Section 2: Biological Aspects of Drug Abuse: An Introduction to the Nervous System and Pharmacology

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This Section will begin the more physiological/pharmacological part of the course.  I know that people often come into this part of the course with varying levels of background in, and comfort with, biological processes and terms.  As an introductory-level course, I'm not assuming any background.

A common question (complaint?) has to do with the extent of coverage of biological aspects in this course.  The justification is that, as defined, a drug is a biologically active chemical that alters the body's functioning in some meaningful way.  Drugs' dangers, effects, addictive qualities, and, ultimately, the ability to treat an addict, relies on biological principles.  To understand addiction, or even why a drug like alcohol is more likely to be abused than, say, Maalox, requires us to understand what's going on in the brain-- down to the molecular level.

One thing that I hope you will get from this section is a better sense of how drugs affect someone and an appreciation for the role that biological processes play in this societal problem.  Another goal of mine is for students to become aware of the commonalities among different drugs.  Even between drugs with effects as different as opiates and stimulants the mechanisms that underlie pleasure and addiction seem to be very similar.  We'll cover that later in this Section.

Outline:  Here's a little more detail about how information will be presented in this Section:

  1. •Introduction to the nervous system:  This will be a brief tour of the brain that will then move to the components-- neurons, neurochemicals, and receptors.  The focus will be on the functions rather than their location, but this will also be a vocabulary-rich portion.  Chapt. 2, in its entirety (pp. 50-71), will be the reading. 
  2. •Drug administration and distribution:  If a drug is going to have an effect, it needs to get into the body and, more specifically, to the area of the body where it will have its effects (the "site of action").  These issues make up the area known as pharmacokinetics.  Chapt. 3, pp. 79-89.
  3. •Mechanisms of drug action (pharmacodynamics):  A good principle to remember is that drugs simply take advantage of natural nervous system activity-- either increasing or decreasing actions to place system out of balance.  How drugs do this will be covered.  Chapt. 3, pp. 89-94.
  4. •Mechanisms of addiction and tolerance:  Building on the principles covered in the preceding lessons, this one will cover how the brain (the person) can become addicted to a drug, and what that means at a physiological level.  Chapt. 3, pp. 94-103.
  5. •Pharmacology of opiates and stimulants:  Even though brief examples of different drugs are given throughout this section, it's useful to compare and contrast different substances in some detail.  For that we'll be looking at opiates (pp. 199-205) and stimulants, including cocaine and amphetamines (188-194).

The Nervous System

My approach to this is to start with the whole organ-- the brain-- and introduce the parts and what they do followed by the things that make up the brain and make it work (the neurons and neurochemicals).  Once we've established these pieces, we then work through how drugs work on those systems.  

Hey there!  Here are a couple of web sites that offer some good ways to study information about the brain and nervous system!

WEB EXERCISE

            Explore the brain virtually!  The Internet has a wealth of resources for exploring the nervous system, including its anatomy and physiology.  You can also explore the effects when areas of the nervous system become dysfunctional from disease, development, drug use, or other causes.  The following links provide not only different views of material presented in the present chapter but also ways to go beyond our discussion so far.  Some examples:

The following link for "psycheducation.org" provides basic information about brain anatomy and physiology, but does so in an easy-to-read fashion and focuses on the brain in relation with mental disorders (e.g., depression, schizophrenia, etc.):  http://www.psycheducation.org/emotion/introduction.htm

For more detailed drawings of brain areas, go to:
http://pegasus.cc.ucf.edu/~Brainmd1/brain.html

At the following site, explore many aspects of the brain and nervous system, including the role of chocolate on brain functioning: http://faculty.washington.edu/chudler/introb.html   

The "Neurology Channel," sponsored by Healthcommunities.com, provides information on a variety of brain-related issues, including sleep disorders, ADHD, and other conditions.  Go to: http://www.neurologychannel.com/  

The Whole Brain Atlas, produced by the Harvard Medical School , provides animated graphics and information on brain disorders such as Alzheimer’s disease.  Go to: http://www.med.harvard.edu/AANLIB/home.html

     To understand drug use and addiction one needs to understand what happens on the more physiological level.  If drug use were simply a matter of will-power, it would be much easier to deal with.  Also, individuals would not keep returning to a substance when they truly have a desire to stop using it.  Knowing what a drug is doing in the body can also take some of the mystery out of the effects.   Drugs are not going to create new sensations as much as manipulate the body's existing systems, either accentuating their actions or lessening them.  It's how these activities act in balance with one another that determines what people feel.

     The first issue, of course, is in understanding the variables that affect how a drug enters the body (and what happens to it once in the body).   Keep in mind that for a drug to work it needs to reach the site of action (its BIOAVAILABILITY).   This is generally done by travel in the bloodstream.  The body will be breaking a drug down as soon as it enters.  Most of this METABOLISM occurs in the LIVER.  Pay attention to where a drug will need to go before reaching the brain if it is introduced into the body ORALLY vs. through INJECTION vs. INHALATION vs. SUBLINGUALLY, etc.  What are advantages and disadvantages of each?   Why?

Secondly, a drug's BIOAVAILABILITY will be affected by anything that will alter rates of ABSORPTION or of METABOLISM or affect the area of DISTRIBUTION (see for example alcohol and the effects of % body fat) or access to the SITE OF ACTION.  For example, drug metabolism tends to be slower in children and in older adults than in young adults.  What would this say about how a drug should be prescribed over the life span?

    Thirdly, pay attention to how drug effects change across different doses (see Section 3-1c in the text) and the relationship between effective doses and lethal doses.    How can you tell whether a drug is safer than another?  

   Similarly, note that how fast a drug reaches its peak level, and how fast it is eliminated from the system, affects how psychologically dependent or physically dependent a person will likely become to that drug. 

Want a refresher on neuroanatomy?  brain and nervous system diagrams can be found at:
brain_overheads

IN SUM, the functions of the relevant brain parts are as follows:

Medulla oblongata (or just medulla):  The lowest structure in the hindbrain region of the brain; important for the regulation of breathing, heart rate and other basic life functions.  Overdoses of opiates or depressants can disrupt activity in this area suppressing breathing.

Reticular formation (or reticular activating system):  Pathway of neurons running through the hindbrain into the midbrain that regulates brain arousal and alertness.  Depressants and stimulants both are thought to have effects in this system.

Cerebellum:  Hindbrain region important for fine motor control, coordination, and some reflexes.  Alcohol's effects on balance and coordination would occur through disruptions of the cerebellum's activity.

Hypothalamus: The body's homeostatic center, regulating internal environment and stimulating responses based on the body's needs.  This brain area is affected by emotional reactions and part of the body's drive or motivational system.  Every addictive drug would have indirect or direct effects on hypothalamic activity.

Limbic system:  Emotional tone and encoding information into memory.  Considering the emotional effects of drugs and of addiction and the ways in which events trigger desire for use, the limbic system is an important group of structures for any drug.  Note the specific functions of the amygdala and the hippocampus. 

Cerebrum:  The outer area of the forebrain region of the brain, the outer-most layer is the cerebral cortex.  The cerebrum contains the areas necessary for coordinating input and information; the cerebral cortex is responsible for decision-making, perception, and initiating purposeful actions.  Any drug that affects any of these functions (which include all of the psychoactive drugs) is relevant.  Different areas of the cerebrum, however, are affected by different drugs.  Among the lobes of the cerebral cortex, pay attention to the frontal lobe.

 Note the textbook's introduction of the mesolimbic dopamine pathway (pp. 56-57).  These are relevant to the reward system (discussed again on p. 98-101).

After studying the different parts of the brain, try the following matching exercise:

 

"Feelings" aren't restricted to the brain.  The AUTONOMIC NERVOUS SYSTEM, especially the SYMPATHETIC nervous system, is responsible for the changes felt  in the body (e.g., arousal from stimulants.)


     The functions of the areas noted above are mediated by neurotransmitter-receptor interactions.  (Note the neurotransmitters, discussed pp. 64-68.) What happens if you alter the availability of an excitatory neurotransmitter?   If you increase the ability of GABA to do its job?   For a neurotransmitter such as DOPAMINE, that was described as having both excitatory and inhibitory actions, what will account for the type of action that is seen?

* Note the different ways (described in class and noted in the textbook on pp. 91-93) that one can affect  the availability of a neurotransmitter at a synapse, either by affecting synthesis, storage, release, breakdown, or re-uptake.  Click on the picture below for more review of that information and an interactive review of the information:

synapse_pre-release.gif (20550 bytes)

 

After studying the different types of neurotransmitters, try the following matching exercise:

 

The following link gets you to a great site that outlines how drugs work in the brain.  Be sure to check out Mouse Party!!!

http://learn.genetics.utah.edu/units/addiction/drugs/ 

 

Concept check:

Knowing these different drug effects on neurotransmitter availability, what will be the net effects of such a change?  If a person were to take a drug that has one of these effects, what will they experience?
Let's check this idea using one neurotransmitter as an example: norepinephrine.  As you may recall, norepinephrine is an excitatory neurotransmitter that has effects in the sympathetic nervous system and in the brain.  In the brain, norepinephrine has mood and other effects.

Increased levels of norepinephrine result in increased sympathetic nervous system activity, such as increased heart rate and blood pressure, and is related to heightened emotional arousal, including excitement and anxiety.

Decreased levels of norepinephrine result in decreases in sympathetic nervous system activity and are related to feelings of lethargy and depression.

With these ideas in mind, click on the button below to go to a short "quiz" that will ask you to determine if a given drug will cause feelings of "excitation" (i.e., increased norepinephrine effects) or "depression" (i.e., decreased norepinephrine effects):


Click Here!

Brain fried yet?  For more on the topic, see the following 6:15 minute video clip from the recent HBO series on Addiction seen in class.  In this particular clip, Dr. Nora Volkow, currently the director of the National Institutes on Drug Addiction (NIDA) and an authority on brain mechanisms in addiction, works with a methamphetamine addict, assessing the impact of his drug use through brain imaging techniques.  Included here are discussions of the reward pathways and principles of dependence discussed in class:

Brain Imaging 

This other 9 minute film focuses on two teenage kids who have been dealing with addictions.  The relevant aspect for us in the present section of the course is the focus on how the adolescent brain is particularly prone to impulsive and addictive behaviors (see. p. 69-70).

The Adolescent Addict

 

 

*     All of this becomes relevant when we consider the REWARD SYSTEMS in the brain (associated with the mesolimbic pathway discussed in the textbook, p. 98-101).  There appears to be a system of brain areas that are activated by both natural rewards (food, sex, water) and artificial ones (addictive drugs).  The "reward" system is made up of
(1) the VENTRAL TEGMENTAL AREA* (VTA),
(2) the NUCLEUS ACCUMBENS (NA), and
(3) their projections to the PREFRONTAL CORTEX.
        (* The VTA has close association w/ the hypothalamus and limbic system)
 

(See the slide of the reward pathway again:   Reward system, slide 1 ) 

    The drug most studied in relation to this system is cocaine. Cocaine has the effect of blocking re-uptake of dopamine.  As the slide in class showed ( Cocaine, slide 1 ), this occurs in a number of areas-- each accounting for different effects related to cocaine.  You should have also noticed, though, that cocaine's actions were concentrated at the NA and the VTA-- which are rich in dopamine synapses (where it is excitatory).   The net result is an increase in activity in the "reward" centers (see   Cocaine, slide 2 ).

As pointed out in lecture and the movie, other drugs (that create very different feelings than cocaine) also increase dopamine's activity in the reward system.   Opiates and marijuana were presented as examples in class.    Opiates, such as heroin, do not act at dopamine synapses directly:   Instead, by acting at the opiate receptors, heroin (most likely) decreases GABA activity which allows an increase in dopamine release ( Opiates, slide1 ).  The net result, then, is the same: Increased dopamine activity that increases "reward" ( Opiates, slide 2 ).

(Incidentally, with marijuana, the active ingredient (THC) acts at the VTA and the NA ( Marijuana slide ).  THC's actions here are VERY recently found and not fully understood.  One possibility is that THC acts at a THC receptor (recently discovered) that either (a) directly  increases the release of dopamine or (b) (as with heroin) inhibits the inhibitory action of (probably) GABA.  The net effect is, then, again, the same.)

NOTE: Although commonality exists between drugs in their stimulation of dopamine in the mesolimbic, or reward, pathway, the textbook properly points out that it would be simplistic to assume that this is the single cause of reward and addiction.  However, it has provided a richly important step toward understanding addiction at a neurological level.

(Above images and information obtained from NIDA's web site.)

Tolerance:

BASED HEAVILY ON THE IDEA OF HOMEOSTASIS, tolerance refers to a decreased responsiveness to a drug.  That is, the same amount of drug will result in a diminished amount of change or more drug is needed to maintain the same level of effect.  (Pp. 94-96)

The basic idea underlying tolerance is that the body wishes to maintain homeostasis.  Hence, when you're cold, you shiver; when you're hot, you sweat.  Your body is trying to regain an internal level of balance.  A drug disturbs that balance, so the body's response is to try and counteract that change.  Once that change has taken place, it will take more drug to cause the same shift in balance (like a game of tug-of-war between the body's changes and the drug's effects).

PHARMACOKINETIC TOLERANCE:  This type of tolerance comes from CHANGES IN DRUG DISPOSITION.  That is, this describes changes in the body that lessen the amount of drug available to reach the site of action.  Somewhat rare, but the textbook provides one example for for alcohol: 

habitual, heavy use of alcohol increases the number of enzymes in the liver needed to metabolize alcohol, thus increasing speed of elimination.  Accordingly, it takes more alcohol to 'flood' the system and lead to intoxication.

PHARMACODYNAMIC TOLERANCE:-- This is a more typical form of tolerance and refers to changes at the site where the drug has its effects.

Where drugs are receptor agonists or cause increased neurotransmitter availability, tolerance can occur because of:

  1. a decrease in the number of available receptors on the receiving neuron.  This makes it harder for the receiving cells to fire, thus counteracting the over-activation caused by the drug;

  2. through a decrease in sensitivity of the receptor to the transmitter.  This makes it more difficult for the cell to fire;

  3. a change in the receiving cell, once the receptor has come in contact with the drug or natural transmitter.  This also makes it harder for the receiving cell to fire;

  4. the body produces or releases less of the neurotransmitter whose effects are being boosted by the drug;

  5. the body produces more of the neurotransmitter(s) that normally counteract the effects of the boosted neurotransmitter.

  6. And other areas of the body may come to compensate for changes in activity in another system.  So, increases in sympathetic nervous system activity, for example, may result in a counterbalancing increase in parasympathetic activity.

Where drugs are receptor antagonists or cause decreased neurotransmitter availability, tolerance can occur through means opposite those described above:

  1. an increase in the number of available receptors on the receiving neuron.  This increases the chance of contact by whatever neurotransmitter is available, thus it's easier for the receiving cells to fire;

  2. through a increase in sensitivity of the receptor to the transmitter.  This makes it easier for the cell to fire;

  3. a change in the receiving cell, once the receptor has come in contact with the drug or natural transmitter, making it easier to move the cell to firing;

  4. the body produces or releases more of the neurotransmitter whose effects are being reduced by the drug; 

  5. the body produces less of the neurotransmitter(s) that normally counteract the effects of the boosted neurotransmitter.

  6. And, again, other systems may kick in to compensate.

 

In any case, the drug's effectiveness would be diminished by these alterations made by the body.  The user will then compensate for the reduced drug effects by taking more and more of the drug.

 

Another effect of this building tolerance, is that the body has changed its own normal way of functioning.  The body now expects the presence of the drug in order to be near balance.  As with a game of tug-of-war, if one side decides to let go, the other will go falling backward because they've lost the counteracting pull.  In the case of the body, the result is that when the drug is removed the body's compensatory response is acting without the "pull" of the drug.  Thus, the body is pushed out of balance-- but in the direction opposite of that caused by the drug.  That's the characteristic of withdrawal symptoms.  That is the reason why withdrawal symptoms tend to be in direct opposition to the effects of the drug-- 

amphetamine use (stimulant) → depression and lethargy withdrawal symptoms;

alcohol or barbiturates (depressants) → anxiety and possible seizures, etc., as withdrawal symptoms

Finally, don't forget to look at the textbook's info. on the pharmacology of opiates (pp. 109-205) and stimulants, including cocaine and amphetamines (pp. 188-194).  

I won't be adding much to the information provided in the text. Primarily, I'll just provide some guideline as to what to get from the reading.  Here are the main points I want you to get:

  1. The basic pharmacology of each type of drug-- what neurotransmitters are involved, how do the exert their effects on those systems (i.e., alter availability or act at the receptor (and how));

  2. What the effects are from that change in neurotransmitter activity (how does the brain and body react and how does that make a person feel);

  3. Tolerance to the drug and effects of withdrawal.  Although we talked about tolerance and withdrawal in a general sense in class, be aware of what occurs specifically with these drugs;

  4. What a person might expect after short-term or long-term use of these drugs;

  5. How cocaine and amphetamine are similar and ways in which they are different.

All these tie together and really stem from the changes that occur in the specific neurotransmitter systems.

After reading this material, watch the following short video from the "Addiction" series shown in class.  The clip follows a young couple who are both addicted to opiates.  It explains opiate addiction a bit, discusses the brain mechanisms, and explains replacement therapies.  The people in the movie do not match the stereotype of  opiate addicts, but do reflect a segment that's out there: Young, employed, and without the insurance necessary to pay for treatment....

Opiate addiction: A new medication

(Time: 9:50)

 
Click below to test yourself on the pharmacological information:

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Lastly:

This material touches on a number of complex issues that connect physiology with addiction.  Use the Internet to explore these issues more deeply and help your understanding:

The following link for "The Brain from Top to Bottom" provides interactive information about brain anatomy and physiology, and allows you to explore different issues about brain activity from “beginner” to “advanced” levels.  If you choose the icon labeled “Pleasure and Pain” you’ll learn more about the reward centers:  http://www.thebrain.mcgill.ca/flash/index_d.html

Another web site that provides interactive overviews of topics covered in this chapter, including drugs and genetics and natural reward pathways, is the University of Utah’s “The New Science of Addiction: Genetics and the Brain” website.  Access it at:
http://learn.genetics.utah.edu/units/addiction/ 

What’s the most addictive drug?  How does heroin’s addictiveness compare to nicotine’s?  Do a Google search on “rank of addictiveness” or similar terms.  You’ll find various links that rank-order substances based on different criteria.  Do you agree with the criteria used?  How much variability do you notice among ranks?

Still eager for some self-testing on neuroendocrine information?  See:

Brain Trivia game and flashcards