is a genius of the first order.  Alexander Pushkin is the greatest Russian poet, and one of the greatest revolutionary thinkers Russia has ever produced.

Eugene Onegin is a story of a young girl, Tatyana, who is passionately in love with young rake Eugene.  Eugene has inherited a country estate from his uncle; a man whom Eugene despised; adjacent to Tatyana's ancestral village.  Eugene is a man notable for treading upon theatre patrons feet with crass indifference.  Eugene has a remarkable tendency to offend people with a cavalier swagger.  Eugene is a misanthrope; a precursor to the superfluous man; a wealthy landowner without any purpose in life, who is imprisoned by social convention, and who is unable to make any meaningful contribution to society.  This lack of social graces will prompt Eugene to make callous decisions that will chart the decision-making process of Tatyana after she has matured into a sophisticated societal married woman and is forced to make a choice.  Tatyana is stifled in a world of social ennui, but when forced to choose she refuses to abandon her husband for Eugene who is now passionately in love with her.

Tatyana is a young woman trapped on a landed estate in rural Russia before the emancipation of the serfs.  Russia during this time was a highly stratified society with classes of people ranging from landed serfs to aristocratic gentlemen.  Social mobility between classes was impossible.  However, it was not uncommon for serf girls to become impregnated by landowners.  Pushkin fathered a child with a servant girl on his family estate while in exile.  Pushkin abandoned this girl, and when she died, he expressed in a poem no regret or interest in her or his child.  On rare occasions, a landowner would marry a serf girl.  But in most villages, the land owner's illegitimate children would live with the mother in poverty and would run about among the peasant children.  However, for women, standards were inflexible and exacting.  The slightest indiscretion could ruin the reputation of a young woman forever.  A young woman writing a young man an innocent love letter was expressly forbidden.  Public shaming of women accused of infidelity was not uncommon.  Smearing pitch on a gate post of a home of an accused woman would invite public community ridicule and shame her forever.  Even if the accusation had no basis in fact.

Tatyana faced a second problem.  Young Russian women above twenty-five years old were considered by frantic parents as destined spinsters.  Plus the availability of desirable suitors was limited by geography and class.

One fine day, Eugene agreed to accompany Lensky on a visit to the Larina household.  Lensky was enamored with Olga Larina, a silly, flighty girl.  Instantly, the family and community declared Eugene and older sister Tatyana Larina a perfect match.  Tatyana was under tremendous family and social pressure to find a husband.  Tatyana was willing to accept Eugene as a suitor.  But was Eugene willing to accept Tatyana?

Occasionally Eugene would accompany Lensky when he visited Olga.  Tatyana longed for these visits to see her imagined lover.  On one occasion, when Eugene and Lensky left her home, Tatyana spied upon Eugene from her bedroom window.  Tatyana passionately drew the initials E.O. in the frost on her windowpane.  Tatyana loved Eugene!

Tatyana was a wholesome Russian girl, superstitious, she would not have refrained from casting salt over her shoulder to ward off the evil eye.  She loved the outdoors and rustic life.  Tatyana was also an impulsive, impatient, headstrong girl.  When Eugene did not respond to her advances, Tatyana made a rash decision to send him a letter declaring her intention to serve as his faithful devoted wife, and she arranged a clandestine meeting with him in her family garden to discuss her proposition.

The letter and meeting were very dangerous for Tatyana if she were to be discovered.***

Before the meeting, Tatyana spent time in flights of fantasy, she would visit her favorite grove of trees and pick her favorite flowers.  On the night of the engagement, when Eugene arrived, Tatyana raced from her bedroom down the stairs to the garden to speak to her lover before anyone could intervene.  Eugene declined to offer Tatyana marriage, but Eugene did assure Tatyana he would extend her respectful "brotherly love." ****

Tatyana turned away from Eugene "in despair."

Vladimir Lensky was an idealist and a romantic with poetic aspirations.  In contrast to Eugene, Lensky loved social gatherings and life.  Lensky persuaded Eugene to attend a name day party for Tatyana, under the pretense there would be few guests.  However, when they arrived at Tatyana's residence, every landowner in the district was in attendance at a grand ball.  Eugene was extremely irritated by Lensky's ruse and vowed revenge.  Losing all restraint, the impetuous Eugene taunted Lensky by forcing Olga to dance with him all evening.  Lensky was so incensed he challenged Eugene to a duel. *****

Some may argue Eugene was a heartless beast who went to the duel with callous indifference as to the consequences of his actions.  I disagree.  I think Eugene did not care to fight and he would have found a plausible excuse to avoid the whole issue if it were not for the prompting of his second, Monsieur Guillot.  Monsieur Gulliot is portrayed poetically as a retired military officer, a confused busybody, incompetent opportunist, drunkard, and mountebank.  Eugene overslept, missing the scheduled rendezvous, and he would have probably dismissed the whole duel with ennui had not his second, Monsieur Guillot, arrived reminding him that he was late for the engagement.  When Eugene killed Lensky he was horrified at this senseless act.

The specter of Lensky would haunt Eugene forever.

Eugene disappeared.  He did not wish adieu to Tatyana, he simply ordered his carriage and horses one morning and vanished to parts unknown.  Tatyana was abandoned without a thought.  Alone and sorrowful Tatyana would take long walks until one day she arrived at Eugene's abandoned estate.  There she conversed with the old caretaker who out of sympathy allowed Tatyana to access Eugene's study and to peruse Eugene's books.  This was the pivotal moment for Tatyana.  Tatyana diligently studied the underlined passages and marginal notes in Eugene's books to discern Eugene's soul.  Also, the passage of time heals all wounds in love.  Separated from Eugene her ardor cooled.  Tatyana's feelings for Eugene had changed.  Tatyana now knew the true Eugene.  Tatyana saw her naive romantic idealism shatter like a pane of glass.******

After Eugene departed without a word after he killed Lensky in the duel, Tatyana stubbornly refused numerous proposals for her hand.  But for poor Tatyana times were changing.  Although Tatyana and Olga made numerous forays to Lensky's lonely grave to mourn Lensky shortly after the duel, over time memory fades and people are replaced.  Tatyana's bosom companion Olga soon forgot poetic Lensky.  Olga met and married a military man who was on assignment to a distant front.  After Olga left with her husband, Tatyana faced terrible loneliness.  Determined to do something, Tatyana's desperate mother decided to take Tatyana to Moscow to the matchmakers and marriage market.  Tatyana was placed in a sleigh, driven to Moscow, shopped among balls, and eventually, she married a "fat general".**  The idyllic lifestyle Tatyana had envisioned as a simple country housewife with Eugene had vanished forever.

Eugene traveled from one station to the next over countless versts for two years aimlessly wandering all over Russia.  But one fine day he appeared at a social ball in Moscow.  Victims of Eugene's old pranks were not happy to see him.  But who did Eugene see dressed like a queen in her resplendent glory?  A woman he had completely forgotten, Tatyana!  Worse she was married to a fat general!  When Eugene approached Tatyana she greeted him with majestic glacial reserve.

But instantly, Eugene fell madly in love with Tatyana!

The roles had been reversed.  Tatyana was now indifferent to Eugene.  When Eugene and Tatyana met by chance at receptions, Tatyana always met him with the same icy reserve.  Eugene was so disconcerted he went into seclusion, a veritable recluse, he retired to his study reading books round the clock as a diversion.  Did Eugene think Tatyana would thaw if he improved himself after a wasted youth of slothful dissipation? Eugene even penned two sincerely heartfelt letters to Tatyana.  But these letters were never acknowledged by Tatyana with a reply.  Nothing Eugene did improved his relationship with Tatyana.  Tatyana was as cold and reserved as ever.

Driven to despair, Eugene was unable to endure another moment without Tatyana.  Eugene threw down his book, ordered his coach and horses, and sped to Tatyana's home.  Stealthily passing Tatyana's housekeeping staff, Eugene clamored up the stairs and burst into Tatyana's room.  Tatyana was sitting on a chair sewing some lace.  Eugene fell upon his knees and declared if Tatyana would forgo the "fat general" and renounce her unhappy artificial repugnant social life, he would take her to his country estate, provide for her welfare, and remain loyal to her forever.  But Tatyana would not budge.  Tatyana woefully explained even though she still loved him, and even though she did honestly prefer the homespun lifestyle she outlined in her letter, nevertheless, she would continue to live her current loveless life no matter how stifling.

Tatyana was convinced if she separated from her husband Eugene would regard her as a conquest, a trophy, to be bragged about in jest to all his deplorable friends and rivals all over Moscow.  Tatyana simply did not trust Eugene.  Tatyana thought Eugene's protestations of love poor acting and insincere attempts to manipulate her under false pretenses.  Tatyana hated her husband and lifestyle but she would remain faithful all the same.

The "fat general"** makes an unexpected entry into the room ending the conversation.

Eugene and Tatyana are destined to live miserable lives forever apart.

Tatyana was wrong in her reasoning.  I believe Eugene had abandoned his nefarious life and he had grown weary of his nomadic wanderings.  Eugene did not return to Moscow by accident.  I also believe the death of Lensky weighed like an albatross around Eugene's neck.  The chance encounter with Tatyana gave Eugene a new sense of purpose in life.  Eugene regretted his stupidly squandered years of dissipated youth.

But the reconciliation was not to be.

Afterward

Alexander Pushkin had intended a sequel for Eugene Onegin.  But Alexander Pushkin was killed in a duel by Georges d'Anthes.  Georges d'Anthes allegedly sent Alexander Pushkin an anonymous letter "Certificate of a Cuckold" implying that the court historian, Alexander Pushkin, had been made a cuckold by Czar Nicholas.  There was abundant court rumor beautiful Natalia Pushkina and Czar Nicholas was entangled in a torrid affair.  The insulting anonymous taunting letter prompted Alexander Pushkin to arrange a duel with Georges d'Anthes on January 27, 1837.  The combatants approached each other in waist deep snow.  Alexander Pushkin was shot in the hip, but Alexander Pushkin managed to return fire, the slug grazed Georges d'Anthes hand and knocked him off his feet.  Despite the heroic effort of Konstantin Danzas, who performed on-site surgery, Alexander Pushkin died of infectious complications two days later.  Alexander Pushkin was thirty-seven years old.  It was reported that Alexander Pushkin from his sick bed looked at the books in his library and shouted: "goodbye old friends!"  Thus, the Eugene Onegin sequel was never written.  A great tragedy for Russia and world literature.

Footnotes

*Lays. Old Russian fables or songs were passed from father to son and recited or sung to audiences.  Many lays cited Russian heroes and heroines.  Many of these Russian heroes and heroines possessed supernatural powers.  The content of the lays would evolve over time with additions and subtractions.  For centuries, written language, except for a few clerics, was almost non-existent among the Russian people.  The Lay of the Host of Igor was the first lay to be written down on paper in a Slavic language.  Illustrations were added to the lay by cleric artists at unknown dates.  It is important to note that in 1840, out of a Russian population of ten million souls, only one hundred and fifty thousand people could read.  In certain aristocratic homes people could not speak or read Russian.  Tatyana, when composing her letter, struggles to master fluent Russian grammar.

**In Russian literature generals are often lampooned derisively as bombastic, uncouth clowns.

***This concept was beautifully conveyed in opera when Tatyana began to compose her letter.  She would write a line, stop in frustration, crumple up the sheet of paper, and toss it on the floor.  A peasant servant enters the room and begins to gather up the discarded drafts of the letter, oblivious of the contents, or of the danger to Tatyana.  The Peasant cannot read!  To the peasant, the discarded drafts are nothing but useless rubbish to be removed and thrown out.  The problem?  If Tatyana's mother or nefarious vindictive people who could read discovered these drafts by accident, Tatyana could face hysterical recriminations, blackmail, or tragic social censure.

****In the poem and opera, Tatyana accuses Eugene of rejecting her in the country because of her rural upbringing and demeanor, but because of her newly acquired social polish and wealth, Eugene changed his mind and is now willing to accept her.  Tatyana's bitter feelings are understandable, but her conclusion totally misses the point.  Eugene did not care if Olga, Tatyana, or Catherine the Great wrote the letter.  Eugene would have reacted to all of these women with the same aloof indifference.  Social status meant nothing to Eugene.  Eugene was so detached and jaded at the time from social anomie, he would have scoffed at the ardent desires of any woman without a pang of conscience, including the Czarina of Russia.  And totally forget her next day.  Eugene understood the tremendous pressure Tatyana was undergoing from her family to get married.  After all, the community had matched Eugene and Tatyana and a wedding announcement was expected soon.  Eugene demurred because he thought after attaining security, the good elements of marriage; love, beauty, would be replaced with self loathing and poisonous recriminations.  A harebrained opinion Tatyana would make Eugene dearly pay for.  But somewhere on the road, Eugene faced an existential crisis, thinking about the duel and Vladimir Lensky.  Eugene wanted some relief from his pointless social malaise.  A wife and family life suddenly seemed to be a better option than aimlessly wandering about Russia from one dirty station to the next.  Eugene offered to take Tatyana away from her pointless social suffering and he had the means to make her happy.  Tatyana refused because of the books she read, she did not understand the metamorphic change in Eugene.  Pushkin could have turned Eugene Onegin into Anna Karenina, the general could have refused to give Tatyana a divorce, and the poem could have devolved into a long psychological dissertation of Tatyana and the brutal Russian process of obtaining a divorce for a woman against the wishes of her husband.  But for Tatyana one intolerable situation would have been exchanged for another, with no net gain.  Or Tatyana could have said "yes" to Eugene, "and they lived happily ever after," which would have destroyed the purpose of the story.  Pushkin left the audience in agony over the fate of Eugene and Tatyana.  This is why Eugene Onegin, "a novel in verse" will be acted out in operatic plays forever.

*****Opera, as a time saving device, always has Lensky challenge Eugene to the duel during the ball in front of Tatyana and Olga.  But in the poem, Olga and Tatyana have no clue.  Lensky pays one last charming visit to Olga, while Tatyana spends a sleepless night jealously angry at Eugene.  Unexpected news of the death of Lensky would come as a complete surprise to both Olga and Tatyana.

******A Russian language professor once told me it is important to note that Tatyana read all of Eugene's books.  Tatyana was not satisfied with a casual examination of Eugene's soul.  Tatyana wanted to know everything about Eugene.  Tatyana was very disappointed with what she found.  Tatyana could not forgive Eugene for his amorphous indifference to life or for his callous disregard to her needs and interests.  Tatyana was furious Eugene abandoned her.  Tatyana wanted a husband who would take care of her, her children, and the village.  Tatyana did not want a detached absentee landowner who places the enterprise into the hands of a unscrupulous overseer who would ruthlessly savage the peasants and swindle Eugene out of revenue by under reporting crop yields.  Tatyana did not want to live with a dandified Oblomov in Moscow while the village decayed into dust.  I think Tatyana developed a psychological aversion to Eugene no amount of begging or pleading could rectify.  This may explain why Tatyana was so cold and unfeeling in Moscow, and why she rejected Eugene's entreaties point blank.

Tom Danielson Tests Positive Again

Tom Danielson has tested positive on the "B" sample for an "anabolic agent" according to USADA.  There is some speculation that the "anabolic agent" is DHEA, a testosterone precursor that can also be used as a masking agent.

Oddly enough, Mr. Danielson originated this speculation by making an announcement prior to the 2015 Tour of Utah he had received a letter from USADA stating he had tested positive for synthetic testosterone. This is most unusual. Generally, the regulatory agencies are on the phone to L'Equipe long before the ink is dry on the Lab Document Package with breaking news. Amazingly, neither USADA or the UCI leaked the story.

Perhaps the regulatory agencies have finally learned not to initiate a witch hunt before the athlete has a chance to collect his wits and prepare an adequate defense.

Mr. Danielson does not appear on the "provisionally suspended" list. Perhaps the secretary is on a coffee break?

Jonathan Vaughters is backpedaling as fast as he can from the situation by informing the fanatics of some astounding news.  Cannondale Garmin informed Mr. Danielson that his contract would not be extended before Mr. Danielson tested positive for an anabolic agent.  What Mr. Vaughters omitted was why the contract was not extended.  One could speculate Mr. Vaughters is suggesting that Mr. Danielson hired Levi Leipheimer as a personal coach, trainer, consultant, and bulked up with drugs in order to win the Tour of Utah in order to prove to other teams he was still a valuable asset. (A person should avoid contact with such people to avoid impropriety, especially as Levi Leipheimer is an expert on how to dope and avoid detection.) Others might suggest that the contract was terminated because Mr. Danielson is 37 and about to join the masters.  Others might suggest that Cannondale Garmin knew Mr. Danielson was using drugs, or Cannondale Garmin was complicit in this behavior.  Why would Mr. Vaughters wonder why neither USADA or the UCI has told him what Mr. Danielson tested positive for?  True.  Mr. Danielson was still employed by Cannondale Garmin when he tested positive, which is suggestive. But since Mr. Danielson has been terminated by Cannondale Garmin, is it any business of Jonathan Vaughters?  Perhaps, Mr. Vaughters could hold another press conference and be more forthcoming about the circumstances of why Mr. Danielson's contract was not extended.

The next step for Tom Danielson is the USADA Anti-Doping Review Board.  There he will have an opportunity to argue he was accidentally poisoned by a tainted supplement or he was a victim of sabotage.  At considerable expense.

Tom Danielson Tests Positive for Synthetic Testosterone

In cycling nothing is sacrosanct. Tom Danielson, two-time winner of the Tour of Utah, has tested positive for synthetic testosterone in an out of competition test. Synthetic testosterone is determined by carbon isotope ratio testing. USADA has informed Mr. Danielson that his A sample has tested above the threshold for synthetic testosterone. However, the confirmation B sample is still under examination.

It would be premature to jump to conclusions at this point. When the test is confirmed then it may be proper to cast aspersions upon Mr. Danielson. But at this point, it would be more proper to attempt to remain objective and consider his case. Mr. Danielson is mystified by the result, he wants to explore all possibilities. Some would consider this as the standard approach, denial with expostulations on the love of the sport. Indeed, others would point out that Mr. Danielson has tested positive for doping before, and he provided evidence against Lance Armstrong with a deal for a reduced sentence. So, does this provisional second doping offense require a two or four-year ban? Does the USADA golden boy turned pariah get another sweetheart deal?

Of course, Tom Danielson rides for Slipstream Sports and Jonathan Vaughters, the "no tolerance to doping" team. Right. For two straight years, Garmin dominated the Tour of Utah, "riding clean," much like Team Sky dominates the Tour de France "riding clean." The cleanest teams have the best results. Jonathan Vaughters is pounding his chest bragging that Slipstream has never had a positive doping test, until now. Of course, nobody is accusing Slipstream or Sky of running an organized team doping program. But, knowing USADA, some backroom deals could be arranged, information for a reduced sentence.

Slipstream fired Tom Danielson point blank, as always. These clean teams can't wait to distance themselves from their accused riders. 

Jonathan Vaughters says if Slipstream is involved, he, Jonathan Vaughters, should be banished from cycling forever. Recall that Mr. Vaughters is another doper who volunteered to make depositions against Lance Armstrong, and instead of being banished from cycling he was rewarded with running a cycling team. So there should be no problem with Mr. Vaughters providing USADA and the public with all pertinent rider medical information that may be requested to prove that Slipstream had no role in Mr. Danielson's provisional positive doping test. Travis Tygart should demand transparency. Of course, USADA could insist that the entire Slipstream staff be required to testify in order to build non-analytical-positive cases, as was done with Lance Armstrong.

You are laughing, ladies and gentlemen? Truly teams should be severely interrogated when their riders test positive for dope. How many times have team doctors been implicated, but who are never punished? How many times do the regulatory agencies turn a blind eye to team responsibility? Unpunished, the doping programs continue unabated. Riders are collateral damage, thrown out like rubbish to fend for themselves, the system is structured. Teams that have riders who test positive for dope should automatically be sanctioned then investigated under the philosophy that the team is guilty of a doping infraction until proven innocent. This philosophy applies to the riders, does it not?

I wish Tom Danielson well. I am accusing him of nothing. The evolution of his case will be a fascinating study.

Schizophrenia, Neuroleptic Drugs, and Extrapyramidal Movement Disorders

Terry D. Holfeltz

Forest water cascades down a precipice with a deafening roar-a jest.

Author note: This paper was written in 1990 when I had a passion for biological psychology, in a manic burst of energy. T.M. was a fellow I worked with at the University of Utah. His end was very tragic, even though I was not there to see it. Apparently, he had a bad habit of eating scraps of food out of garbage cans. One fine day he died after vomiting blood at work. There were earlier reports, in the student newspaper, before his death, when T.M. after switching medications was seen racing around the building where he worked shouting death threats at people. The etiology of that malady would have been an interesting study and might have contributed something to the literature if anyone had cared enough to write a summation. Essentially, this whole paper was written precisely to understand what was happening to T.M., and to learn something about a topic that was of considerable interest to me at the time.

The history of neuroleptic drugs and schizophrenia has been a controversial and interesting one. For instance, it was once thought that dopamine was only a precursor to norepinephrine, and that dopamine did not exist independently as a neurotransmitter within the brain.  It was not until 1964 when Dahlstrom and Fuxe discovered a histological technique to distinguish dopamine from norepinephrine that dopaminergic pathways in the brain were considered seriously. Now with the biochemical isolation of dopamine beta-hydroxylase, an enzyme that regulates the production of norepinephrine from dopamine, and from electron microscopy, which has revealed both storage boutons and chemical synaptic membranes, has the existence of a separate and distinct dopamine active neuron been identified.

The pharmacological action of the neuroleptic drugs was once thought to block dopaminergic post-receptor sites, increasing the release and turnover of dopamine within both the mesolimbic/mesocortical and nigrostriatal pathways of the brain. However, recent research has determined that the biochemical action of these pathways may not be identical, in fact, many theorists have argued that the nigrostriatal and mesolimbic/mesocortical pathways work quite independently. The therapeutic properties of several neuroleptic drug derivatives may, in fact, depend upon specific actions of receptor sites. For example, thioxanthenes are D1 receptor type-specific, some phenothiazines block D1 pre-receptors and D2 post-receptors, and butyrophenones are D2 specific post-receptor blockaders. Therefore, variations in pharmacological action would be expected both in acute immediate reactions and over chronic durations, including rates of dopamine syntheses and turnover, and tolerance effects to the neuroleptic drug in question.

This paper will briefly review the neuroanatomy of the dopaminergic systems of the brain. Then this paper will attempt a limited discussion of some recent efforts to solve the puzzle of neuroleptic drug action in the fight against certain schizophrenic disorders, and the consequent acute and chronic extrapyramidal side effects of these drugs. This paper will then attempt a limited review of some theories of schizophrenia, including hemisphere disorders, acute positive symptom schizophrenia that is dependent upon excess dopamine in the brain, chronic negative symptom schizophrenia that may be due to organic dopaminergic neuronal damage, and how this condition resembles idiopathic Parkinson disease. Then there will be a brief presentation of two acute Parkinson movement disorders attributed directly to neuroleptic drug action, akinesia, and akathisia. Then we will discuss tardive dyskinesia, a disorder known to directly result from chronic administration of neuroleptic drugs. Next, we will attempt to discuss some current theories of dopamine receptor subtypes, the adenylate cyclase, cAMP theory, the D2 post-receptor supersensitivity theory, and the D3 autoreceptor theory. As will be seen these receptors work in a quite independent fashion, they may have quite different roles to play in schizophrenic management with neuroleptic drug therapy and may contribute quite differently to extrapyramidal movement disorders. Then we will conclude with a case study of a person receiving neuroleptic drugs. Where does his behavior "fit" in this scheme?

Neuroanatomy: The Dopamine Pathways

The dopamine system has been divided into four major subdivisions: nigrostriatal, mesolimbic, mesocortical, and tuberoinfundibular. The tuberoinfundibular dopaminergic pathways of the brain originate within the hypothalamus and extend to the pituitary gland and govern mainly endocrine functions; inhibition of growth hormone and release of prolactin. There has yet to be any definitive proof that either schizophrenic symptomatology or extrapyramidal side effects are contingent upon the tuberoinfundibular region, however, several receptors have been identified within in vitro experimental techniques, especially with the bovine parathyroid gland (cAMP-dependent) and with prolactin release (non-cAMP-dependent.) More of this research will be discussed under the dopamine receptor segment of this paper.

The mesolimbic/mesocortical region, or neuron group designated through the histological techniques of Dahlstrom and Fuxe (1964), as A10 dopaminergic neurons, seem to mediate certain positive schizophrenic states, and neuroleptic drugs seem to act by the post-receptor blockade to reduce acute schizophrenic symptoms. The anatomy of the mesolimbic/mesocortical system has been described as follows. "The cells of origin for this pathway are found in the midbrain. They primarily surround the interpeduncular nucleus in the ventral tegmental area. Areas demonstrated to be innervated by these cells include the olfactory tubercles and accumbens nucleus, central nucleus of the amygdala, and lateral septal nucleus. Recent evidence also suggests that A10 cells may project to the lateral basal and posterior-lateral nuclei of the amygdala as well as to the ventral lateral caudate nucleus. It is not known at this time if the A10 cells branch so that one cell innervates both the limbic and cortical areas or if there are separate cells for each system. In terms of responses to drugs, the A10 cells appear relatively homogeneous. In contrast to the diffuse innervation of the cerebral cortex by the norepinephrine (NE) system, the dopamine (DA) innervation was found to be localized to discrete areas of the cortex: the gyrus cinguli, entorhinal cortex, and prefrontal cortex." (Bunney and Aghajanian, 1978).

The nigrostriatal dopaminergic pathway originates within the zona compacta containing over 3000 dopamine endogenous cell bodies with collaterals ascending throughout the extrapyramidal motor system of the brain.  The extrapyramidal system is defined as "a functional, rather than anatomical, unit comprising the nuclei and fibers (excluding those of the pyramidal tract) involved in motor activities; they control and coordinate especially the postural, static, supporting, and locomotor mechanisms.  It includes the corpus striatum, subthalamic nucleus, substantia nigra, and red nucleus, along with their interconnections with the reticular formation, cerebellum, and cerebrum; some authorities include the cerebellum and cerebrum and vestibular nuclei." (Dorland's Pocket Medical Dictionary, 1977).

It has been argued that the mesolimbic/mesocortical and nigrostriatal dopaminergic pathways work in an independent manner, with separate and distinct pharmacological action. For example, A10 neurons are thought not to contain receptors that are adenylate cyclase-dependent. However, it has been thought that A9 neurons do contain cell bodies that are endogenous to the caudate nucleus that is cAMP-dependent. It is also interesting to note that the site of action of certain neuroleptic drugs on A9 neurons is thought to block both presynaptic and postsynaptic receptor sites, while on A10 neurons the site of action of the same drugs is thought to postsynaptic only. In a related study, it was found that thioridazine, chlorpromazine, and fluphenazine enanthate, in acute and chronic treatment significantly elevated homovanillic acid (HVA) levels in the striatum and limbic areas. However, the caudate nucleus, but not the limbic areas, showed a reduction in HVA following each of the three drugs when acute and chronic treatments were compared. (Bunney and Aghajanian, 1978). This is of extreme importance in explaining why neuroleptic drugs cause motor dystonia after prolonged use and may explain why mesolimbic/mesocortical receptors do not become tolerant to neuroleptic drugs over time.

Acute Schizophrenia and Hemisphere Dysfunction: Some Possibilities

There have been several theories to account for the etiology of schizophrenia.  One theory suggests that acute schizophrenia, composed of auditory and visual hallucinations, delusional states, a flight of ideas, and hyperactive stereotyped behaviors, may be associated with an excess of dopamine in the mesolimbic/mesocortical dopaminergic pathways in the brain.

In relation to dopamine and hemisphere specificity, it has been hypothesized that dopamine content in the brain is left hemisphere specific and may govern effector responses, mostly motor in origin. This motor effector system is thought to work in conjunction with acetylcholine. Norepinephrine is thought to be right brain-specific and probably mediates orientation responses. This orientation system is thought to work in conjunction with 5HT serotonin. (It is interesting to note that norepinephrine and dopamine are thought to be the excitatory neurotransmitters of arousal and exploratory behavior, while acetylcholine and 5HT serotonin are thought to act as inhibitory transmitters. Thus a homeostatic balance is maintained within the organism with this synergistic neurotransmitter system. Disruptions in the system reasonably can be assumed to cause irrational behavioral/cognitive states).

It is thought that novel stimuli impinging upon an organism are first processed by the right brain orienting system that works in a holistic fashion. The right brain is thought to process information like an analog computer, while the left brain is thought to process information like a serial computer. Therefore, it has been hypothesized that novel information is first analyzed in large chunks of information, which is right-brain dominant, and this process is thought to continue until selective chunks of information become manageable enough to transfer to left-brain information processing centers. After the left brain association cortex has serially processed the right brain inputs, the emphasis is thought to transfer to effector dopaminergic extrapyramidal (nigrostriatal) centers for proper motor responses. Synergistic imbalances of neurotransmitter substances dopamine and acetylcholine are thought to produce an overload of responsiveness to habituated stimuli resulting in stereotyped behavior. This type of behavioral stereotypy has been observed in rats who have been subjected to toxic doses of amphetamine, a catecholamine agonist. Note: acetylcholine is thought to have two different receptors, nicotinic and muscarinic. The extrapyramidal system is thought to contain endogenous cell bodies that are 90% muscarinic in origin.

In relation to brain hemispheres and emotions, the evidence is still not conclusive. The right cortex is thought to mediate the afferent input of emotionality, including facial cues, auditory interpretation of other-directed vocalizations, and other significant semantic contextual clues. Right frontal lobe damage is thought to interfere with emotionally specific cues resulting in agnosia and blunted flat or inappropriate affect. (Tucker, 1981)

One study has directly found excessive dopamine levels in the left amygdala of deceased schizophrenic patients, but dopamine levels within the right amygdala appear to be normal. (Tepper, 1985) In relation to the imbalance of neurotransmitters in left limbic structures such as the amygdala, which is thought to mediate startle responses and rage responses, it may be hypothesized that dysfunction in this structure would result in states of hyperarousal, panic attacks, and inappropriate bursts of anger. It may also be suggested that in theory, a left hemisphere amygdala that is malfunctioning due to an overload of dopamine, would create severe startle responses and severe displays of euphoria, commonly seen with patients suffering from amphetamine toxicity. An overload of dopamine in the left amygdala may also create a condition resembling mania, a condition characterized by expansive ideas, global nonserial reasoning, an over positive self-image, over-enthusiasm of the self, an inability to perceive bodily faults, and an under-responsiveness to criticism. This may happen due to a left amygdala signal override of afferent information that cancels out the normal inhibitory right amygdala inputs, and/or other regulatory neurotransmitters resulting in a scrambled stimulus-response network.

The Role of Amphetamine Psychosis and Catecholamine Excess

Several studies have determined that amphetamine is a direct catecholamine agonist. Amphetamine acts to release both dopamine and norepinephrine, blocks synaptic re-uptake, and exerts direct action at postsynaptic receptors. Toxic levels of amphetamine produce symptoms that are indistinguishable from acute schizophrenia. These symptoms include well-formed paranoid delusions, various forms of stereotyped compulsive behavior, and either visual or auditory hallucinations. (Angrist and Gershon, 1980) Animal studies utilizing amphetamine have added strength to the excessive brain dopamine theory. One study has suggested that chronic use of amphetamines may produce long-lasting or irreversible depletion of dopamine in the caudate nucleus. This change is associated with the development of exaggerated startle reactions, dyskinesias, and postural abnormalities, possibly resulting from secondary supersensitivity of dopamine receptors in the caudate nucleus. (Jaffe, 1980)

The implication is obvious. Post-receptor affinity changes have occurred to compensate for a lack of caudal dopamine synthesis encountered in chronic amphetamine use, resulting in new post-receptor set points that are super sensitive to dopamine release. If the natural depletion of dopamine has resulted in post-receptor affinity changes as described above under chronic amphetamine abuse, then the cessation of amphetamine would increase the motor stereotypy

In a related study, it was found that hyperactivity and stereotypies occurring after administration of amphetamines to rats were blocked by pretreatment with alpha-methyl-tyrosine, which inhibits the synthesis of both norepinephrine and dopamine. Also, blocking dopamine receptors with pimozide or haloperidol before administering amphetamine prevented the appearance of stereotypy and hyperactivity, suggesting that dopamine may be the significant neurotransmitter in these behaviors. Thus, the dopamine-induced psychomimetic effects of amphetamines prompted further investigations into the possibility that excessive dopamine neurotransmission is responsible for schizophrenic symptoms. (Garver, 1975)

It has been known for several years that neuroleptic drugs such as the phenothiazines and butyrophenones are effective in counteracting amphetamine psychosis, and in reducing symptoms of acute positive symptom schizophrenic states. Neuroleptics have been found to directly block dopamine post-receptor sites, increasing dopamine turnover, at least acutely, as measured by increases in 3H-Dopamine, and central nervous system (CNS) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), and to block norepinephrine receptors reducing the synthesis and turnover of this transmitter. Norepinephrine over synthesis has been known for years to be a direct cause of manic states in man. So a possible hypothesis to explain the neurotransmitter interaction of reduced schizophrenic/manic states and hypermotility associated with these disorders may be reduced norepinephrine synthesis and increased dopaminergic neuron hyperpolarization working in combination.

Chronic Schizophrenia and Idiopathic Parkinsonism: DA Neuron Lesions?

Chronic negative symptom schizophrenic disorders seen in catatonic disorders, with rigid muscular posturing, and flat affect, do not respond well to neuroleptic treatment. It has been hypothesized that chronic schizophrenia may be due directly to striatal/caudal/cerebral/endogenous organic brain damage, or to conditions resulting in neuronal atrophy. This may result in dopaminergic under activity. This may also explain why the dopamine precursor L-DOPA is effective with some chronic negative symptom schizophrenic patients.

L-DOPA is a well-known dopamine agonist and for years has been effective in improving symptoms of idiopathic Parkinson disease. As is known, idiopathic Parkinson disorders are the direct result of the degeneration of neostriatal dopaminergic pathways in the caudate nucleus. Since Parkinson disease is composed of muscular rigidity and lack of spontaneity in movement, it has been hypothesized that L-DOPA may increase dopamine synthesis and turnover in the caudate to compensate for the intrinsic destruction of dopaminergic neurons, and reduce post-receptor site activity. These pharmacodynamics may account for the improvement of chronic schizophrenic patients as well.

Parkinson Side Effects: Akinesia and Akathisia

An immediate extrapyramidal side effect observed with neuroleptic drug administration beside muscle tonus is the Parkinson like disorders akinesia and akathisia. Akinesia is characterized by rigid posturing, fixed gaze, lack of normal arm movements from side to side when walking, shallow voice, and flat affect. Akinesia disorders have been artificially generated in animals using reserpine. The main action of reserpine is to prevent the storage of dopamine in neuronal granules by blocking dopamine reuptake for packaging. Neuroleptic drugs by blocking postsynaptic dopamine neurons may produce the same effect: producing a shortage of synaptic dopamine-making contact with post-receptor sites. This may occur even though the action of neuroleptic drugs is to initially increase dopamine turnover.

Reserpine is not thought to have action on post-receptor sites and consequently does not cause chemical denervation of these receptors. However, it has been thought to cause post neuronal damage with long term administration, due to an unnatural depletion of neurotransmitters. Other causes of akinesia may be increased dopamine turnover without compensating an increase in positive post-receptor sensitivity, or an increase in receptor numbers, at least initially. This effect is no doubt time and dose-dependent. This hypothesis has limited behavioral support. Some patients who exhibit akinesia do so for only limited amounts of time, usually under acute neuroleptic treatment. Chronic neuroleptic treatment studied for long amounts of time generally sees motor improvements. (Personal observation; Case #T.M.,1990) Increases in motor responsiveness over time may reflect direct synaptic changes of the neurotransmitter, or dopaminergic neuronal changes, or receptor affinity changes.

One note of caution concerning patients with akinesia disorders. Under acute treatments when the Parkinson type disorder is observed, many psychiatrists confuse the neuroleptic drug side effects with chronic schizophrenic motor disorders. The problem may be connected with the indifference to environmental stimuli studied in patients with chronic schizophrenic disorders. A study has been initiated to test environmental perception by rats undergoing neuroleptic treatments. The test consists of the classical conditioning of rats to avoid shock (the conditioned avoidance response or CAR). Rats conditioned to avoid shock onset with a visual cue, such as a diminution of light, were later tested under clinical doses of neuroleptic drugs. Even though rats under normal untreated conditions escaped shock onset, rats on neuroleptic drugs no longer did so. This suggests that although rats perceived the conditioned stimuli, they no longer perceived it as important. This indifference to conditioned stimuli was reversed by dopamine agonist drugs.

In a related study, rats could avoid being shocked by climbing a pole in a certain amount of time, after the onset of a signaling stimulus. The stimulus would continue throughout the period of the shock (such as diminished light) and restored to normal (standard laboratory lighting) after cessation of the shock period. Therefore, the rat could discriminate between cues requiring avoidance versus non-avoidance behavior, could perceive the onset of danger, could determine how long to continue avoidance behavior and when to determine when to discontinue this behavioral response. Under chronic neuroleptic treatment, the rats continued to step down onto the electrical apparatus even after the signaling stimuli were given, suggesting that the aversive stimuli were not perceived correctly. This was thought to be a direct result of the drug efficacy and not due to the sedative effect of the drugs. The normal response pattern of avoidance was resumed with dopamine agonist drugs. The step-down test has been used for years as a measure for testing the efficacy of neuroleptic experimental drugs.

This indifference to environmental cues may also result from a lack of motivation. Rats with striatal lesions will swim if thrown into a tank cold water even after they have maintained rigid posturing for hours. This has also been discovered in patients with idiopathic Parkinson's disorders. People with this condition will leap up and run out of the room when someone shouts "fire!" although they have been immobile for hours. So, in conclusion, reduction in behavior suggesting the side effects of certain schizophrenic disorders should be gauged extremely cautiously to ascertain whether the behavior is due to the disease state or the treatment regimen.

Akathisia is a Parkinson like disorder characterized by the subjective feeling of restlessness. People suffering from this disorder are unable to sit in one place for any period of time, jog in place, resort to obsessive-compulsive hand wringing among other hyper activities. Given doses dopamine agonist the symptoms increase in frequency and intensity. The direct cause of akathisia is unknown but it may be the result of increased striatal turnover of dopamine bombarding post-receptor sites that have not made setpoint changes to accommodate this increase of neurotransmitter. In conclusion, akathisia, a Parkinson like disorder may be a result of hyperarousal of the mesolimbic/mesocortical dopaminergic pathway. This may partially explain why hyperarousal in this disorder is beyond conscious control.

Chronic Tardive Dyskinesia

Chronic Tardive dyskinesia is the only extrapyramidal system disorder known to be directly attributed to chronic neuroleptic treatment regimens. Long term schizophrenic patients in countries that do not use neuroleptic drug regimens, lack patients with Tardive symptoms. (See an excellent review by Baldessarini and Tarsy, 1978) Tardive dyskinesia is characterized by orofacial, buccal, lingual dystonia, fly catching, grimacing, and in extreme cases body dystonia, leaning tower of Pisa disorder, and many others. The cause of Tardive disorders is unknown but according to one study, "there are rare reports of neuropathologic changes following prolonged neuroleptic treatment of patients without persistent extrapyramidal syndromes, noting scattered areas of neuronal degeneration and gliosis without convincing localization, and some suggestions that patients with drug-induced Parkinsonism or Tardive dyskinesia have post mortem changes in the basal ganglia and midbrain." The same study concluded that prolonged exposure of animals to a neuroleptic agent leads to a prolonged (weeks) requirement for increased doses of the same agent (tolerance) or a dissimilar neuroleptic agent (cross-tolerance) to block the behavioral effects of apomorphine; a dopamine agonist. (Baldessarini and Tarsy, 1978) This suggests that neuroleptic drugs do long term or irreversible damage to neostriatal dopaminergic pathways. This also suggests that long term chronic neuroleptic drug administration creates both super sensitive dopaminergic post receptors or the absolute number of these receptors within the neostriatum. A study designed to treat this idea was done with long term schizophrenic patients under neuroleptic drug treatment. The hypothesis originally tested the idea of receptor supersensitivity by suggesting that apomorphine, a dopamine agonist drug would intensify Tardive Dystonia. The conclusion of this experiment was correct. However, the suggestion was advanced that perhaps with long term administration of apomorphine receptor sensitivity would change from a state of supersensitivity to a state of hyposensitivity due to the effects of increased dopamine activity. Ironically enough the experiment produced the desired effect, reduced Tardive symptoms to a state of remission for several years! (Baldessari and Tarsy, 1978) Due to the limited follow up of the patients of this study the results should be taken with a grain of salt, however, the prospect looks promising.

Extrapyramidal Effects: Dopamine and Acetylcholine Imbalance?

It has long been determined that anticholinergic drugs are effective in reducing extrapyramidal movement disorders induced by neuroleptic drugs. According to one study, the interactions of dopamine and acetylcholine neurons are as follows. Acute blockade of dopamine neurotransmission by antipsychotic agents increases the turnover and release of acetylcholine by within the striatum. Dopamine agonists exert the opposite effects. (Tepper, 1985) This contention has many psychiatrists convinced that the efficacy of neuroleptic drugs and the extrapyramidal sedative side effects are interdependent and act pharmacologically at the same site. However, this contention has been recently questioned.  It appears that not all neuroleptic drugs work in the same fashion. Piperazine phenothiazines have a high incidence of acute extrapyramidal side effects and are probably the first choice of physicians who deal with violent patients, the sedative effects are obvious. However, neuroleptic drugs do exist that do not produce extreme sedation or high levels of extrapyramidal side effects. Clozapine and thioridazine (Mellaril) are two effective antipsychotics that do not produce extrapyramidal side effects. There have been several theories to account for this phenomenon. Some authors suggest that these drugs work on selective A10 dopaminergic pathways, mesolimbic/mesocortical, but not neostriatal, A9 neurons. According to one author, "Clozapine has a strong action on dopamine turnover in the limbic system and a relatively weak one in the striatum. Coincidentally, clozapine has antipsychotic efficacy but very few extrapyramidal side effects." (Bradley, 1986) It also appears that clozapine has an ability to block dopamine receptors in the nucleus accubens, but not in the caudate nucleus. This might provide an explanation other than it's an anticholinergic activity for clozapine's unusual combination of antipsychotic efficacy and lack of extrapyramidal side effects. (Bunney and Aghajanian, 1978) Of course, the best theory is that clozapine does a partial blockade of dopamine receptors. Thus catatonic patients show marked improvement with increased awareness and behavioral energy.

However, some authors suggest that a more probable explanation is the interaction of clozapine and thioridazine on dopamine/acetylcholine interactions in the brain. Most studies agree that neuroleptic drugs increase the release and turnover of disinhibited choline. This is one reason why some psychiatrists attempt to control the unwanted motor effects of neuroleptic drugs with anticholinergics. The action of clozapine and thioridazine is thought to work without the increase in choline release by having a selective affinity for muscarine receptors. (Creese and Snyder, 1978)

In addition, it has been found in relation to the interaction of dopamine and acetylcholine in motor disturbances, "it was found that drugs that blocked the action of norepinephrine and dopamine interfered with avoidance responding, but interestingly, these effects were also blocked by atropine and scopolamine, (an acetylcholine, muscarinic receptor antagonist) indicating that cholinergic neurons are part of an important link in the chain of neurons that maintains avoidance behavior." (Bartholini and Lloyd, 1980)

To summarize the dopamine/acetylcholine problem one author suggests that "Parkinson disease is a neostriatal dopamine deficiency syndrome. The loss of neostriatal dopamine disrupts the balance between the neostriatal dopaminergic and cholinergic systems that are thought to regulate normal activity in the neostriatum. The dopaminergic agonists presently used may achieve some of their therapeutic effects by directly stimulating dopamine receptors; however, some of their therapeutic effects may be a consequence of stimulating the dopamine receptor upon the cholinergic interneuron and thereby restoring the balance between the dopaminergic systems in the neostriatum. Prior to the advent of L-DOPA therapy for Parkinsonism, cholinergic antagonists were widely used." (Stoof, 1985)

Receptors

The roles of dopaminergic receptor subtypes have been controversial and confusing. Up to eight receptor subtypes have been proposed. However, three receptors have been theorized to have some part in the reduction of schizophrenia and extrapyramidal side effects due to neuroleptic receptor blockade. A summary of receptor subtypes is given below, from (Kebabian,1983)

Dopamine D1 Receptors: Adenylate cyclase.
Radioligand: 3H-thioxanthenes.
Dopamine: Agonist m molar potency.
Apomorphine: Partial agonist or antagonist.
DA Ergots: Potent antagonists n molar potency.
Selective Antagonist: Unknown.
Radiolabeled Ligand: cis-flupenthixol.

Dopamine D2 Receptors: Unassociated.
Radioligand: 3H-butyrophenones.
Dopamine: Agonist n molar potency.
Apomorphine: Agonist n molar potency.
DA Ergots: Agonist n molar potency.
Selective Antagonist: metoclopramide.
Radiolabeled Ligand: dihydroergocryptine.

Dopamine D3 Receptors: Unassociated.
Radioligand: 3H-Dopamine.

Note: The classification of D3 receptors was not included in Kebebian's classification beyond the information provided.

D1 receptors are indigenous to the striatum, have cell bodies within the striatum with collaterals ending within the substantia nigra. This receptor system was originally found in the bovine parathyroid gland. It has been found that dopamine causes a twenty to thirty-fold increase in the content of cAMP in dispersed bovine parathyroid cells. (Brown and Dawson-Hughes, 1983) Increased synthesis of thyroxine has been discovered when these parathyroid cells were subjected to doses of dopamine agonist drugs. Neuroleptics countered this effect.

Originally dopaminergic receptors were thought to work by a dopamine-sensitive adenylate cyclase, which in turn regulates a second messenger 3'5' cyclic adenosine monophosphate system. The cAMP synthesis and storage in D1 receptors seem to be mediated by excitatory guanosine triphosphate (GTP) link, which works on the adenylate cyclase to produce neurotransmitter by a process that is still unknown. (Kebabian, 1983) D1 receptors were once thought to be causal in schizophrenic disorders, but this assertion has been seriously questioned.

According to one study, "only the DA-stimulated adenylate cyclase is effectively inhibited in a competitive manner by the addition of low concentrations of neuroleptic drugs." (Clement-Cormier, 1974) The implication was, of course, that selective dopamine antagonist drugs would reduce dopamine synthesis and turnover by blocking the production of cAMP. However, it was discovered that the destruction of endogenous D1 receptors in the striatum with 6oxyhydrodopamine (6OHDA), a dopaminergic neurotoxin, did not significantly lower striatal dopamine levels identified with [3H]-antagonist binding assays. In addition to this discovery, there was an autopsy done to determine whether chronic schizophrenic brains subjected to chronic neuroleptic drugs showed damage and regeneration of D1 neurons or increased radioligand binding. Neither consequence expected from neuroleptic drug lesions occurred. According to one author, D1 receptor sites are not involved with the dopaminergic transmission in the brain. The in vivo accumulation of cAMP induced by apomorphine in the striatum was not blocked by sulpiride and haloperidol whereas the behavioral effects were blocked by both drugs. When labeled neuroleptics were injected into rats, the radioactive [3H]-antagonist binding was never found on D1 receptor sites." (Laduron, 1983) In conclusion, it may be asserted that in both the neostriatum and the substantia nigra the dopamine-sensitive adenylate cyclase receptor is in search of a function.

Recent experiments have determined that a dopamine receptor may exist that is not cAMP-specific. This was discovered in animal studies measuring melatonin secretion. Melatonin is a chemical that has an active process in animal skin colorization. It was found that dopamine inhibits the production of melatonin. But when using dopamine antagonist drugs to increase melatonin synthesis it was found that the increase was not cAMP-dependent, suggesting that some other receptor than D1 is responsible for this process. This receptor has been designated D2. D2 receptors seem to work in the exact opposite fashion as D1 receptors, meaning that guanosine triphosphate (GTP) works to inhibit adenylate cyclase, which in turn inhibits cAMP synthesis. (Kebabian, 1983) D2 receptors have been found to be responsible for several other functions that are not D1 receptor-dependent including inhibition of the chemoreceptor trigger zone. Dopamine agonist drugs such as apomorphine and bromocriptine cause vomiting, while neuroleptics have antiemetic effects.

In studies using kainic acid microinjections within the striatum, which selectively destroys endogenous D1 cell bodies but spares the dopaminergic nerve terminals, a substantial loss of striatal dopamine-sensitive adenylyl cyclase activity was observed, but the procedure did not diminish the content of dopamine as measured with [3H]-antagonist binding assays. (Lee and Seeman, 1980.) Tritiated compounds such as [3H]-Haloperidol and [3H]-Spiroperidol compete with D2 receptor antagonists at post-receptor sites. It has been suggested that "the clinical potency in the schizophrenia of different types of neuroleptics correlates very closely with their D2 receptor antagonistic activity and their affinity for D2 receptors as measured by [3H]-antagonist binding." (Bradley, 1986) An additional study found that "the impressive correlation between the clinical, anti schizophrenic actions of neuroleptics and their blockade of D2 receptors labeled with [3H]-Haloperidol or [3H]-Spiroperidol is more striking than has been observed for any other biochemical effects of these drugs. It, therefore, seems likely that this action is intimately associated with the antischizophrenic effect of these drugs." (Creese, 1976) This study also found in relation to the motor effects of neuroleptics, "potency's of neuroleptics in competing for [3H]-Haloperidol binding correlates extremely closely (r>0.9) with their potency's in blocking apomorphine or amphetamine-induced stereotyped behavior." (Creese, 1976)

In reference to neuroleptic drugs a persistent question has been raised, if the immediate effect of the drugs is a post-receptor dopaminergic blockade, why is there a delay in the observed behavioral responses? One hypothesis maintains that immediate D2 receptor antagonism is not directly responsible for the antipsychotic effects of these drugs. Neuroleptic drugs may be mediated by secondary processes that are time-dependent. Two such possibilities have been considered. (1) Slow induction of depolarization block of dopamine neurons by neuroleptics. (2) Homeostatic receptor changes involving dopamine autoreceptors. Recent electrophysiological studies in animals indicate that in A10 neurons (the origin of the mesolimbic pathway) antipsychotic drugs produce a slowly developing depolarization block, which has a greater effect in reducing dopaminergic transmission than the initial dopamine receptor antagonism. (Ashton, 1987)

There has been a monumental effort recently to discover new neuroleptic compounds that are effective as selective receptor blockers that have good anti schizophrenic efficacy but that do not create extrapyramidal side effects. For example, it has recently been found that certain stereoisomers have potent active antipsychotic effects that are isomer specific. For example, recent evidence has shown that for many phenothiazines and thioxanthenes, which inhibit the dopamine stimulated the formation of cAMP, that only the (+) isomer of butaclamol and the alpha isomer of flupenthixol have dopamine antagonist activity, and only these isomers have antipsychotic effects. (Iversen, 1981) Isolating specific isomers in the battle against schizophrenia has produced some exciting new research efforts including computer modeling of hypothetical compounds that may mimic the action of known dopamine agonists and antagonists. The hope of this research is to discover new and better dopamine specific drugs and to reduce as far as possible extrapyramidal motor syndromes.

The Protest

Actual experimentation has been devised to test hypotheses related to dopamine depletion, receptor changes, and resultant motor behaviors in animals. The procedure, known as the protest, has been devised to test motor actions of rats subjected to dopaminergic agonists or antagonists after specified extrapyramidal system lesions. Hypothesis: if post-receptor Super sensitivity occurs after the destruction of endogenous D2 cell bodies lesioned with neurotoxins such as 6OHDA or kainic acid, will the animal turn contralateral to the lesioned side, ipsilateral to the lesioned side, or neither? The expected result would be that the lesion should cause a depletion of dopamine on the lesioned side resulting in turning that is dependent upon the non lesioned side. Therefore, the animal should turn ipsilateral to the lesion. (Hemisphere-specific.) However, in an attempt to maintain some sort of homeostatic balance, the post receptors on the lesioned side should produce either numerical increases in receptors or affinity changes to compensate for a lack of dopamine content, then over time, the animal should turn ipsilateral to the non lesioned side. This suggests that the turning is a direct result of receptor changes even with a reduced quantitative amount of endogenous dopamine within the lesioned extrapyramidal hemisphere. The results of an experiment conducted to test a similar hypothesis resulted in the following conclusions. (1) Behaviorally super sensitive rats show a 20-120% increase in [3H]-Haloperidol on the lesioned side compared to their own contralateral unlesioned side. (2) Rats that do not turn display essentially any augmentation in binding on the lesioned side. (3) The occurrence of enhanced dopamine receptor binding in association with behavioral supersensitivity indicates that the increased number of receptor sites may, in part, account for the behavioral effect of the lesion. (Creese, 1978)

Protest procedures testing receptor activities within the extrapyramidal motor system with experimental drugs such as (3-(3-Hydroxyphenyl)-N-n-propyldiperidine, (3-PPP), a drug that is not D2 receptor-specific, or cAMP-dependent, produced turning that could not justify current models of receptor supersensitivity and created serious doubts concerning the excessive dopamine theory. This prompted neurologists to inquire into the