WEEK 1 - Flashcards
WEEK 1
The course has two main themes:
- Non-medical drug use & addiction
- How initial use of a drug may lead to abuse, and possible addiction
- What distinguishes drugs from other enjoyable things (e.g., food)
- Why some people are more vulnerable to addiction than others
- What the consequences of drug use, abuse and addiction are for the individual and society
- How to manage or treat the negative consequences of these behaviors
- Medical use of drugs to treat mental illness
- How drugs are used to treat serious disorders such as schizophrenia, depression, manic-depression, severe anxiety, and addictive disorders
- What drugs can tell us about the causes of these disorders
- The pro’s and con’s of drug treatment
- Similarities and differences between non-medical and medical drug use
Drug use influences and is influenced by __________ which of the following factors.
Socio-cultural (e.g., ethnicity), Sub-cultural (e.g., university students), AND Cellular (e.g., nerve cell)
Pharmacology
The formal study of drugs is called Pharmacology.
The term Psychoactive describes a property of certain drugs. It means that the drug has the ability to alter thoughts or feelings.
This course deals strictly with the small group of drugs that are psychoactive.
For the sake of simplicity throughout this course, we will be using the term “drugs” to refer to “psychoactive drugs,” with the knowledge that, in fact, we are referring to a small sub-group of drugs.
It may surprise you to know that most, if not all, of us (myself included) are drug users - psychoactive drug users. If you have ever had a cup of coffee you are a drug user. Caffeine is a psychoactive drug that acts as a stimulant to our central nervous system.
Even if you only use “natural” preparations, like ginseng or gingko, you are still a drug user. These herbs meet all the formal criteria of a drug.
Drug Abuse and Drug Dependence
It is important to distinguish between drug use, drug abuse and drug dependence. Drug use is something we all engage. It involves use of a drug that entails few if any negative consequences. For reasons we will discuss later, the lack of consequences implies that our drug use is low in frequency and low in quantity per occasion (dose).
When we use a drug frequently or at high doses, we will often experience negative consequences (e.g., irritability from too much caffeine, hangover from too much alcohol). If we continue to use a drug in this manner, despite these consequences, we have moved from drug use to drug abuse.
When frequent or heavy use of a drug continues for some time, our bodies come to expect the drug as part of the normal chemical balance.
Eventually we become less sensitive to the drug (e.g., it takes 2 or 3 coffees to wake up, or 4 or 5 beers to relax).
This loss of sensitivity is referred to as “tolerance,” and it is one of three defining features of drug dependence.
A second feature is referred to as “withdrawal” a disturbance in biological functioning that occurs when the individual does not receive his or her usual dose at the usual time.
Withdrawal is usually accompanied by unpleasant physical and emotional symptoms. For example, a caffeine-dependent individual would likely experience headache, confusion, and depression during withdrawal.
An alcohol-dependent individual would experience tremors, intense anxiety, hallucinations, and possibly seizures during withdrawal.
A final feature of drug dependence is pre-occupation with thoughts about the drug, particularly where and when you will get your next dose.
Drug dependence is the most extreme form of involvement with a drug and comes closest to the concept of “addiction.”
Drugs vary greatly in the frequency and amount of use required to give rise to dependence.
It may take years for a person to become dependent on alcohol, even if he or she drinks quite heavily.
On the other hand, it may take only months or weeks to become dependent on nicotine, the psychoactive ingredient in cigarettes.
By the time a person is smoking daily - even if it’s only one or two cigarettes - they will likely display some of the hallmark symptoms of nicotine dependence.
What motivates a person to start using a drug in the first place?
The most common reason people start using drugs is modeling: we see other people using a drug and enjoying it, and we decide to try the drug ourselves.
The most influential models are our peers - people like us.
They exert a powerful influence on us (sometimes without our awareness), usually because we not only want the positive effects of the drug, but also because we want the positive effects that result from adopting drug use behavior.
In other words, drug use is a form of conformity (behaving in accord with a socially-prescribed group standard) as well as a means of affiliation (a way to make friends).
Why do people continue to use a drug after they have tried it?
The same factors that promote initiation also promote continuation of drug use.
However, there are usually intra-personal (i.e., within the person) as well as social factors involved in continued drug use.
The former director of the National Institute of Drug Abuse, Alan Leschner, stated that there are basically two reasons why people use drugs:
“To feel good, and to feel better.”
The average person experiences a rating that varies from 4 - 6 out of 10, where 10 is the happiest possible, and 0 means completely unhappy.
Use of a drug can elevate the happiness rating of the average person from a 6 to an 8 or a 9, and can do so quite consistently. This is what Leschner meant by using a drug “to feel good” rather than just average or normal.
A substantial minority of people are chronically unhappy.
The reasons for this unhappiness may be social, economic, psychological or medical. For these individuals, a typical happiness rating might be 1-3, or quite unhappy.
Under these circumstances, use of a drug can elevate the happiness rating from 3 to 5 or 6 - that is, into the average or normal range for the majority of people. This is what Leschner meant by using a drug “to feel better.”
Notice that in both of the examples above, the direction and amount of change in the happiness ratings produced by the drug was the same.
However, in the first case the drug made the person better than normal whereas in the second case, the drug simply reversed a pre-existing deficit.
These two motivations for drug use correspond precisely to the two basic motivations for All behavior: Positive Reinforcement and Negative Reinforcement.
What is Positive Reinforcement?
Positive reinforcement refers to the enhancement in happiness over and above some neutral state (e.g., eating an ice cream cone after a satisfying picnic lunch).
What is Negative Reinforcement?
Negative reinforcement refers to the restoration of a neutral state from some deficient state (e.g., eating a picnic lunch when you have not eaten all day and are very hungry).
In simple terms, positive reinforcement can be described as “reward,” and negative reinforcement can be described as “relief.”
Positive reinforcement and negative reinforcement are not mutually exclusive; we still enjoy the taste of our sandwich - the pure pleasure of it - when we are eating due to hunger.
However, these two motivations can predominate as a reason for drug use in a given individual.
So, most people are motivated to use drugs both for reward and for relief.
However, Sylvia may use drugs primarily to for reward, whereas Gwen uses drugs primarily for relief.
Most evidence suggests that use of drugs or alcohol primarily for negative reinforcement is a greater risk factor for eventual addiction than use of these substances primarily for positive reinforcement.
This is because the drug-free state is unpleasant to the negative reinforcement seeker, while the drug-free state is at least tolerable, if a bit blasé to the positive reinforcement seeker.
As a result, when a person finds that a drug is an effective negative reinforcer (i.e., relieves unhappiness), they may come to rely on it to escape their unhappiness.
That is, the negative reinforcement seeker may come to rely on the drug for relief from unhappiness.
This reliance often develops before the person is actually “dependent” on the drug in the sense we referred to above.
The belief that one needs a drug in the absence of a physical requirement for that drug is termed “psychological dependence.”
This can be distinguished from the conventional form of dependence described above (i.e., tolerance, withdrawal, pre-occupation), which is often termed “physical” or “physiological” dependence to reflect the disturbance in bodily functioning associated with this more extreme level of drug involvement.
Cybernetic Model of Drug Use
We have noted that drug use conforms to the same basic principles as other behaviors: we use drugs because they increase our pleasure (bring reward) or decrease our displeasure / pain (bring relief).
From these basic principles, we can define a general model that predicts and explains when and why we will use drugs.
The term used to describe this model is “Cybernetic,” a term that, like Pharmacology, derives from Greek.
The term “cybernetic” means:
guidance
The cybernetic model assumes that every individual has some Optimum Internal State or Standard - that he or she is motivated to attain or maintain.
For example, if I feel an itch, that experience indicates a Deviation from my optimum internal standard.
When I experience this deviation from my ideal standard, it motivates me to do something - in this case, scratch my skin where the itch has occurred.
The act of scratching then reduces the feeling of itch, restoring my subjective state - what I am experiencing - to its optimum ideal.
In terms of the model, the itch = A Signal, which indicates deviation from my ideal.
This signal initiates scratching = A Response designed to reduce this deviation.
When the itch is gone, my body receives a second message (the absence of itch) indicating that I have returned to my internal optimum = Feedback that turns off the scratching response.
These 4 elements -
- internal standard,
- signal (of deviation),
- response, and
- feedback,
Guide my activity at all times. They enable me to be a self-regulating organism (hence the term “Cyb-org”).
How does the Cybernetic Model apply to drug use?
signals –> response –> feedback
Depression, anxiety, and boredom are all Signals indicating a deviation from the internal ideal standard.
Drug use is a Response that reduces deviation from the ideal standard.
The drug effect then creates a new state of consciousness that more closely approximates our ideal (i.e., is happy, calm or entertained), which sends Feedback saying we have restored our system to its standard.
The more effective the drug is at “scratching our itch” - be it depression, anxiety or boredom, the more likely we are to use drugs again.
Alternatively, if we are feeling normal or okay, and take a drug that makes us feel better than okay, this experience can Change Our Standards of what is Ideal.
As a result, when we are feeling okay, we may still experience a Signals indicating deviation from our standard, which is now set at “Better Than Okay.”
We then use the drug again, to re-attain our New standard.
If the drug effect achieves this, the Feedback tells us, we can stop using the drug (i.e., stop scratching our symbolic itch) for now.
In short, drug use is a very effective means of self-regulating our internal states to minimize deviations from our internal standard.
Scratching an itch, eating a meal, or taking a drug all serve the same purpose in cybernetic terms, they restore the organism to its ideal subjective state.
Drugs are especially likely to be used cybernetically because:
(a) they directly alter consciousness (i.e., feelings of happiness, sadness, pleasure, or pain),
(b) they are very reliable (i.e., we can count on them to do what we hope they will), and
(c) they require little effort on our part (i.e., unlike exercise, meditation or therapy, for example, we don’t have to work to get a drug effect).
The effect of a drug (increased pleasure, decreased pain) most closely corresponds to _____ component of the Cybernetic Model.
the feedback: The drug effect provides feedback to the organism indicating that the deviation from the standard has been removed; that is, that the optimum subjective state has been restored
The Effects of Drug Use
If drugs are such effective cybernetic tools, why is drug use such a problem?
Unlike non-drug reinforcers (e.g., food, sex, sleep, meditation), many drugs induce a reaction in our body, which compensates for the drug effect.
So if a drug increases our pleasure by 3 happiness points, the body may compensate by taking away 2 happiness points.
Example
the initial effect of the drug elevates our happiness rating from 5 to 8.
The body’s response is to reduce our happiness rating from 8 to 6
When the drug effect wears off, we are left in a deficit position - we are at 3 instead of 5 in terms of happiness.
This effect is what accounts for a hangover the night after heavy drinking, the edginess or irritability we experience 3-4 hours after a strong cup of coffee, the decreased concentration and anxiety we experience 1-2 hours after a cigarette.
It is not clear why the body compensates for drug effects in this way, while not compensating for other kinds of rewards.
Perhaps it is because drugs directly access structures in the brain that are designed to regulate how much pleasure we feel, i.e., the emotional thermostat, which then moves in the opposite direction to keep our happiness quotient in balance.
Whatever the reason, the effect is clear: the body’s compensatory response to the drug creates a Further Deviation from our optimum internal standard - we are now at a 3 instead of 5 in terms of happiness.
This deviation then motivates Further Drug Use, designed to restore the optimum.
Thus, whether we initially use drugs to reduce displeasure/pain or to increase pleasure, we end up using drugs to reduce displeasure/pain brought on by the compensatory response of the body.
This is the Vicious Cycle of Drug Use.
It accounts for many fundamental features of addictive behavior and it also predicts which substances will be “most addictive.”
Effects depending on the drug:
Crack cocaine:
the initial effects of smoking a bowl of crack cocaine = sharp increase in happiness
sharp decrease in happiness as the drug effect wears off
Notice that happiness is now below the level it started at
This deficit will motivate further cocaine use.
Coffee:
increase in pleasure is much more modest
and the deficit that follows when the caffeine effect wears off is also more modest.
The motivation to drink more coffee is much more modest than the motivation to smoke more cocaine
he extent to which a drug creates a “high” is directly related to the degree of compensatory “low” produced by a drug
The more extreme the pattern of highs and lows, the greater is the so-called Abuse Liability of the drug.
Recall that drug abuse involves re-administration of a drug despite the consequences.
drugs with high abuse liability will promote drug re-administration because the compensatory “low” of the body to them is so unpleasant the user does not care about the long-term consequences. All that matters at this time is Relief.
How does the compensatory response of the body to a drug alter the elements of the Cybernetic model?
It increases the deviation between the current subjective state and the internal standard and It increases the strength of the signal that motivates behavior
Summary WEEK 1
Jim is anxious in social situations. He often has a couple of beers to make him feel more comfortable before going to a party or dance. The primary effect of beer for Jim is?
negative reinforcement
Drug X has greater abuse liability than Drug Y. In terms of the happiness curve, drug X is associated with _________ than drug Y.
a higher maximum value and a steeper slope
WEEK 2
MODULE 2 History of Recreational Drug Use; History of Medicinal Drug Use
Introduction
This module will examine patterns of drug use.
The focus of this week is the history of non-medical and medical drug use and the understanding of drug use in evolutionary terms.
What distinguishes the rat (being given cocaine) from the man smoking?
The human is aware of his drug self-administration behavior
Humans and animals have the same key structures in their brains that respond in the same ways to most psychoactive drugs. Both humans and animals are equally vulnerable
Self-awareness
Self-awareness is a blessing to human drug users because it enables us to catch ourselves when we are at risk of administering a drug (i.e., when we are about to “fall off the wagon” when we’re trying to abstain from smoking or drinking).
Self-awareness is a curse to human drug users because in some cases, the compulsion to use the drug may be so overwhelming that we do so despite our awareness that we shouldn’t.
The brains of humans and all vertebrate animals contain structures that are “dedicated” to the experience of pleasure.
These structures become activate when we eat food, drink water, engage in sex, or awaken from a good night’s sleep.
Our brains hardwired to enjoy and to repeat certain behaviors.
Collectively, the brain structures responsible for these effects are called The Limbic System.
In humans, these structures form a branch or Limb connecting the primitive regions of the brain with the more advanced regions of the brain.
Widespread use of psychoactive drugs (apart from alcohol) first began?
Several thousand years BC
Psychoactive drugs appear to have been used in a variety of civilizations since the earliest days of recorded history.
“The deliberate seeking of psychoactive experience is likely to be at least as old anatomically (and behaviourally) as modern humans: one of the characteristics of Homo sapiens sapiens” Sherratt, 1995, p. 33).
Where do the vast majority of non-medical psychoactive drugs come from?
Plants are the largest source of the psychoactive chemicals in non-medical drugs
Marijuana and hashish come from the cannabis plant (temperate regions worldwide)
nicotine comes from tobacco (North and South America)
cocaine comes from the coca leaf (South America)
heroin, morphine and opium come from the opium poppy (Asia)
alcohol comes from fermented fruit and vegetables (temperate regions worldwide)
LSD and magic mushrooms come from fungi
Why should some drugs possess psychoactive properties?
From an evolutionary standpoint, this would increase the chances of animals eating them as opposed to other plants.
Why is this good for a plant?
Because animals can move around, whereas plants cannot. As a result, animals can transport plant seeds wherever they go, and deposit them widely (along with natural fertilizer to help ensure their growth).
Thus, an inter-dependence appears to exist between plants and animals that increases the likelihood of animals eating plants containing psychoactive chemicals, which in turn increases the chance of survival of those species of plants.
In summary
animals and humans have a built-in capacity to enjoy psychoactive drugs
These drugs are often naturally occurring and are widely distributed worldwide
Humans and animals likely too, have been ingesting psychoactive drugs in plant form since the earliest days of civilization.
This pattern of use also serves a valuable purpose for plants
These trends suggest that to some degree, use of psychoactive drugs may represent a natural behavior, or a “Fifth Drive.”
The problems with drug use - that is when it ceases to be adaptive, is:
when it is removed from a context that serves to restrain the level of use (e.g., chewing coca leaves to sustain energy while working)
when the chemicals in drugs are synthesized to much more potent forms that vastly increase the highs they produce (and subsequent lows), paving the way for abuse and addiction
The History of Non-Medical Drug Use
Alcohol
The earliest reports of alcohol use come from Egypt and Mesopotamia (present day Iraq) 4000 years BC
These civilisations discovered beer, which probably first resulted from fermented grain stored in granaries with little air or light
The ancient Greeks and Romans began the practice of wine making by fermentation of dates and grapes in 1000 BC, much as we do today
A similar process was used to create a wine called Mead from honey by medieval Europeans in the early centuries AD.
Other Psychoactive Substances
Marijuana
The plant, cannabis sativa, was first cultivated in present day Romania, the Caucasus (a mountain range in present day Russia), and China around 3000 BC
These civilisations found that it was useful in making hemp, a sturdy fibre for rope and clothing.
Smoking hemp was a common practice among sailors in these regions who had large quantities of rope onboard during their voyages.
A mixture of cannabis, ephedra, and papaver, known as Soma was synthesised in India around 1000 B.C.
This concoction had some of the mildly hallucinogenic effects of hemp coupled with the stimulant effects of ephedra - and euphoric effects of papaver (a derivative of the opium popium)
This combination of effects provided a unique experience to Soma users enabling them to experience dream-like pleasures without falling asleep.
Opium
The opium poppy was first cultivated by civilisations in the Middle East and China around 2000 B.C
Opium is a potent heroin-like drug that is particularly addictive when smoked
Like heroin and morphine, opium possesses strong pain-killing properties and also slows down the activity of the intestinal tract.
As a result, opium was widely used not just recreationally, but also as a medicine to soothe pain or treat diarrhoea and dysentery, a disease that kills by diarrhoea-induced dehydration
Tobacco
This crop was cultivated, chewed and smoked by indigenous tribes in North and South American long before the arrival of the Europeans to the Americas.
Its combined stimulant and anti-depressant effects made it useful for maintaining energy and long hours of work under difficult physical or climatic conditions
It was introduced to Europe by Sir Walter Raleigh in the late 16th - early 17th century.
Peyote and Mescaline
These hallucinogenic drugs were derived from cacti and were used by ancient inhabitants of Mexico (Aztecs) and central America (Mayans) as early as 2000 BC.
Some North American tribes still use these drugs as a means of achieving contact with the Spirit world, and are granted legal access to them for religious purposes.
Cocaine
Has been used by indigenous South Americans for several 1000 years.
Chewing of coca leaves provided energy for difficult agricultural work in the low oxygen air of the Andes mountains in Peru
Cocaine was introduced to North America in the 19th century.
Its initial use here was as a topical painkiller in dentistry, and was later replaced by a synthetic version, called novocaine.
When alcohol was outlawed during the 1920’s prohibition, cocaine became a popular substitute because it was difficult to detect.
This shift in drug use practices led to an increase in smuggling and the deliberate use of cocaine to create addiction and manipulate women into prostitution.
Cocaine and derivatives of opium (e.g., laudanum) provide an example of how medicinal use of drugs in Europe and North America in the 19th century made a transition to recreational use and eventual abuse outside the contexts (to facilitate work, treat disease) that otherwise constrained their levels of use.
Religious Prescription: drugs as religious sacrament
Over the course of history, organized religion has played a key role in establishing standards of “appropriate” drug use.
These guidelines remain with us today in the form of social “norms” - unwritten rules of how drugs should be used.
It is not surprising that drugs should have found a role in religious practice, given their ability to transform consciousness.
These uses range from the symbolic (i.e., a sip of wine in the Communion ritual) to the biologically relevant (i.e., ingestion of hallucinogens to commune with God)
Regardless of the purpose of the drug use, the circumstances (when, where, how much, by whom) of use were clearly defined in these religious rituals.
This set of rules almost always aimed to prevent excessive use - i.e., gross impairment or intoxication.
As such, they served as a governor on excessive drug use.
Some examples of religious ritual use of drugs
Wine
- Judaeo-Christian religions have used small amounts of wine to bless significant religious events.
- Communion is the clearest example in Christianity.
- The drinking of wine to welcome the Sabbath and during the festival of Passover are examples of prescribed alcohol use in Judaism.
Marijuana
- Central and South American religions use marijuana for similar purposes.
- The dose and manner of consumption are carefully controlled, and the smoking occurs under prescribed conditions.
Peyote
- Some Aboriginal Americans (First Nations peoples) eat peyote buttons, derived from cacti, to achieve hallucinogenic experiences, similar to, but milder than, those induced by LSD
- The term “Psychedelic” has been used to describe the “mind-manifesting” properties of such drugs
- It is the belief of those who use peyote and similar hallucinogens for sacramental purposes that they can induce mystical states in which the person has direct contact with the divine
- Experimental evidence on the effects of psychedelic mushrooms in seminary students supports their ability to create bona fide mystical states of consciousness
- The use of peyote in a communal context helped to ensure that the drug was not abused, but instead used “instrumentally” - that is - as a tool to achieve communion with others, with nature and with God.
Tobacco
- Although the low doses of tobacco typically consumed as cigarettes do not possess hallucinogenic properties, at high doses, tobacco can alter consciousness in a manner similar to LSD
- However, most smokers would experience a toxic reaction (e.g., heart attack, seizure) before they felt these hallucinogenic effects
- Tribal leaders in South America, known as “shamans” or medicine men, appear to possess the ability to ingest these very high doses, due largely to tolerance (decrease in the response to a standard dose) acquired from years of heavy tobacco use.
- For these shamans, one cigarette might produce the same effect as one puff for a regular cigarette smoker.
Caffeine
- While the South Americans used tobacco, indigenous tribes in central Africa ate Kola nuts, containing caffeine.
- The stimulant effect of the drug facilitated rituals involving dancing and song, again, in the context of well-defined rules.
Religious Prescription: drug use as “intemperance”
A prescription is an order to do something (e.g., to take a drug).
A proscription is an order to NOT do something (e.g., to not take a drug).
Just as religions have served to promote moderate drug use in the context of specified rituals, they have also acted to restrict drug use outside these ceremonial contexts.
Religious Prescription: Alcohol
Western religions view excessive use of alcohol as undermining our “humanity.”
Since we are made in God’s image, alcohol intoxication can be seen as befouling this state.
Not surprisingly, there are strong social prohibitions against excessive drinking in Judaism and Christianity.
In Islam, any alcohol is seen as compromising the ability to connect spiritually with Allah.
As a result, observant Muslims are expected to abstain from alcohol (and all other drugs).
Historically, the social carryover effects of religious attitudes towards alcohol have varied widely.
When organized religion was influential (14th century AD), attitudes towards excessive drinking were similarly negative.
When religion was less influential (18th century AD), attitudes towards excessive drinking became more lax.
The Women’s Christian Temperance Movement was a socio-cultural force in the early 20th century.
It asserted that alcohol debased the mind and soul, enabling the devil to infiltrate an otherwise devout individual.
Advocates of this movement argued for complete abstinence from alcohol and played a role in the bringing in of prohibition laws (outlawing alcohol use) in the US in the 1920’s.
Religious Prescription: Opium
In the East and particularly, China, opium was the most widely used drug, and therefore, the most likely drug to be abused.
Laws restricting the sale and use of opium were an economic tool used by Britain to retain control over its colonies (i.e., Hong Kong)
The ability to achieve large profits from opium trade would give considerable economic power to the native Chinese, which Britain opposed.
Thus, commerce rather than religion drove the restriction of opium use in the East.
Caffeine
In continental Europe, an alternative to alcohol emerged - coffee.
Excessive use of this drug was rare due to its mild psychoactive properties and its unpleasant side effects at high doses.
For many, coffee thus became the “sober” social drug.
The coffee shops that today line our streets are the offspring of the coffee houses that have existed for decades in Europe.
Religious rules for the proper use of psychoactive drugs primarily serve to?
Prevent excessive drug use
These rules are designed to promote responsible use of drugs or temperance - a little pleasure, but not too much.
The History of Medical Psychoactive Drug Use
The 19th Century
Cocaine
In North America and Europe, cocaine was first used as a topical analgesic - one applied to the surface of the skin or gums - in dentistry.
In moderate doses it effectively numbed the tissue enabling gum surgery or tooth extraction, which would otherwise have been too painful for dental patients to tolerate.
Accidental or experimental inhalation of the ground powder would have produced the pleasurable “high” that is the familiar effect of cocaine we recognize today.
Because of its powerful addictive potential (high abuse liability), it was just a matter of time before such experimentation led to systematic use of cocaine for reward as opposed to pain management.
Cocaine also had a role in early psychiatric practice.
Like other stimulant drugs, cocaine activates parts of the brain and nervous system responsible for feelings of power and confidence.
Early psychiatric practitioners, particularly Sigmund Freud, became strong advocates for cocaine as a cure for “neurosis” - the pervasive doubt and low self-confidence typical of people who are depressed or anxious.
Only after experiencing the downside of cocaine (the crash), and the concomitant craving for more, did Freud realize the inherent dangers in cocaine.
Fortunately, at this point, he ceased to advocate its use in psychiatry.
However, by that time, the “genie was out of the bottle” and abuse of cocaine for pleasure had begun.
The History of Medical Psychoactive Drug Use
The 19th Century
Nitrous Oxide
Nitrous oxide - or laughing gas - was also used to alleviate dental pain.
Because it was harder to distribute, initial abuse of nitrous oxide than cocaine was likely restricted to dentists or their assistants who had ready access to the gas.
The doctor in the film/book, The Cider House Rules, by John Irving provides an illustrative example of how nitrous oxide could be abused to escape into reverie for a time.
The History of Medical Psychoactive Drug Use
The 19th Century
Morphine
The term “morphine” comes from the Greek term “morpheus” - to dream.
The powerful analgesic effects of this opium derivative were first extensively utilized in the latter part of the 19th century.
The American Civil War left many soldiers maimed and suffering from chronic pain.
Morphine was often prescribed to manage this pain.
The sheer numbers of soldiers injured and receiving morphine contributed to its unintended transition into recreational use and abuse.
Like cocaine, its powerful addictive potential and abuse liability led many of those who experimented with it recreationally to quickly become dependent.
The power and confidence produced by cocaine resulted from its _____effects on the brain and nervous system
stimulant
The History of Medical Psychoactive Drug Use
The 20th Century
Amphetamine
A number of related chemicals, called amphetamines, were synthesized in the early 20th century for the treatment of respiratory ailments, like asthma.
The stimulant effects of these drugs resulted in their application to the treatment of sleep disorders such as narcolepsy (a tendency to fall asleep quickly and involuntarily).
The appetite suppressing of these drugs led to their use in situations where energy was required for long periods but eating was not practical, specifically fighting in trenches in the First World War.
Amphetamines have many of the same psychoactive effects as cocaine, and the proliferation in their abuse was similarly rapid.
The History of Medical Psychoactive Drug Use
The 20th Century
LSD
LSD was unintentionally synthesized in the late 1940’s.
Its powerful psychedelic or “mind-manifesting” properties led psychiatrists at the time to consider its use as a means of rapidly accessing unconscious concerns that otherwise took years to reveal in therapy.
However, the very rapidity of its effects, made it rather uncontrollable, often causing intense confusion and mental disturbance rather than insight.
he US and the Soviet Union were locked in the Cold War at that time, with each side attempting to gain an advantage over the other.
LSD’s mentally disruptive effects coupled with its extreme potency - a half teaspoon could produce a full-blown “trip” in the entire population of New York City - led the US secret service to consider its use as a means of “chemical warfare” against the Soviets.
Distribution of the drug into the drinking water could throw the Soviet citizenry into confusion and thereby facilitate a US attack.
Experiments conducted during the 1950’s document the perils of LSD use
By the 1960’s LSD had become a popular tool of youth to achieve altered states of consciousness, and leaders of the counter-culture, such as Timothy Leary and Ken Kesey, advocated its use.
The History of Medical Psychoactive Drug Use
The 20th Century
MDMA
MDMA or Ecstasy has a similar story.
This amphetamine derivative was first synthesized with the other amphetamines in the early part of the 20th century.
However its apparent lack of therapeutic effects caused it to be shelved for the next half century.
By the 1970’s psychiatrists had begun to experiment with the use of MDMA as a means to facilitate open communication in marital therapy.
The ability of the drug to produce strong feelings of empathy and understanding led to its abuse by a small underground contingent in Europe at that time, which burgeoned in the 1980’s.
By the 1990’s Ecstasy use had become widespread - most often in the context of Raves - or all-night dance parties.
At the turn of the 21st century, Ecstasy use had escalated dramatically - even outside the Rave scene
Unlike LSD, MDMA appears to have the potential to cause brain damage
By the end of the 20th century the toxic effects on brain tissue and mental function were well documented
Unfortunately, the popularity of MDMA persists despite the mounting evidence of irreversible brain damage.
The continued use of Ecstasy in the face of this evidence provides a powerful illustration of how the reinforcing effects of a drug promote its continued use, despite the consequences - the hallmark feature of “abuse.”
Psychotropic Drugs - Treatment of Mental Illness
Chlorpromazine & Schizophrenia
Prior to the 1950’s, treatment of schizophrenia consisted of ice baths, massive doses of sedatives, electro-shock therapy, and in extreme cases, surgical removal of brain tissue (lobotomy).
None of these treatments had any reliable effects in schizophrenia, a devastating disease whose symptoms included delusions (beliefs not based in consensus reality) and hallucinations (sensory experiences with no physical source - e.g., hearing voices)
As a result, hundreds of thousands of patients with schizophrenia lived in state or provincial institutions, as there was no way they could function in general society.
However, a landmark discovery occurred in Paris in 1950 that would drastically change this scenario.
A scientist named Laborit was testing the effects of anti-histamines in rats in an effort to discover ways to reduce allergic reactions.
He noted that one of these drugs produced a form of “artificial hibernation” - powerful sedation in his animals.
He considered that this drug, chlorpromazine, might be effective in managing schizophrenia without resorting to massive dosing.
To his surprise and that of the entire medical community, chlorpromazine not only effectively calmed patients with schizophrenia; it actually reversed their delusions and hallucinations.
Almost overnight, individuals who for years were plagued by thoughts of persecution and inner voices were “restored to sanity.”
The drug, chlorpromazine was the first formal anti-psychotic medication.
The term “anti-psychotic” refers to the reversal of psychosis - or thought disorder - that typifies schizophrenia
Although anti-psychotic medications are used for purposes other than treating schizophrenia, the alleviation of thought disorder is their defining feature.
De-Institutionalisation
Because of the remarkable effectiveness of chlorpromazine, huge numbers of patients who for years had lived in locked hospital wards were quickly granted freedom.
Unfortunately, although the drug alleviated their symptoms it could not replace the years of socialization, education and work experience they had lost during their hospital stay.
As a result, most of these people were unable to find jobs and thus became indigent.
To this day, the vast majority of homeless people suffer from schizophrenia.
The stress of life on the street, or the false promise of sustained normalcy that arose when patients took chlorpromazine often led to relapse, and re-institutionalisation
In the first case, stress aggravated the brain systems that were disturbed in schizophrenia causing a breakthrough of symptoms and a need for heavier dosing
In the second case, the clarity of thought produced by chlorpromazine made patients wrongly believe they were cured, and to stop taking the medication.
In either case, it quickly became apparent that chlorpromazine was not the panacea, or cure-all, for schizophrenia that people first believed.
In the decades since de-institutionalisation, new steps have been taken (group homes, sheltered work shops, community mental health centres) to provide a support structure for people with schizophrenia.
These steps reflect the growing recognition that treatment of psychiatric symptoms by a drug is only a small piece of the problem of mental illness.
Lithium and Bipolar Disorder
Around the same time of Laborit’s discovery, another Frenchman identified a drug that had the ability to prevent deviations in mood.
While investigating immune reactions in rats, Cade found that a simple salt, lithium carbonate, exerted a strong stabilizing effect on activity and emotional responses in his animals.
The normal agitation or freezing that rats typically exhibited under stress were quickly abolished by this drug.
Based on this finding, lithium was adopted as a treatment for bipolar affective disorder, which at that time was called manic-depression.
Bipolar disorder involves extreme mood swings from exhilaration to exhaustion and thoughts of suicide.
These were effectively counteracted by lithium so that the patient’s mood did not get too high or too low.
Although lithium was very effective, it could also be toxic if levels accumulated in the blood stream.
For this reason, close monitoring of patients in lithium treatment was required.
As in the case of chlorpromazine, lithium alleviated the symptoms of bipolar disorder but did not cure the disease.
Thus, patients receiving lithium typically continued to take it throughout their lives.
Mono-amine Oxidase Inhibitors and Depression
In the 1950’s, doctors searching for a cure for tuberculosis ran some experiments on patients who were housed in sanitaria.
Because these patients were isolated they often experienced bouts of depression.
During the course of the experiments, the mood of the patients receiving the experimental treatment began to lift.
Their tuberculosis symptoms, ironically, remained unchanged.
Based on these observations, the doctors considered using the experimental drugs to treat depression in patients without tuberculosis.
In line with their suspicions, the drugs worked and the first bona fide treatment for clinical depression was born.
If schizophrenia represented the cancer of the mind, depression represented the common cold.
It was extremely prevalent, occurring in about 15% of all people over the course of their lives.
At the same time, left untreated, the symptoms typically resolved spontaneously after about 6 months.
Nevertheless, the symptoms of depression could be very disabling
These included disturbances of sleep and appetite, emotional sensitivity, intense sadness, and most troubling, thoughts of hopelessness and suicide
Because of the real threat of suicide in depressed patients, it was not acceptable to “wait out” the 6-month cycle of depression.
A treatment was needed to control the symptoms until the body’s natural emotional rhythms returned to normal.
The mood-elevating drugs used in tuberculosis patients, called mono-amine oxidase inhibitors (MAOI’s) made drug treatment of depression possible.
Like chlorpromazine and lithium, the MAOI’s were not without their downside.
Because these drugs acted to disturb the function of critical enzymes in the brain and body, the role of these enzymes as catalysts was disturbed.
In particular, the ability to digest dairy products was lost, turning milk, cheese and yoghurt into poisons that the body could not metabolise
As a result, patients taking MAOI’s had to adopt a strict diet that excluded dairy products and other common foods or drinks (e.g., red wine)
The possibility of a toxic reaction made eating in restaurants or other unfamiliar venues hazardous
At the same time, residual symptoms of depression - like suicidal feelings - in patients receiving these drugs could lead to deliberate consumption of forbidden foods to induce the toxic reaction.
Thus, while the MAOI’s provided valuable relief to the clinically depressed, they had inherent risks.
Benzodiazepines and Anxiety
Collectively, anxiety disorders such as generalized anxiety, phobias, panic, and post-traumatic stress disorder are the most prevalent form of mental illness - accounting for nearly half of all psychiatric referrals.
Prior to the 1960’s these disorders were treated primarily with drugs called barbiturates.
These drugs were sub-optimal because they were highly addictive due to their potential for euphoric effects at high doses, and rapid development of tolerance at therapeutic doses.
In addition, barbiturates were extremely dangerous because of a high risk of accidental overdose, particularly when combined with alcohol.
A clear need existed for a medication to manage anxiety without these risk factors.
Hundreds of experimental trials were run in the laboratories of Hoffman-LaRoche, a large pharmaceutical company.
During these trials, the chemical compounds synthesized consistently failed to work
The chemists who developed these compounds noted a crystalline residue that was a frequent by-product of their experiments.
After years of discarding these “pretty crystals,” the lack of success with the intended compounds led to the suggestion of using the by-products.
The crystalline substance, chlordiazepoxide, trade name Librium, was introduced in the late 1950’s as the first benzodiazepine for the treatment of anxiety.
This drug was much safer than barbiturates, had lower risk of abuse and addiction, and effectively reduced anxiety without producing undue sedation.
It was soon replaced by an even more popular drug, diazepam, trade name, Valium
The effectiveness and safety of Valium for the management of anxiety, led doctors to begin to prescribe it as a way to pacify day-to-day stress in people without clinical anxiety disorders
By the mid-1960’s the little yellow pill had thus become known as “Mother’s Little Helper,” for its widespread use as a lifestyle aid
To this day, benzodiazepines collectively remain the number 1 prescribed psychoactive drugs
In the years since their advent, there has been a growing recognition of the subtle risks of these drugs.
First, they reliably impair memory, making it difficult for people who take them on an ongoing basis to retain new information.
Second, some benzodiazepines have abuse liability and can be used to produce euphoria rather than to manage anxiety.
Third, tolerance will develop to these drugs, requiring increased dosing and eventual dependence, particularly when they are used as a sleep aid.
Such dependence is revealed when people try to get off the drugs and experience rebound increases in anxiety well above their original levels.
Benzodiazepines also appear to disinhibit behaviour leading to a paradoxical increase in aggressive or impulsive behavior in patients using them.
Finally, these drugs operate on a chemical system that is also affected by alcohol, so that even social drinking can produce extreme intoxication.
Like barbiturates, benzodiazepines can produce a toxic reaction when combined with large amounts of alcohol.
The psychoactive medications developed in the 20th century were ___________ effective in treating mental illness.
partially/sometimes dangerous but
Medical Psychopharmacology
The 20th century witnessed exceptional developments in the field of medical psychopharmacology.
However, in each case, the medications were limited in important ways - either in effectiveness or associated risk.
Because drugs require no effort on the part of the patient or the physician, they remain an attractive option to the time-consuming, often painful work of therapy.
Most research shows that the best results occur when medication and interpersonal therapy are combined.
The medical use of psychoactive drugs is the clearest case of negative reinforcement - continued use of a substance to relieve discomfort rather than to achieve reward.
The primary difference between the medications developed in the 20th century and those used in prior centuries was that 20th century medications, in general possessed less abuse liability.
This was a major step forward due to the potential for drugs to “cross over” from medical to recreational use.
The generally low rewarding effects of newer psychoactive medications provide a natural constraint on abuse.
The social norms and religious rules serve a parallel purpose in constraining levels of non-medical drug use.
Despite these constraints, the unique ability of psychoactive drugs to directly tap motivational structures in the brain gives them the ability to override conscious intentions (e.g., decisions not to use or to limit the dose taken).
As a result, initial use of drugs all too often escalates to abuse and eventual addiction.
The biological processes that underlie this escalation are the focus of the next two modules.
Summary
Learned that most psychoactive drugs originally come from plants
Discussed ways in which drug use is similar to the other 4 drive-based behaviors: eating, drinking, sex, and sleep
Proposed an evolutionary role of drug use
Considered the pervasiveness of drug use over time and across culture
Examined similarities and differences between non-medical and medical psychoactive drugs
Each of the following support the possibility that drug use is a fifth drive EXCEPT?
psychoactive drugs often lead to addiction
Discovery of most psychoactive drugs in the 20th century came about by?
accident
The consequences of de-institutionalisation indicate that ____________ .
drugs are usually not sufficient to produce ongoing mental health
environmental factors often interact with biological factors
compliance (taking a drug as directed) is a critical issue in drug treatment
WEEK 3
MODULE 3 Basic Structures and Functions of the Nervous System I
Introduction
This module will examine the structures and functions of the brain and the central nervous system.
Although drug effects are profoundly influenced by the environment (setting) in which the drug is used and the beliefs about its effects (expectancies), ultimately drugs modify thoughts and feelings through their effects on the brain.
A basic understanding of the brain is therefore necessary to an understanding of psychoactive drug effects.
The focus of this week is an overview of the nervous system and the brain, and a discussion of brain regions “dedicated” to motivation, emotion, and the experience of pleasure
As noted in previous modules, these areas are vital to the subjective and behavioral effects of drugs and to addiction.
The nervous system branch
The body of vertebrate animals, including humans, is comprised of several systems, e.g., digestive, cardiovascular, nervous, etc.
The nervous system has the responsibility of co-ordinating the activity of all the other systems.
The cells of the nervous system branch out like a vast cable network throughout our bodies.
This network is organized in tiers or levels.
This organization plan is called a hierarchy: Structures on the top level direct the activity of structures at lower levels.
CNS
At the top of the hierarchy is the central nervous system (CNS), which consists of the brain and the spinal cord.
The CNS can be thought of as the CEO and top management team of the nervous system organization.
PNS
Below the CNS is the peripheral nervous system or PNS.
This is comprised of everything that is not part of the CNS.
The PNS can be divided into two branches, the Somatic and the Autonomic.
SOMATIC
The Somatic branch contains all those nerves that send messages from the brain to the muscles for example, and relay messages from the body (e.g., skin) back to the brain.
AUTOMATIC
The Autonomic nervous system is responsible for controlling the activity of our internal organs.
This system operates automatically - we don’t need to think for our heart to beat, our lungs to breathe, or our stomachs to digest.
PARA AND SYMPATHETIC
The Autonomic Nervous system in turn is divided into 2 sub-branches, the parasympathetic branch and the sympathetic branch.
These two branches govern the activity of our internal organs during periods of relaxation and activity, respectively.
The operation of the parasympathetic and sympathetic sub-branches is mutually inhibitory.
That is, when the parasympathetic branch is operating, the sympathetic branch is not, and vice versa.
Some parasympathetic activities include digestion and excretion.
The sympathetic nervous system takes over when our body is active, and most specifically in times of stress.
This system is specially designed to ensure the survival of the organism in the face of threats to its welfare - i.e., stress.
When we encounter a situation that we perceive as stressful (i.e., threatening), a characteristic response of the sympathetic nervous system kicks in.
Flight or fight response
This response is a complex set of reflexes that work together to enable the organism to run away from or confront an adversary
A cascade of events is set in motion that includes detection of the threat by the brain, the secretion of a hormone from a region in the brain that mobilizes the activity of the body by signaling the adrenal glands to release adrenaline into the blood stream.
Adrenaline in turn causes the heart to beat faster and lungs to breathe more rapidly enabling the organism to run at top speed or fight with utmost strength.
Additional responses include contraction of the skin producing goose bumps and dilation of the pupils of the eye to enable maximum visual information input.
At the same time this cascade of events is occurring, the vegetative functions controlled by the parasympathetic nervous system are turned off - digestion stops and other maintenance and repair activities are put on hold.
The same brain structures that signal the lower levels of the nervous system to flip into “sympathetic” mode also signal the organism to seek out safety.
Repeated use of a drug appears to trick the organism into recalling drug-related behavior patterns, as if drugs somehow serve a survival purpose or means of escape from threat.
Activation of this circuitry by stress may account for the strong association between stressful events and relapse to drug use in users who have stopped using drugs.
CNS Summary
In sum, the CNS and brain in particular govern the activity of the body through a highly coordinated network of nerves.
This enables the body to respond effectively to challenges and adapt to the environment.
The evidence linking the body’s stress response system with the system that governs drug use is particularly noteworthy
It suggests that the idea of drug use as “escape” may in fact reflect the operation of a hardwired instinct, which like all instincts may be extremely difficult to override.
Because stress is an inevitable part of life, it is not surprising then, that a defining feature of addiction is relapse.
The organization of the human nervous system is best described as a:
hierarchy
The nervous system is stratified with the higher levels controlling the lower levels, and the brain the topmost position
Organization of the Brain
The human brain can be divided into three main regions
- hindbrain
- The region at the back
- It is the most primitive region in terms of evolutionary development and sophistication
- This part of the brain exists in very low organisms like fish.
- The role of the hindbrain is to govern basic maintenance functions such as respiration and circulation.
- It does this through its connections with the autonomic nervous system
- midbrain
- more advanced
- This region exists in reptiles and amphibians, and could be called the “frog brain.”
- This region enables the organism to orient in space, make simple decisions and to scan the environment
- This provides some flexibility and independence to the organism such that it is no longer limited purely pre-programmed behaviour.
- forebrain
- leftmost region
- the most advanced in evolutionary terms
- This region is represented in mammals, the most sophisticated forms of animals
- The forebrain is responsible for complex acts like goal-directed behaviour
- The greater the proportion of forebrain to the other regions, the more advanced the organism
- Rats have a very small forebrain to mid/hind brain ratio
- By contrast, humans and monkeys have a very large ratio of forebrain to mid/hind brain, reflecting our high degree of sophistication and relative autonomy over our behaviour (i.e., choosing to act rather than following instincts or drives alone)
The Limbic System
A set of structures extends from the mid- to the forebrain in mammals
These structures together are called the Limbic System because they form a branch of limb connecting the mid- and forebrains
The limbic system controls motivation, emotion, reinforcement (pleasure/pain) and memory
Through limbic connections with the forebrain, these “drive-based” activities can influence and in some cases over-ride conscious “higher” functions such as planning, decision-making and reasoning
Indeed, this powerful influence contributes to the experience of “loss of control” that often accompanies addictive behaviour
Although the individual consciously knows that continued drug use or relapse is wrong (i.e., dangerous), he or she feels compelled to do it despite all rational beliefs to the contrary
The term “addiction” captures this feeling of compulsion - the siren song that beckons the user
In Latin, “ad” means “toward” and “dictum” means “a calling or command.”
Addiction thus involves the calling to drug use and the activity of the limbic system is the neural basis for this experience.
Indeed, the activity of the brain can be characterized as a complex pattern of signals, whose net effect determines the emotions we feel and actions we perform.
Neurons
Signals in the brain are conducted by highly refined nerve cells called “neurons.”
These cells are like electrical wires of varying lengths and densities
They communicate with each other by chemical messengers, and this communication is the physical basis of experience
It is important to note that no experience can occur without a physical event (and more likely thousands or millions of events) taking place in the brain.
Thus, even effects that we presume are “strictly psychological” have a physical basis in brain activity - that is, they are real
The range of experiences we can have is virtually infinite.
This diversity owes to the 100 billion neurons in the brain, almost all of which have the capacity to interact with the others.
Nerve cell
Unlike cells in the body, when a nerve cell in the brain dies, it is not replaced.
Nevertheless, the brain is not depleted over time due to a vital process of linkage that occurs among the individual nerve cells.
That is, neurons that start out as individual, isolated cells forge connections with adjacent cells to create a network.
Neural network
The network of interconnected neurons has a greater capacity to process information than each individual cell alone
Thus, the forging of connections with other neurons is how the brain “grows,” and offsets the depletion of individual neurons as they die off
Learning
The process responsible for forging the connections is learning
The interconnection of formerly isolated neurons is the physical manifestation of the experience we have when we acquire knowledge or have a new experience.
Some of the most powerful connections - the strongest forms of learning - involve emotional events.
A single traumatic event, such as being bitten by a dog as a child, can create a learned association between dogs and fear that leads to a lifelong avoidance of dogs, even if at some level the person knows it’s irrational.
Similarly, a powerful positive experience, like the “high” felt from a dose of cocaine, can forge a learned association between cocaine and pleasure, that leads to a lifelong pursuit of cocaine even if the person knows at some level that it’s irrational or dangerous.
In short, learned associations in the brain, forged by powerful chemical transmissions between neurons, can bias our behavior away from or towards a stimulus sometimes forever.
In this way, drug use etches itself on the neural hardware of our brain
With each new dose of a drug, the linkage becomes stronger, increasing the likelihood of further use - a “vicious cycle” of reward and re-administration mediated by learning
Learning is best described as a:
mental event, physical event, and lasting representation of experience
Structures and Functions of the Neuron
Neurons are cells in the brain and nervous system designed to transmit information by means of chemical messengers.
The structures of the neuron may vary depending on what the neuron is designed to do, but the essential components are the same.
The overall design of a neuron is like an electric cable, and that in fact is what it is.
It conducts an electric pulse, called an action potential, from one end to the other
The action potential only occurs when the neuron is stimulated; at other times, the neuron is dormant or inactive.
The neurotransmitter
The event that stimulates the neuron is the binding of a chemical - the neurotransmitter - with specialized gates on the neuron
The gates are called receptors
Each receptor is designed to bind with a particular neurotransmitter - like a specific key fits into a specific lock and opens it
When enough receptors are stimulated by neurotransmitter molecules, they signal the neuron to become active
The signal is sent along the dendrites (neuronal branches) into the body of the neuron (the soma)
At that point, the charge builds up until there is enough energy to surpass the cell’s threshold for activation
At that moment, the neuron fires the action potential, which can be thought of as an electrical pulse or blast - an all-or-nothing event
In other words, if the threshold for activation is exceeded, the cell will generate a complete action potential; if it does not exceed the threshold, no action potential will occur
There is no in-between state; either the action potential fires or it doesn’t
The axon
Once the action potential fires, it is propagated down the length of the neuron on a filament or cable called an axon
This is like the electrical cord carrying electricity from the outlet to an appliance
And like an electrical cord, many axons are insulated with a fatty substance called myelin, which prevents the electricity from leaking out into the extra-cellular fluid
Exocytosis
When the action potential reaches the end of the neuron it causes another important event - exocytosis - the release of neurotransmitter contained within the neuron (i.e., the cell’s own neurotransmitter) from the terminal buttons
The transmitter is contained in tiny film-like sacs called vesicles that disintegrate soon after the transmitter is ejected from the terminal buttons
The synapse
The region into which the transmitter is released is called the synapse - a gap between neurons
If sufficient transmitter makes its way across the synapse to bind with the receiving neuron, it may instigate an action potential in that cell, starting the process all over again
This sequence of events occurs in milliseconds
Millions of these events cause an electro-chemical cascade throughout the brain.
This cascade is the physical basis of the thoughts and feelings we experience and the behaviors we perform.
Neurotransmitters can be excitatory or inhibitory
Although we have talked in terms of neuronal stimulation, it is also possible for a neurotransmitter to de-activate or inhibit the activity of a receiving neuron
This would make it less able to fire an action potential even if it were stimulated by another kind of transmitter.
Receptors for both of these types of transmitters often co-exist on the same neuron
Whether or not an action potential fires in a receiving neuron depends on the net balance or summation of excitatory (stimulating) and inhibitory (de-activating) transmitters that bind with the receptors
It’s not unlike an election: if enough votes are cast for a particular candidate relative to the votes cast for her opponent, the candidate wins (and she immediately fires an action potential to signal her victory)!
Defining Features of Neurotransmitters
The transmission of chemical messengers across the synapse is the critical mode of communication between neurons
Intense of repeated patterns of transmission are important in forging the links between neurons that we associated with learning.
Neurotransmitters are specialized chemicals that have a range of properties or effects
Although particular transmitters play particular roles in the brain and other parts of the nervous system, there are some features common to all of them.
- Neurotransmitters are synthesized from chemicals in our bodies
- Most often these chemicals come from our diet
- Amino acids are a very common dietary source or precursor for neurotransmitters
- Amino acids are relatively small molecules that link together to form polypeptides, which when they get long enough are called proteins
- So when you eat a steak, you are eating the raw materials for neurotransmitters
- Neurotransmitters are localized in neurons
- They do not float freely about the brain or body.
- A mechanism exists to turn off the activity of neurotransmitters
- The neurons are constantly recycling or destroying unused neurotransmitters from the synapse
- This occurs by two means: (a) Re-uptake, a vacuum-like process by which excess transmitter is sucked into the sending cell by a re-uptake pump or transporter. The second form of re-cycling is called (b) enzymatic degradation.
- Enzymes are chemical catalysts in our bodies that both synthesize and digest other chemicals.
- In the case of neurotransmitters, enzymes in the synapse will prowl about in search of excess transmitter, which they will literally digest or break down into smaller molecules that are then washed away into the fluid that bathes the brain and spinal cord
- Neurotransmitters act over short distances
- Unlike other chemical messengers in our bodies (e.g., hormones), neurotransmitters exert their effects over very short distances (cell to cell) rather than at a distance
- As a result, neurotransmission is a very rapid event (millisecond duration)
- However, because it is going on constantly, these discrete transmissions are experienced as an ongoing process
- Neurotransmitters are specialized
- A given neurotransmitter will only bind with its own receptor
- Moreover, it will only perform a particular function at that receptor (either inhibition or excitation)
- Without this specificity - the dedication of a particular transmitter to a particular receptor, communication within the brain and nervous system would be a hodge-podge of garbled messages rather than the exquisitely synchronized pattern of transmissions that defines our experience
- Even the experience of being confused is likely caused by a very specific set of events at the neuronal level in the brain
The pathway between the body and the CNS
Neurotransmitters exist in the brain as well as in the body
However, the same chemical serves a different function inside and outside of the CNS
Indeed, the pathway between the body and the CNS is heavily guarded by a densely-packed layer of cells called the blood-brain barrier
These cells are fatty in nature and therefore only permit fat-soluble - or very small water-soluble - molecules to pass through
Think of oil and water - you cannot dissolve oil in water or vice versa
Similarly, you cannot dissolve a chemical that will dissolve in water in fat
In short, the only chemicals that can get into the brain from the body are either fat-soluble or very small and water-soluble
What is the evolutionary (i.e., adaptive) purpose of the blood-brain barrier?
to protect the brain from harmful chemicals (e.g., germs, poisons)
The blood-brain barrier and drugs
The blood-brain barrier can influence the effect a drug has on the brain
The reasoning is as follows:
Drugs exert their effects at specific target sites: most often the neuronal receptors in the brain
In order to reach these sites, the drug must be delivered by the blood stream to the brain
Indeed, there is only 1 way for a drug to produce a psychoactive effect - to enter the brain by way of the blood stream
The more rapidly a drug diffuses through the blood-brain barrier, the more of it that will be available to “hit” its target sites at a given time
Drugs that are small or highly lipophilic (fat-soluble), pass rapidly through the blood-brain barrier.
The greater fat solubility of heroin vs. morphine contributes to heroin’s more intense subjective effects (and greater abuse liability).
The “functional dose”
We know that dose makes a big difference in the strength of drug effects
The rate of diffusion into the brain determines the “functional dose” that acts on a particular set of neurons
Other things being equal, the faster the diffusion rate, the greater the effect for a given dose
Alcohol/water-soluble drugs
Alcohol is a very small, hydrophilic (water-soluble) molecule
Its small size enables it to pass through the tight mesh of the blood-brain barrier even though it does not dissolve too readily in fat
Once inside the brain, alcohol is widely distributed throughout the various brain regions, because water is everywhere in the brain
This accounts in part for alcohol’s widespread effects on different structures in the brain; it literally affects every cell and neurotransmitter
In general, the more water-soluble a drug is, the more diffuse or widespread its effects will be in the brain
THC/fat-soluble drugs
The more fat-soluble a drug is, the more focal or restricted its effects will be
This is because water is distributed rather evenly throughout the brain, whereas fat is more densely concentrated in certain regions than others
THC, the major psychoactive ingredient of marijuana, is highly fat-soluble
THC is the classic example of drug with a focal effect
If you were to perform a brain scan of a person under the influence of alcohol or marijuana you could see these differences
The brain of the person under alcohol would light up evenly all over, while the brain of the person under marijuana would light up very brightly in a few regions but be completely inactive in many others
Note, however, that a focal drug effect may be just as intoxicating as a diffuse drug effect
The intoxicating and impairing effects of a single dose of marijuana are comparable in many ways to those of a single dose of alcohol
Neurotransmitters as Mediators of Drug Effects
Drugs produce psychoactive effects by altering the naturally occurring process of neurotransmission
Some drugs increase the rate of activity of neurotransmitters; others decrease their rate of activity
Some drugs mimic the effects of the neurotransmitters themselves (e.g., heroin, nicotine)
Other drugs fit nicely into the receptors for a particular neurotransmitter but rather than activate them like the transmitter, they sit inert, thereby preventing the transmitter from activating the neuron (e.g., PCP)
Whether a drug increases or decreases the spontaneous rate of neurotransmission does not predict its subjective effects
Instead, a drug’s subjective effects are determined both by its mode of action (increase/decrease neurotransmission), and by the neurotransmitter(s) it acts upon
What are the basic processes involved in neurotransmission that may be influenced by a drug?
- Receptor Activation.
- The primary process responsible for experience and behavior is the binding of a neurotransmitter with its receptor
- (a) One way a drug can influence experience or behavior therefore, is to increase the amount of neurotransmitter available to bind with its receptors
- Some drugs cause the sending neuron to release more of the transmitter thereby increasing the amount available to bind with its receptors. Amphetamine is a good example of a drug with this effect
- (b) A second way that a drug can increase receptor activation is by mimicking the effects of the neurotransmitter itself at the receptor site
- The molecular structure of some drugs is so similar to the neurotransmitter that the receptor cannot distinguish between the drug and the transmitter
- As a result, the receptor (i.e., “the lock”) may activate (open) in response to a chemical that it “believes” is the neurotransmitter (i.e., “the key”) when in fact the chemical is actually a drug (i.e., a lock-picking device, like a “bobby pin”)
- As noted above, heroin and nicotine are good examples of drugs that exert their effects primarily by binding directly to the receptors for their respective neurotransmitters.
- Enzyme Inhibition
- Enzymes in the gap between sending and receiving neurons - the synapse - break down excess neurotransmitter, thereby preventing this residue from binding with receptors on the receiving neuron
- Drugs may inhibit the normal operation of the enzyme
- By preventing the enzyme from doing its job, the neurotransmitter that would normally be broken down by the enzyme remains available to bind with the receptors on the receiving neuron, causing a net increase in neurotransmission
- It’s as if the garbage man stopped taking away your garbage. Pretty soon you have a huge pileup outside your house
- Thus, if an enzyme decreases neurotransmission, a drug that inhibits the enzyme will increase neurotransmission
- The saying I use to remember this process is: “The enemy of my enemy is my friend.”
- The enemy of the neurotransmitter is the enzyme
- The enemy of the enzyme is the drug that inhibits it.
- The first drugs used to treat depression, called monoamine oxidase inhibitors (MAOI’s), worked in this way
- “Monoamine” was the name of the class of neurotransmitter.
- Monoamine oxidase was the enzyme that normally broke down these neurotransmitters
- And monoamine oxidase inhibitors were the drugs that prevented the enzyme from exerting this breakdown effect
- Re-uptake Blockade
- Another process involved in turning off the action of neurotransmitters is re-uptake
- This process is essentially recycling of excess transmitter from the synapse by ferrying it back into the sending neuron
- The structure responsible for this is the re-uptake transporter or re-uptake pump
- Drugs that block the re-uptake pump, prevent it from recycling the excess transmitter, leaving more available in the synapse to bind with receptors on the receiving neuron
- In other words, re-uptake blockade leads to a net increase in neurotransmission
- Thus, the effect of re-uptake blockade is the same as enzyme inhibition (increased neurotransmission), although the mechanism of these two effects is different
- Cocaine is a good example of a drug that blocks re-uptake of a neurotransmitter
Some Major Neurotransmitters
There are over 100 neurotransmitters in the CNS, and more chemicals are being discovered every day that meet the criteria of neurotransmitters.
Nevertheless, there are a half dozen neurotransmitters that are believed to play critical roles in many aspects of our experience and behavior.
These are the chemicals that have received the greatest attention and that are still the primary focus of attention in the study of drug effects.
Acetylcholine
The first transmitter to be discovered was acetylcholine
This chemical is critically involved in memory and specifically the consolidation and storage of new memories
Acetylcholine is derived from the dietary amino acid, choline.
What major psychiatric disorder is believed to involve a deficiency in acetylcholine neurotransmission?
Alzheimer’s
Monoamines
Monoamines are a class of neurotransmitters implicated in depression
However, each of the members of this class plays an important role in psychopathology (mental illness) as well as addictive behavior
Dopamine
This is perhaps the best candidate for the “Star” neurotransmitter in psychopathology and addictions
Ultimately, many of the effects of the other major neurotransmitters appear to derive in some way from the manner in which they interact with and influence dopamine
The principal role of dopamine is in the initiation and maintenance of motivation
Dopamine helps orient the organism to potentially important stimuli; it impels movement towards (approach) these stimuli when they are beneficial and impels movement away (avoidance) from these stimuli when they are dangerous
Once a stimulus is encountered, dopamine labels its effects as positive (i.e., rewarding) or negative (i.e., punishing)
In this way, dopamine regulates the process of reinforcement
Although dopamine was originally believed to underlie the experience of pleasure, more recent research indicates that, although dopamine can create one kind of pleasure, its primary role in this regard is to designate or label stimuli as pleasurable rather than causing the pleasurable experience itself
It’s as if dopamine puts a chemical “ü” mark on chocolate (pleasurable) and an “x” on broccoli (not pleasurable)
Whether the actual pleasure of eating chocolate results from dopamine transmission however, remains a matter of debate
The association of meaning to a stimulus can result in some profound effects on behaviour
For example, dopamine is believed to underlie the effects of “cues” or “triggers” on drug and alcohol use
One reason why Alcoholics Anonymous demands complete abstinence from its members is because of the triggering effects of the first drink.
In other words, even though the first drink may not cause intoxication just the smell or taste of alcohol can set of an intense craving for more, which ultimately can result in a full-blown relapse
Dopamine transmission is believed to underlie the triggering effects of cues associated with drugs as well as the subjective experience of craving or compulsion to use that often follows exposure to these cues
Excessive dopamine transmission can also alter thoughts
When stimuli that are normally unimportant are infused with meaning (i.e., labelled as rewarding or punishing), distortions in thought can arise about those stimuli
ex. People walking behind you are perceived as “following you.”
People who try to give you something to eat or drink or who invite you to stay with them are perceived as “plotting to kill you.”
These distortions in thoughts (delusions) are believed to derive from excessive dopamine transmission
They are a hallmark symptom of schizophrenia
Norepinephrine
Norepinephrine is involved in the modulation of attention, arousal and mood
Activation of norepinephrine results in an involuntary focusing of attention on a stimulus - like the stop-and-listen reflex we exhibit when we hear a loud bang
Maintenance of attention, or concentration, that is critical to mental tasks is also influenced by norepinephrine
The feeling of alertness we experience just prior to an important event (e.g., a test or competition) is governed by norepinephrine
Finally, the feeling of calm, and in particular, calmness in the presence of others (e.g., potential competitors), is governed by norepinephrine
Deficits in norepinephrine have been implicated in the cognitive (difficulty concentrating) and social aspects (feeling worthless) of depression
Excesses in norepinephrine have been implicated in the hyper-vigilance and arousal associated with panic disorder
Both norepinephrine and dopamine are synthesized from a dietary amino acid called tyrosine
Serotonin
If dopamine is the “Star” of the neurochemical show, serotonin is the star’s “manager.”
Serotonin serves a modulatory role on dopamine as well as many other neurotransmitters
This means that serotonin regulates how much / how little dopamine activity is allowed to occur as well as the turning off of dopamine after it has served its purpose
In this way serotonin modulates appetite (for food and drugs), aggression, mood (highs and lows), sleep, and pain
In general, increased serotonin reduces appetite, aggression, pain and sleep, while stabilizing mood
Drugs that powerfully increase serotonin, like LSD, can produce a complete cessation of appetite, and a super-awake like state (the opposite of sleep) that is involved in the heightened sensory experience of the LSD “trip.”
Drugs that enhance serotonin in a more measured way, like Prozac, provide energy while also stabilizing mood.
Antidepressants that act on serotonin appear primarily to reduce “the lows” of depression, resulting in a better balance of positive/negative experience, rather than directly increasing the highs
By providing energy, these antidepressants also reduce the effort that a person must expend to do things that will bring reward or pleasure (e.g., going to work, doing exercise, interacting socially)
This is another indirect way they reduce depression
Serotonin is synthesized from a dietary amino acid called tryptophan.
Which of the following statements is false?
activation of neuronal receptors by acetylcholine reflects the direct mode of action of this drug
Drugs that inhibit enzymes in the synapse would be expected to?
decrease the break down of neurotransmitters and increase neurotransmission
Whereas the action potential is _____________, activation of receptors is ___________.
an all-or-nothing event; a graded event
WEEK 4
MODULE 4 Basic Structures and Functions of the Nervous System II
Introduction
This module will examine how drugs alter biological processes to produce their effects, and factors that influence the strength and nature of those effects.
The focus of this week is defining “drug effects” in biological terms.
For decades, cocaine was considered not to be addictive.
The advent of crack - a smokable form of cocaine - in the 1980’s showed that cocaine is in fact one of the most addictive substances.
Ecstasy and LSD both influence a common neurotransmitter system in the brain and both produce hallucinogenic effects.
However, Ecstasy often causes permanent brain damage to the user, while LSD does not.
What accounts for these differences in the effects of similar types of drugs? The answer lies in the biological mechanisms of drug action - what the drug does to the brain and conversely what the brain (and body) do to the drug. That is the focus of today’s module.
Two Basic Types of Drug Effects
Drugs produce their psychoactive effects by altering the spontaneous (i.e., drug-free) activity of neurons in the brain.
Neurotransmitters are the agents that turn on or turn off neuronal activity
Thus, the effects of drugs are “mediated” by their actions on neurotransmission or chemical signaling between neurons
The two basic types of drug effects are:
(1) to increase the spontaneous effects of a neurotransmitter
(2) decrease the spontaneous effects of a neurotransmitter.
When a drug increases, or facilitates the spontaneous effects of a neurotransmitter it is called an AGONIST (which derives from the word “to go” in Latin)
When a drug decreases, or opposes, the spontaneous effects of a neurotransmitter it is called an ANTAGONIST (which derives from the word “to go against” in Latin)
Two Basic Mechanisms of Drug Action
A drug can increase the spontaneous effects of a neurotransmitter in one of two basic ways:
- It can mimic the effects of the drug at the receptor site, tricking the neuron into believing it received its neurotransmitter (instead of the drug)
- Alternatively, the drug can increase the amount of neurotransmitter molecules that are available to bind with the receptors on the receiving neuron
The same basic reasoning applies to drugs that decrease the effects of a neurotransmitter.
- A drug may decrease the ability of neurotransmitter molecules to bind with their receptor by blocking the receptor sites but not turning on the neuron (i.e., this is a bit like the plastic child-safety plugs that are used to prevent accidental shock by blocking the flow of electricity from wall outlets)
- A drug can also decrease the activity of a neurotransmitter by:
a) impairing the ability of the neuron to fire its action potential
OR
b) by increasing the activity of processes that normally act to stop neurotransmission like enzymatic degradation and re-uptake
In both (a) and (b) the decrease in activity results from some process other than blockade of the receptor sites.
DIRECT
When a drug exerts its effects (increase or decrease neurotransmission) by binding directly with neuronal receptors the drug effect is said to be DIRECT
INDIRECT
When a drug exerts its effects (increase or decrease neurotransmission) by some mechanism other than receptor blockade, the drug effect is said to be INDIRECT.
Notice that the type of drug effect (increase/decrease) and the mechanism of a drug effect are completely independent: Either type of effect can be combined with either mechanism and vice versa.
Type of Effect table
Mechanism of Effect:
Direct increase: (A) Binds with receptors and mimics Neurotransmitter effect
Direct decrease: (B) Binds with receptors and blocks the ability of neurotransmitter to activate receptors
Indirect increase: (C) Increases levels of transmitter in synapse that are available to activate receptors WITHOUT binding with receptors (e.g., block re-uptake)
Indirect decrease: (D) Decreases ability of transmitter to produce action potential in receiving neuron WITHOUT binding with receptors (e.g., makes receiving neuron leaky or unable to conduct an action potential).
The table above shows four classes of drug action: A, B, C, and D.
Direct Mechanism of Action
Listed are some examples of non-medicinal and medicinal drugs of each type - A, B, C, D.
(A) direct agonist:
Nicotine (transmitter=acetylcholine)
Valium (transmitter= GABA)
(B) direct antagonist:
PCP (transmitter=glutamate)
Chlorpromazine (transmitter=dopamine)
indirect mechanism of action
(C) indirect agonist:
Cocaine (transmitter=dopamine)
Prozac (transmitter=serotonin)
(D) indirect antagonist:
Alcohol (transmitter=norepinephrine)
Reserpine (transmitter=dopamine)
The type and mechanism of a drug effect tells us nothing about whether or not it is primarily a medication or primarily a drug of abuse.
The psychoactive effects of a drug are due primarily to:
a) increased binding of the neurotransmitter with its receptors
b) decreased binding of the neurotransmitter with its receptors
c) increased neurotransmission by binding with its receptors
(a) and (b) are self-evident.
(c) is true because neurotransmission is increased when the drug binds with receptors and mimics the neurotransmitter effect.
For example, 10 transmitter molecules could bind with 10 receptors to turn on the neuron, or 5 transmitter molecules and 5 molecules of drug could together bind with 10 receptors (total) to turn on the neuron. In the latter case, neurotransmission is increased over what it would be without the drug (i.e., only 5 receptors would be activated).
Neuronal Receptors
In a previous Discussions discussion the issue of individual differences in vulnerability to drug abuse was discussed.
Today we will examine some of the biological factors that influence vulnerability to drug abuse.
As we all know, genes play a critical role in a variety of personal traits, ranging from eye colour to athletic ability and in some cases even intelligence.
Genes also play an important role in risk for addiction.
For example, the son of a male alcoholic has a 4 times greater risk of becoming an alcoholic himself than the son of a non-alcoholic father.
This is true even if the son was adopted by a non-alcoholic family at birth.
This consistent risk of alcoholism based on the biological father’s alcoholic status is strong evidence of a genetic component to alcoholism.
How do genes translate into risk for alcoholism or drug abuse?
There are many possible answers to this question.
One very important way that genes influence risk for addiction is by dictating the number or sensitivity of receptors on a particular class of neurons.
Specifically, genes tell the organism how to link various chemicals when building cells within the body.
The genes literally provide the blueprint for the body’s structure.
In the brain, genes provide the code for the structure and number of neuronal receptors, which in many cases are basically made up of proteins.
If a person’s genes code for highly sensitive or highly populous receptors of a particular class of neurons (e.g., dopamine), that person will have a different response to drugs that affect neurotransmission at those receptors, compared to someone whose genes code for low sensitivity or low density of receptors.
The D-2 Story
The term “D2” is used to describe a sub-class of receptors for dopamine neurons.
These receptors have proven to be extremely important to the understanding of abnormal thought and motivation.
Recall that dopamine is the “star” of the neurotransmitter show, apparently acting as a neurochemical signal for events with adaptive significance (i.e., things that are important for survival).
Research shows that dopamine receptors play a critical role in individual differences in dopamine transmission.
Moreover, genes appear to dictate the expression of high or low numbers of dopamine receptors.
In recent years, technology (Positron Emission Tomography - PET scans; genotyping - characterising an individual’s genetic profile based on samples of his/her blood or tissue) has enabled us to examine the relationship between genes, dopamine receptors, and individual differences in novelty or sensation seeking.
The results of these investigations are remarkable.
Ex. the relationship between D2 receptor density, prevalence of schizophrenia, and prevalence of cocaine abuse.
Recall that cocaine is a potent dopamine agonist, increasing levels of dopamine transmission by blocking its re-uptake from the synapse.
Schizophrenia involves excessive dopamine transmission, due in part to their heightened levels of D2 receptors.
The figure indicates that individuals with high levels of D2 receptors show high rates of schizophrenia.
In contrast, individuals with low levels of D2 receptors show high rates of cocaine abuse.
A high level of D2 receptors would lead to abnormally high dopamine transmission, whereas a low level of D2 receptors would lead to an abnormally low level of dopamine transmission.
Individuals with low levels of D2 receptors - (those at risk for cocaine abuse) - tend to be sensation seekers.
They love risky activities and things that provide a rush.
Such individuals would really enjoy a roller coaster or skydiving.
Individuals with high levels of D2 receptors are just the opposite; for them everyday activities may be overly stimulating and “exciting” activities would probably be experienced as stressful or frightening.
When individuals with low levels of D2 encounter a substance like cocaine, they tend to like it.
As a result, such individuals progress to abuse and addiction much more rapidly than individuals with high levels of D2 receptors.
It is as if cocaine provides a chemical equivalent of a roller coaster for the low-D2 individual.
For these people, cocaine exerts a powerful “cybernetic” function: It brings them closer to their internal optimum state.
Thus, the abuse liability of cocaine is greater for individuals with low levels of D2 receptors, whose internal state is chronically discrepant with their ideal (i.e., under-stimulated).
The relationship between D2 receptor density and subjective “liking” of a standard dose of cocaine in normal individuals.
Notice that low-D2 individuals prefer the cocaine as compared with the high-D2 individuals.
This is called an inverse relationship: The lower the baseline transmission, the greater the preference for a drug that enhances that transmission.
Thus, even normal individuals (non-cocaine users, non-schizophrenics) show predictable differences in their preference for a stimulant drug, as a function of their levels of D2 receptors.
Is there such a thing as an addictive personality?
Yes, and it appears to involve an inverse relationship between baseline transmission of a particular neurotransmitter and liking of a drug that acts on that transmitter.
The addictive personality is likely specific to certain drugs or types of experience.
The lower the baseline activity of a neurotransmitter, the higher the liking of a drug that increases activity of that transmitter (an inverse relationship).
Different drugs/activities influence different transmitters - when a drug or activity specifically acts on a transmitter whose baseline levels of activity are low, the individual is more likely to use that drug to achieve his/her internal optimum.
However, a drug that does not act on a transmitter system that is deficient will not assist the achievement of one’s internal optimum standard and therefore may not be especially appealing to that individual.
Down-Regulation, Super-Sensitivity
As mentioned in previous lectures, the body reacts to the administration of a drug.
That is, it compensates for changes in neurotransmission induced by the drug.
This is especially true when the drug is given repeatedly (i.e., chronic administration).
If a drug increases neurotransmission by increasing levels of transmitter in the synapse, the body may compensate by reducing the number of sensitivity of those receptors.
It’s as if the body is trying to preserve conditions as they are - the “status quo.”
If you administer cocaine repeatedly, you increase the levels of dopamine in the synapse each time.
To compensate, the body will then reduce the number or sensitivity of dopamine receptors available to be activated by the transmitter = “Down-Regulation.”
Thus, regardless of where a person starts out in terms of D2 receptors, after chronic cocaine use, his/her D2 receptors will decline in sensitivity or number
Normal individuals with lower levels of D2 receptors like cocaine more.
Therefore, regardless of baseline D2 receptor sensitivity, chronic cocaine use will increase the preference for cocaine relative to before cocaine use. This is the addictive spiral.
Chronic cocaine users often report that cocaine initially made them feel high, whereas now it only serves to make them feel normal - it just allows them to function.
An important difference between drugs and non-drug reinforcers is that drugs possess the ability to produce intense prolonged activation of neuronal receptors.
It is this intense activation that promotes compensatory responses (down-regulation) by the body, which in turn promotes further drug use, just to restore one’s subjective state to “normal.”
Non-drug reinforcers can occasionally produce such intense activation.
However, the probability and severity of this effect is usually much less.
As a result, drugs are much more likely to produce “addiction” than non-drug reinforcers.
Down-Regulation and Psychoactive Medication
Down-regulation is not only involved in the pathological effects of psychoactive drugs (i.e., addiction).
It appears to be involved in the therapeutic effects of some psychoactive medications.
A universal feature of antidepressant medications is their “delayed onset” of action.
Drugs like Prozac, or earlier antidepressants, like the Mono-amine-oxidase inhibitors, typically do not produce a therapeutic effect for 2-6 weeks after the individual begins to take them daily.
Evidence from animals shows that during this 2-6 week interval, the receptors for the transmitters affected by the drug (i.e., mono-amines) decline in sensitivity - that is, they undergo down-regulation.
It is at this point that the relief from depression begins to occur.
Importantly, the effects of these drugs on the levels of mono-amines in the synapse occurs with the very first dose.
However, it appears to be the body’s compensatory response to the enhanced levels of mono-amines in the synapse (i.e., down-regulation) that makes the person feel less depressed.
Because of the inherent risk of suicide in depression, it is not always possible to wait 2-6 weeks for a treatment to have an effect.
In such cases, doctors will sometimes employ a procedure called electro-convulsive therapy (ECT), which involves administering a focused charge of electric current to specific regions of the brain ECT has been shown to have rapid therapeutic effects in individuals who are extremely depressed.
This effect appears to involve a rapid compensation (down-regulation) of receptors by the body in response to the massive surge of receptor stimulation produced by the electric current.
True or False: The primary effects of psychoactive drug administration are due to the immediate effect of the drug on neurotransmission.
False
Super-sensitivity
People with schizophrenia, start out with excessive D2 receptor levels = super sensitivity
Drugs that treat schizophrenia (like chlorpromazine) block D2 receptors.
As a result, the net level of dopamine transmission is reduced, to a level more similar to that of people without schizophrenia.
The more effectively a drug binds with D2 receptors and blocks their activation by dopamine, the greater is its ability to reduce the so-called “positive” symptoms of schizophrenia.
Positive symptoms do not imply “good.”
Rather, this term refers to the fact that the symptoms involve behaviours or responses that are “greater than” normal. So if normal = 0, positive simply means > 0 (e.g., +3, +5, etc).
The two main positive symptoms of schizophrenia are hallucinations (sensory experiences that have no real source) and delusions (beliefs not grounded in consensus reality)
A typical hallucination in schizophrenia is hearing voices that nobody else hears.
A typical delusion is a belief that someone is trying to kill you or a belief that you are someone who you are not, e.g., Napoleon or Jesus Christ.
Drugs that block D2 receptors are particularly effective in reducing these positive symptoms of schizophrenia.
In conceptual terms, it’s as if the excessive activation of D2 transmitters were making things more meaningful than they should be (the thought becomes a voice, and the fear and happiness become delusions of paranoia and grandeur).
By reducing the excessive transmission (D2 blockade), drugs that treat schizophrenia restore normal levels of meaningfulness to everyday events.
Because of their ability to reduce disordered thoughts, drugs that treat schizophrenia have been termed “anti-psychotics.”
