The basic question that is being addressed here is, "How does the drug get from the shelf to
the receptive tissue?" We know
from casual experience with pharmaceuticals that drug effects are neither immediate (the headache
does not go away at the
instant the pill is taken), nor permanent (repeated dosages must be taken). The full consideration
of these issues requires a
knowledge of membrane biophysics, acid-base kinetics, and other aspects of cell physiology; all
of which are of critical
importance in the design of pharmaceutical products and in understanding certain aspects of drug
actions. Fortunately, we need
only consider some of the more global aspects of these topics at this point.
One of the most important determinants of a drug effect is the concentration of drug
molecules in the bloodstream or plasma
compartment of the body. The drug concentration is determined by the rate of entry into the
blood stream and the rate of exit
from the bloodstream. In each case, the compound must cross a membrane barrier.
The various membrane surfaces of the body are very similar in terms of their properties that allow specific types of molecules to pass through them. The membrane can be considered as a double layer of lipid molecules sandwiched between an inner and outer layer of protein molecules (Fig. 3.1). Small membrane pores (about 4-8 Angstroms in diameter) penetrate these layers at intervals along the surface. This physical structure determines the way in which a particular molecule will pass through the membrane:
a. Molecules that are smaller than the diameter of the pores cross the membrane by passive diffusion
b. Molecules that are lipid soluble dissolve in the membrane and diffuse through it according to the concentration gradients.
c. Molecules that are too large and not lipid soluble do not pass through the membrane,
except when special metabolic systems
called active transport systems carry the molecules
through the membrane. Such transport mechanisms are fairly common for
endogenous compounds, but do not appear very frequently in the case of pharmaceutical
compounds.
There are many different ways in which a drug can be administered, or in terms of the above
discussion, different ways to make
the drug accessible to the membranes that allow passage into the circulatory system. One way to
modify the accessibility of the
drug is to change the vehicle, or carrier, of the drug. For
example, the drug may be mixed with distilled water, saline, oil, or
even solutions of other drugs to systematically change the characteristics of entry into the
bloodstream. The rate at which a
drug enters the circulatory system varies tremendously, depending upon the route of
administration:
Table 3.1
Major Routes of Drug Administration |
| Oral |
| Rectal |
| Mucous membranes |
| Inhalation |
| Subcutaneous injection |
| Transdermal infusion |
| Intramuscular injection |
| Intravenous injection |
| Intraarterial injection |
| Intraperitoneal injection |
| Intrathecal injection |
| Intracranial injection |
There are, however, some special characteristics of the gastric environment that may cause
difficulties for the administration of
certain drugs. The high acidity of the stomach may alter the structure of the drug, causing it to
precipitate and be less easily
absorbed. Depending on the acid-base characteristics of the drug, the gastric environment may
either increase or decrease the
tendency of the drug to split into ionized (or charged) forms. This is a very important
consideration for large molecules,
because only the non-ionized forms of otherwise lipid soluble compounds will pass through the
lipid barrier of the membranes.
Because of the differences in pH of the stomach and the intestines, some drugs which are not
readily absorbed through the
stomach walls because of ionization change their state when they pass from the stomach to the
intestine and become lipid
soluble. This effectively delays the entry of the drug into the bloodstream. By contrast, other
drugs may become ionized and
ineffective upon leaving the stomach, so that the amount of the original dosage that actually
becomes useful is determined by
the length of time it was in the stomach. Modern manufacturing methods now produce several
different "time release"
formulations that encapsulate the drug into a vehicle that dissolves at some specified rate to
release the drug dosage gradually
over time.
Table 3.2
| Major Routes of Drug Disposition |
| Protein binding |
| Liver Enzymes |
| Renal excretion |
| Body surface |
| Pools |
In most cases, the combination of all of the mechanisms listed in Tables 3.1 and 3.2 leads to a
gradually increasing level of
drug in the bloodstream, a stable level for a time, followed by a gradual decline. The duration of
each of these phases depends
upon the drug, the vehicle, the initial dosage, the route of administration, and the organism's
current physiology--a moving
target in every sense of the word.
We turn now to some considerations of drug dosage as they interact with behavior.
B. DOSAGE AND
BEHAVIOR CONSIDERATIONS
Dose-Response Curves
One of the most important principles of behavioral pharmacology is the concept of the dose-response curve. The simplest and
most general expectation would be that larger dosages produce larger effects. Indeed, this is
almost always true within some
range of the drug dosage, but there is usually some level of dosage beyond which this relationship
breaks down, and larger
dosages produce progressively less of an effect or even an opposite effect.
An example of this type of dose-response relationship can be seen in Figure 3.2, which shows a schematized change in
behavior as a function of various dosages of a drug. Using the same behavioral measure, other
drugs would show differently
shaped curves at different peak plasma levels. The important point is that the effect of a drug on a
behavior cannot be stated in
a simple manner: A particular drug may enhance the behavior at low dosages, have no observable
effect at some higher dosage,
and impair the behavior at still higher dosages. Thus, the appropriate answer to the question,
"What does Drug X do to
Behavior Y?" is "It depends."
This type of noncommittal answer is (or should be) commonplace in the field of behavioral
pharmacology. As shown in Figure
3.3, the plasma concentration of a drug changes continuously over time, as discussed in the
previous section of this chapter. If
one were to transfer sections of this changing concentration curve to the dose response curve in
Figure 3.2, the behavioral
effect at any given time would be changing in accordance with the changing concentration curve.
In fact, with a single large
dosage, it would be possible to show a gradual enhancement of behavior as the drug
concentration was increasing, a decline
and eventual impairment of behavior as the plasma concentration reached very high levels, a
return to enhanced behavior as the
drug concentration began to lower, and finally a return to baseline levels as the drug was cleared
from the plasma compartment
completely. Thus, the effect depends not only on the amount of drug administered, but on the
amount of time that has elapsed
since the administration.
Given the interaction of behavior with drug dosage and the dynamic nature of the drug
concentration, about the best one can
hope for in terms of a stable effect is that shown in Figure 3.4.
Properly spaced multiple dosages of a drug can lead to a more
or less sinusoidal variation in plasma concentrations within the range of dosage that has the
desired behavioral effect.
This same principle can be applied in many cases of the behavioral effects of drugs. As shown
in Figure 3.5, behaviors that
have a moderate baseline respond in the typical dose-dependant manner; an increase at moderate
dosages and a progressive
decline at higher dosage levels. Behavior that begins at high levels is less effected by low dosages
and the first effect that is
observed is a decline in the rate. At lower baselines, the drug-induced increase continues into
higher dosage ranges before
declining.
The law of initial values, as it applies to behavior, is frequently referred to as a rate
dependency effect. That is, the effect of a
drug depends upon the rate of behavior that is observed at the time the drug is administered.
These principles certainly do not
apply to all drugs, but the phenomenon is sufficiently common to make it necessary to consider
the possibility whenever a new
drug and behavior combination is tested.
The law of initial values interacts in a complex fashion with the concept of dose-response
effects. In some sense, it is possible
to hold the plasma level of a drug constant and vary the "dosage" of behavior (low, moderate, or
high) that is used to assay the
effects of the drug. Furthermore, there is very likely a dynamic interaction between the baseline
behavior and the drug-altered
behavior in that a higher rate of behavior (induced by the drug) might be less influenced by the
drug.
Drugs Have
Multiple Effects
It is almost a truism that every drug has multiple effects. Ideally, a drug would have only one
effect, which could be used for a
specific therapeutic purpose. More commonly, any given drug may have several major effects and
several minor effects. As an
example, a particular drug may be given as a muscle relaxant, but have a "side effect" of producing drowsiness. The same
compound may be prescribed for another patient for the purpose of producing drowsiness and
lowered anxiety, with a side
effect of muscle relaxation. Along with these major effects, several minor side-effects might be
common to both prescriptions
and include cardiovascular problems, gastrointestinal upset, skin rashes, and so forth. In general,
the higher the dosage, the
greater the number of different drug effects.
Each of these effects and side effects may have a different dose-response curve. As a result, a typical situation might be that shown in Figure 3.6, in which a dosage prescribed for Effect A might have Side-Effect C. A dosage prescribed for Effect B would be would have Side Effects C and D, as well as the tail end of Effect A, which is labeled Side Effect E. This sort of entanglement of desired effects and side effects prevents many drugs from being marketed.
These considerations are especially important in trying to unravel the effects of a drug upon
complex behavior. Consider, for
example, a situation in which an animal is performing a visual discrimination that enables it to
obtain food and avoid shock
according to a variable interval schedule. A particular drug would very likely influence each
aspect of the task (e.g., visual
perception, hunger, pain threshold, memory, etc.) at differing dosages, and the rate of behavior
engendered by task parameters
would, in turn, interact with the drug dosage. Thus, many different combinations of observations
must be made before a
complete account can be given.
A specific set of examples may help to understand some of the dynamics of these
dose-response curves, multiple effects, and
other complications of interpretation (refer to Fig. 3-7).
Low doses of epinephrine produce a slight drop in blood pressure, whereas high doses
produce a large increase in blood
pressure. This curious reversal of effects can be explained as follows: The molecular structure of
epinephrine allows it to
interact with both alpha and beta receptors. The beta receptors, although fewer in number, are more sensitive
than the alpha
receptors. With low dosages of epinephrine, the beta receptors are the
only ones effected and they inhibit the smooth muscles
of the blood vessels causing a decrease in the pressure through vasodilation. High
doses of epinephrine stimulate alpha
receptors, which cause the constriction of blood vessels and a corresponding increase in blood
pressure. The beta receptors are
also stimulated, but their influence is overpowered by the effects of the alpha receptors. (Careful
observation will show a brief
reduction of blood pressure as the epinephrine first enters the system and as it is finally leaving the
system, reflecting the low
concentrations of the drug at these times.)
Almost exactly the same type of change in blood pressure can be observed with low and high
doses of acetylcholine, but for
different reasons. Low doses of acetylcholine reduce the blood pressure by acting on
the muscarinic receptors which inhibit
the smooth muscles of the blood vessels to cause vasodilation. High doses of
acetylcholine produce a large increase in blood
pressure by stimulating the nicotinic
receptors of the autonomic ganglia (refer also to Fig. 1-9 and Fig. 1-12). These nicotinic
receptors are much less sensitive to circulating levels of acetylcholine, but once stimulated, their
effects are much more potent
than those of the muscarinic stimulation. Under these conditions, the sympathetic ganglia predominate, and the resulting
stimulation of the adrenal gland and release of norepinephrine from the sympathetic fibers cause
an increase in blood pressure.
Thus, the large dose of acetylcholine increases blood pressure indirectly via sympathetic arousal.
In these examples, we see the essence of dos-response interactions. Two completely different
drugs (epinephrine and
acetylcholine) produce identical profiles of change in blood pressure (a decrease at low doses and
an increase at high doses.) In
each instance, the reversal occurs because low doses influence one type of receptor while high
doses influence a different type
of receptor. Furthermore, in the case of acetylcholine, the final effect is actually due to the
indirect activation of an opposing
system. This particular set of results makes sense because the underlying mechanisms have
already been determined. In many
cases of drug and behavior interactions we do not yet enjoy this luxury.
Individual
Differences in Drug Effects
The effectiveness of specific drugs can also be influenced by a wide range of organismic variables such as species, age, sex,
disease status and behavioral history. In many cases, the specific origin of these differences in
drug response cannot be
identified, but some general comments can be made in relation to the dosage considerations
discussed above. The notation of
such variables as age, sex, species, and so forth does not describe the underlying cause of
differences in drug response, but is
rather used as a convenient label for sub-populations that may share some common physiological
variable.
One of the most important physiological differences that interacts with the behavioral effects
of drugs is the neurochemical
status of the brain. There are well documented changes in brain chemistry during the course of
development and continuing
through senescence. The presence or absence of sex hormones, the environment of the organism,
and the behavior that the
organism engages in can all modulate these neurochemical changes. Since most of the
behaviorally active drugs produce their
effects through interaction with these chemical substrates, the variables that alter neurochemistry
interact with drug response.
It is simply easier and more convenient to specify some external variable such as age or sex, rather
than attempting to outline
the more directly relevant neurochemical factors.
Differences in drug response can also occur in the absence of any important differences in the
neurochemical substrates. All of
the ports of entry into and exit from the bloodstream vary as a function of these external variables.
For example, liver function
is not fully developed in the very young and no longer fully efficient in the very old. Differences
in behavioral and dietary
history will alter liver function, gastrointestinal function, cardiovascular efficiency and general
metabolism. Body fat levels
vary in response to a wide range of variables. Each of these changes has the capacity to alter the
drug response through a
simple shift in the time course of effective drug concentration in the bloodstream. The same
relative quantity of drug might
produce an increase in the behavior of a young organism, no change in adult females, and an
impairment of behavior in aging
males. As indicated before, "It depends."
Drugs differ markedly in the actual amount that is effective, ranging from millionths of a gram
up to several hundred
milligrams. Perhaps the most important bit of information about a particular drug is the smallest
dosage that will produce a
desired effect. This measure has been termed the minimum effective
dosage (MED) and is usually determined empirically by
administering varying dosages to a test population to calculate the minimum dosage that is
effective in 50 percent of the
population, the MED-50 (sometimes it is simply referred to as
the ED-50). Since most drugs have the potential for lethal
effects at high dosages, a second measure is calculated for the lethal dosage for 50 percent of the
population, the LD-50. A
safe drug is one which has a lethal dosage that is several times larger (preferably 10 or more) than
the effective dose. This
therapeutic ratio (LD-50/MED-50) represents the
clinical safety factor of a drug. This ratio is not specific to a drug, but
rather to a drug effect: A drug, for example, might have a safe ratio for use in anxiety reduction,
but be dangerous in the
dosage required for muscle relaxation.
C. THE
BLOOD BRAIN BARRIER
All of the preceding discussion of the dynamics of drug dosage has dealt with the general
concepts of the passage of drugs
between the bloodstream and the tissues. Although these general principles continue to apply,
behaviorally active compounds
require special consideration because of some of the unique physiological aspects of the brain. In
particular, the vascular
system of the brain is both quantitatively and qualitatively unique.
The brain is one of the most richly vascularized organs of the body. The two internal carotids
and two vertebral arteries (which
supply all the blood to the brain) branch out into an extremely dense system of capillaries.
Consequently, the brain is
responsible for nearly twenty percent of the body's total oxygen consumption, even though it
accounts for less than two percent
of the body mass. Neurons are particularly vulnerable to ischemia, and such a lack of blood flow for as little as four to five
minutes can lead to serious brain damage.
Ordinarily, organs that are highly vascularized receive a disproportionate share of a circulating
drug, because the rate of
equilibration of drug levels in the plasma and the adjacent tissue is directly related to the rate of
blood flow. However, the
dense capillary system of the brain is very selective in terms of the molecules that will pass
through into the surrounding tissue
space. Water, oxygen, carbon dioxide pass freely through the endothelial walls. Glucose, which
supplies virtually all of the
nutritive requirements of brain tissue, also passes through relatively freely. Thus, there is an
efficient exchange of molecules
that are essential for the high metabolic demands of neural tissue.
The story is quite different for other types of molecules. The capillaries of the brain have two
special features that tend to
prevent the passage of molecules into the adjacent tissue space. The endothelial cells that form
the walls of the capillaries are
densely packed, such that only small molecules can pass through the junctions. Additionally, glial
cells called astrocytes
surround about 85% of the surface of the capillaries, adding a lipid barrier to the system. Thus,
large molecules and molecules
that are not lipid soluble do not easily penetrate the brain. These special features of the cerebral
vascular system have been
termed the blood-brain barrier.
Another special feature of the central nervous system is the cerebrospinal fluid (csf) which fills the ventricles of the brain and
central canal of the spinal cord. The csf is formed by blood vessels within the ventricular system,
most notably the
concentrated groups in the lateral ventricles which are termed the choroid plexus. The csf excreted by these vessels is similar
to blood plasma, except for very low levels of proteins and cholesterol. It is the extracellular fluid
of the brain, which is formed
continuously and absorbed (by the arachnoid villi) at a rate of about 10% per hour. Thus there is
a continual flow of the fluid
which bathes the brain cells. The capillary walls of the choroid plexus have the same dense
epithelial structure as those within
the brain tissue proper, hence provide an extension of the blood-brain barrier.
The blood-brain barrier should not be viewed as a system which isolates the brain, but rather
as one which buffers it from the
changing conditions of the remainder of the body (see Fig. 3.8). The
critically important ions that determine the electrical
excitability of neurons (Na+, K+, Ca++, and Cl-) equilibrate with the brain fluids very slowly,
requiring as much as 30 times
longer than in other tissues. Relatively small molecules such as urea are exchanged rather freely
with muscle tissue and other
body organs, but enter the brain very slowly over a period of several hours. Larger molecules
such as bile salts and circulating
catecholamines (from the adrenal glands and peripheral autonomic nervous system) are essentially
blocked from entering the
brain. (However, the acidic precursors of brain transmitter amines such as L-DOPA and
5-hydroxy tryptophan enter readily.)
Thus, the brain is protected from fluctuations of chemicals in the plasma compartment, allowing
homeostatic processes a
considerable margin of time to correct any deviations while the brain's environment remains
relatively constant.
The physiological paradox that arises is that a buffer system between the fluctuating
physiology of the organism and the brain
also buffers the information that the brain must use to guide the correction of the homeostatic
deviations. This paradox has
apparently been resolved by the presence of a group of structures called the circumventricular organs. As the name implies,
these organs lie adjacent to the ventricular system of the brain and more importantly, lie outside
the blood brain barrier. There
are five such organs, each of which appears to have specific chemical receptors to monitor
changing body conditions and relay
the information to other areas of the brain: The subcommissural organ and subfornical organ are
responsive to levels of
angiotensin and plasma volume, respectively, and are important in the regulation of thirst for the
maintenance of body water
and electrolyte balance. The posterior pituitary is responsive to a variety of pituitary, adrenal,
gonadal and hypothalamic
hormones, and helps to regulate the circulating levels of all of these. The pineal gland is involved
in circadian rhythms. The
functional importance of the supraoptic crest is uncertain.
The nature of the blood brain barrier poses a number of problems in terms of the behavioral
response to drugs. In the most
extreme cases, some compounds simply do not enter the brain in significant concentrations. In
other cases (e.g., dopamine or
serotonin), the relevant compound per se does not enter, but the precursor molecules can be
administered to facilitate the
synthesis of the active form within the brain. The compounds can also be injected directly into the
brain or CSF, physically
bypassing the barrier, but several compounds have so called paradoxical effects on brain tissue.
For example, penicillin
produces convulsions, epinephrine in the ventricles leads to somnolence, and curare can lead to
seizures. Aside from some
general guidelines relating to molecular size and lipid solubility, it is difficult to predict with
accuracy how easily a drug will
penetrate the brain and what the effect will be. In many cases, it is necessary to make an empirical
determination.
A more subtle aspect of the blood brain barrier is that it is differentially effective in different
areas of the brain. The white
regions of the brain are composed mainly of fibers, which are surrounded by glial cells to form the
myelin sheaths. As a result
of this additional lipid barrier, these regions of the brain reach equilibrium with certain drugs much
more slowly than the
cellular regions of grey cortex. To the extent that these different areas serve different behavioral
functions or are differentially
sensitive to the drug, the overall response to a drug dosage over time will become increasingly
complicated.
Finally, the blood brain barrier changes as a function of organismic variables, the most
important of which is probably age. The
myelinization of fibers appears late in the course of ontogenetic development. Consequently,
young organisms are frequently
responsive to drugs that are ineffective in adults. Furthermore, the completion of the process of
myelinization is not uniform
throughout the brain, so that organisms of different ages would have different concentrations of
drug in certain brain areas that
were not fully myelinated.
On the bright side, the blood brain barrier can be a useful stage for certain types of
experiments. One of the best known is that
involving drugs that block the acetylcholine receptor. The systemic administration of such
compounds (e.g, atropine or
scopolamine) influences not only the brain, but also the entire parasympathetic division of the
autonomic nervous system. Are
the resulting effects due to brain actions or the effect upon the peripheral system? The addition of
a methyl group onto the
nitrogen of these compounds (methyl atropine or methyl scopolamine) forms a compound that is
very similar in terms of its
effects in the periphery, but it will not cross the blood brain barrier. Thus, if the centrally active
form produces an effect that
the methylated form does not, a reasonable conclusion is that the effect is caused by the action of
the drug on the brain.
D.
CLASSIFICATION OF DRUGS
Methods of Classification
One of the most important contributions of the scientific method is that of classification. Through
the process of classification,
chaos turns into order and mountains of individual facts turn into simple concepts. As examples,
we have the organization of
plants and animals into an organized system that defines genera, orders, families and species of
animals. We have the periodic
table that organizes elements on the basis of their subatomic structure. In each case, the
classification results in a system that
both facilitates memory and increases our understanding of the interrelationships among the
various subcategories--the
concepts of mammals and heavy metals provide insights that might not be apparent from the
particular examples of llama and
lead.
The goal of the field of behavioral pharmacology is to organize and classify behavior and
drugs into systems that will enhance
our understanding of the relationships between chemistry and behavior. At the present state of
development of this discipline,
there are numerous schemes for organizing the available information, and none of these is as
discrete and well organized as the
systems for organizing chemical elements and species. An additional hundred years or so of
research will certainly improve
this situation, but we already have some useful systems of classification that guide our research
efforts and our thinking in this
area.
There are three major methods of classifying drugs: (a) behavioral, (b) biochemical, and (c)
structural. Table 3.3 shows a few
representative selections for each type of classification. This table is by no means exhaustive, but
simply shows the types of
considerations that go into each scheme of classification.
Table 3.3
| Drugs Classified by
Molecular Structure |
Drugs Classified by
Biochemical Actions |
Drugs Classified by
Behavioral Effects |
| amino acids | receptor blockers | stimulants |
| monoamines | mimickers | sedatives |
| benzodiazepines | synthesis inhibitors | hallucinogens |
| alcohols | false transmitters | antidepressants |
Behavioral categories.
The classification that we are most interested in is that involving the behavioral effect of the drug.
Drugs are administered to
produce some alteration in behavior (or physiology) such as increasing arousal level, combating
depression, lowering blood
pressure, and so on. As information about the effect of each particular compound becomes
available, the name of the drug can
be added to the list pertaining to each desired effect.
This method of classifying drugs by their behavioral action is probably the oldest method
used. As indicated in Chapter 1,
early practitioners discovered various herbs and chemical preparations that produced specific
effects. This method has
limitations, however, in that the categories that define behavioral change may not always be
sufficiently specific and any
particular compound may have several different effects.
The headings in the biochemical scheme of classification are based on the mechanisms of
chemical neurotransmission. A
typical way or organizing the information is in terms of drugs that either impair or facilitate the
action of a particular
neurotransmitter system. Let us consider some of the logical possibilities for changing the
function of a particular transmitter
system (refer to Fig. 3.9):
a. Precursor compounds
In some cases, the amount of transmitter substance that is synthesized and stored for later
release may be increased by injecting
additional precursor molecules.
b. Synthesis blockade
A drug may interfere with the enzymes of synthesis (Es), reducing the amount of transmitter
substance that is available for
release.
c. Transmitter depletion
A drug may cause the gradual and continual leakage of transmitter substance from the
vesicles, resulting in an exhaustion of
the transmitter stores.
d. Prevention of release
A drug may interfere with the release of transmitter that normally occurs when an action
potential arrives at the terminal
bouton.
e. Receptor inhibition
A drug may have chemical characteristics that allow it to occupy the receptor sites and prevent the normal transmitter substance from acting. This can occur in two separate ways: Some drug molecules occupy the receptors in a reversible manner, and simply compete with the real transmitter molecules for access to the receptors (competitive inhibition). Other drug molecules may alter the physical shape of the receptor so that the real transmitter no longer fits, thereby reducing the total number of functioning receptor sites (noncompetitive inhibition).
f. Mimicking
A drug may have chemical characteristics that allow it to occupy the receptor sites and
stimulate the postsynaptic membrane in
a manner comparable to that of the naturally occurring transmitter.
g. Inactivation blockade
A drug may interfere with the enzymes that normally degrade the transmitter substance (Ed).
In low dosages, this can increase
function, but if the accumulation of transmitter is too great, the continuous stimulation can
actually block function by
preventing repeated action potentials.
h. Reuptake blockade
This is functionally equivalent to item g above, but occurs in those systems in which the
transmitter is inactivated by the
process of re-uptake rather than enzyme degradation.
i. False transmitters (-)
A drug may be taken up by the cell, stored in the vesicles, and released along with normal
transmitter during normal
stimulation. To the extent that the drug molecules are less effective, or actually block receptors,
the level of function will be
reduced.
j. False transmitters (+)
This is identical to item i, except that some drugs may be more effective than the naturally
occurring transmitter and increase
the level of function upon release.
k. Conduction blockade
Some drugs may prevent the action potential from being conducted down the axon to the
terminal bouton. In these cases, the
entire synaptic region may be functionally normal, but is rendered nonfunctional because
stimulation cannot occur. These
drugs are usually not specific to a particular transmitter system, but are more likely to be selective
in terms of metabolic
properties, as in the case of some local anesthetics that influence primarily fibers of small size.
As indicated in earlier sections, most drugs have multiple behavioral effects which may be due
to multiple biochemical actions.
Drug dosage would interact in a complex fashion with neuronal function in those cases, for
example, in which low levels of the
drug blocked re-uptake while higher levels also mimicked the real transmitter. Also, as indicated
in items f, g and h above,
excessive stimulation can result in a functional blockade.
Structural
categories.
The third column in Table 3.3 includes categories that are based strictly on the molecular
structure of the drugs. This column
by itself provides no information at all about either the biochemical action of the drug or the
behavioral (physiological) effect of
the drug. As we will see below, it becomes useful only when used in the context of the other two
columns.
Categories are Useful in Understanding
Drug Effects
Therapeutically, the second and third columns of Table 3.3 are completely irrelevant. It would be
possible to list the names (or
numbers, for that matter) of compounds that are known to have each desired behavioral effect.
The drugs could be prescribed
solely on the bases of their effects and nothing more need be known. Indeed, this accounts for a
large portion of day-to-day
therapeutic decisions. Yet, it is an unsatisfactory (and potentially dangerous) state of affairs if this
is done in the absence of an
understanding of how the drugs interact with the brain and behavior. We will now examine more
carefully the progression
from a simple, pragmatic practice of therapeutics to a more fundamental understanding of the
drug interactions with the brain
and behavior.
The complexity of understanding drug effects arises from the fact that any drug produces
multiple changes in behavior and
different drugs may produce similar changes in behavior. For example, Drug A may reduce
depression and also cause tremor.
Drug B may be equally effective in reducing depression, but also cause drowsiness. Why?
The answer to this question must be sought at another level of analysis. Typically,
researchers would determine the
relationship between the biochemical actions of Drug A and Drug B. If both drugs interfere with
the reuptake of Transmitter
X, then one can postulate that Transmitter X may be the basis for the mutual effect of combating
depression.
A test of this postulation might involve moving over to the third column of Table 3.3 to
compare the molecular structure of
Drug A and Drug B. If these compounds are similar in structure, then additional compounds
(Drug C and Drug D) may be
synthesized and administered to determine their behavioral effects on depression and their
biochemical actions on Transmitter
X.
Figure 3.10 schematizes this procedure of interrelating
molecular structure, biochemical activity and behavioral effect. This
process forms the basis for all of our research and can sometimes lead to a relatively complete
understanding of the chemical
bases of behavior. For example, an entire group of compounds may differ only in terms of the
length of the carbon chain that is
attached to a common triple-ring structure. If the effectiveness of these compounds in blocking
the reuptake of Transmitter X
is related to the length of this side chain, then something has been learned about the biochemical
specificity of this reuptake
mechanism.
This type of information is called the structure-activity relationship and has been determined for a number of different systems as will be seen throughout the text. For example if the same compounds that are most effective in blocking reuptake are also most effective in combating depression, then it seems likely that depression may be related to the level of functioning of this particular transmitter system. Additional compounds (e.g., compounds that mimic the transmitter or increase the synthesis) may be studied to further evaluate the hypothesis. The resulting description of the relationship between drug and behavior is far more useful than a simple catalogue of drugs and drug effects.
We have examined some of the basic principles for the organization of the brain and behavior,
some of the considerations that
go into the study of drug effects, and some of the considerations that go into classifying drugs for
purpose of therapeutics and
research. The next section of the text will study specific areas in which these principles have been
especially useful in
furthering our understanding of the chemical bases of behavior.
E. SUMMARY
Principles
1. Drug molecules must reach the appropriate target tissues before they can become effective.
2. The accessibility of the drug molecules to the target tissue is largely determined by the
amount of drug in the bloodstream.
3. Drug molecules may be injected directly into the bloodstream, but they are more
commonly administered by indirect routes
such as oral ingestion.
4. Once the drug has been administered, a host of physiological factors determine the how
fast the drug molecules enter and
exit the bloodstream.
5. Different dosages of a drug change not only the magnitude of the drug effect, but also the
nature of the drug effect.
6. All drugs have multiple effects, and the term side effect is usually applied to an effect that
is not desired.
7. Individual differences such as behavior, gender, age and general health status all influence
the effectiveness of a drug.
8. The blood brain barrier provides a buffer between the central nervous system and the
remainder of the organism's
physiology.
9. The classification of drugs according to biochemical actions and molecular structure
contributes to the development of new
drugs and a better understanding of the chemistry of behavior.
Terms
Active transport