The idea that a brain area was responsible for arousal set the stage for the complementary notions
that a brain area could be directly responsible for putting an animal to sleep, i.e., sleep may be an
active process rather than a passive result of reduced sensory stimulation. The evidence for this
emerged from a number of different experiments that involved transection of the brain at various
levels. Transection at the level of the spinal cord had little or no effect on arousal, transection at a
somewhat higher level resulted in permanent wakefulness (presumably because of separation from
the active sleep centers), and transection at a still higher level led to permanent somnolence
(presumably because of separation from centers for arousal). The overall regulation of sleep and
wakefulness is complicated, but the diagram in Figure 8.2 is a reasonable shorthand version of
It has been known since the early 1800's that electricity was somehow involved in nervous activity
(e.g., observations by Helmholtz and by Galvani), but it was not until 1930 that the first
electroencephalogram was recorded. Berger (1930) inserted needles just under the scalp (of his
son) and was able to record rhythmic electrical waves, the frequency and amplitude of which
changed with the level of arousal. This crude demonstration was the beginning of a very active
field of study which attempts to use the electrical activity as a sort of mirror of mental events.
The results of these studies have not lived up to the hopes (or in many cases, to the
interpretations) of the investigators, with one exception: The EEG has been an indispensable tool
in the investigation of sleep and related processes of arousal.
The rule of thumb is that the rhythmic fluctuations of the EEG become slower and larger as the
level of arousal declines (refer to Fig. 8.3). It is not necessary for the present discussion to go
into the details of the EEG, but there are several important categories that deserve mention.
When the eyes are closed and the subject relaxes (without visual imagery), the normally aroused
EEG slows to about 10 Hz with an increase in amplitude. This is the so-called alpha wave The
alpha state has been touted as a highly desirable state of meditation which can be monitored and
fostered by commercial devices costing up to several hundred dollars (alternatively, one can stop
looking at the catalogue, close the eyes, and achieve about the same state). If this relaxation
continues, the wave slows even more, and the subject enters a rather nebulous state between sleep
and wakefulness. This corresponds roughly to the theta wave. The theta state has also been
viewed as a desirable state for the creative processes, although the creations are frequently
forgotten. Beyond this stage, spiked impulses called sleep spindles appear and the EEG continues
to become slower and larger until large, sweeping delta waves are accompanying by the
behavioral state of deep sleep.
There is one major exception to the relationship between level of arousal and EEG pattern.
Kleitman and one of his students observed periods of apparent deep sleep (arousal was difficult to
obtain) during which time the EEG pattern was rapid and small. This so-called paradoxical EEG
was accompanied by rapid eye movement (REM) and appears to be related to periods of
dreaming (cf., Dement & Kleitman, 1957; Kleitman, 1963).
Most will agree that sleep is a pleasant enough pastime, but it is neither a luxury nor an option.
Attempts to eliminate or reduce the amount of sleep are accompanied by compelling urges to
sleep. If these urges are fought, irritability ensues and performance becomes impaired. Webb
(e.g., 1975) has observed that desert soldiers neglect to keep their canteens filled with water, and
nurses fail to make optional rounds to check patients. Eventually, frank psychotic behavior may
result, but heroic efforts are usually required to allow sleep deprivation to reach this degree.
Webb has remarked that "Sleep is a fixed biological gift and we had better learn to adjust to its
requirements rather than try to make it serve our paltry demands." (p. 28 in Goleman, 1982.)
The phenomenon of sleep serves as sort of a caricature for two important observations: (a) cyclic
levels of activity appear to be a recurrent theme of brain function, and (b) these differing levels of
activity provide different ways of processing environmental information. We turn now to the
effects of varying degrees of arousal within the waking state before examining several classes of
drugs that have been used to alter, in one way or another, these levels of activity.
The pharmacology of sleep and arousal remains poorly understood. Jouvet (e.g., 1974) has been
the champion of the serotonergic theory of sleep, marshaling considerable evidence that serotonin
produced in the raphe nucleus is responsible for the induction of sleep. In general, drugs that
inhibit serotonin cause insomnia while the administration of serotonin causes sleep. More
recently, sleep onset has been related to benzodiazepine receptors (cf., Chapter 4; Mendelson
et al, 1983), but this does not preclude the possibility that these receptors are on cells that release
serotonin as the neurotransmitter. On the arousal side, there are at least three candidates for
neurotransmitters: dopamine, norepinephrine and acetylcholine.
Each of these is released at a
higher rate during periods of arousal, and drugs that block the effects of these compounds can
produce drowsiness. The general features of these systems is summarized in Figure 8.4. Specific
examples will be given later in the chapter.
All of these local changes in sleep patterns and levels of arousal occur against a more global
backdrop of circadian (24-hr) rhythms. There is a powerful rhythmicity for virtually all
organisms and systems within organisms (e.g., Moore-Ede et al, 1982). Although these rhythms
are synchronized with and, in many cases, adjusted by the light/dark cycle, most of these rhythms
continue in the absence of normal 24-hr cues. In a dramatic demonstration of this, sleep
researcher Nathaniel Kleitman and several associates went deep into a deep cave where they
attempted to adapt to an arbitrary 19.5-hr day. None of the individuals could do this; they each
showed a so-called "free-running" rhythm that was somewhat greater than 24 hrs, drifting forward
with respect to the "real" time set by the sun up at the earth's surface (Kleitman, 1963). The
brain area that is responsible for setting many of these circadian events is the suprachiasmatic nucleus, located in the hypothalamus.
This nucleus receives information via an accessory optic
system (and perhaps through other sensory channels) to adjust and maintain the accuracy of its
inherent 24-hr rhythmicity. Injection of radioactive 2-deoxy glucose (2-DG) into brain areas can
provide a graphic illustration of the rate of metabolism for a particular area. When this procedure
is used to study the suprachiasmatic nucleus, it shows a marked circadian rhythm of activity. This
corresponds with fluctuating levels of melatonin that are produced and released by the pineal
gland (see Figure 8.5).
The circadian rhythm is interesting in its own right, but it is especially relevant in the present
context because it provides a constantly changing environment in which drugs must act. Changes
in hormone levels, body temperature, rate of metabolism, heart rate, blood pressure,
gastrointestinal activity, sleep cycles and behavioral activity levels all change markedly on a 24-hr
schedule. A drug that interacts with any of these (and how could one not!) will have differing
effects for a given dosage, depending upon the time of day. This can be shown dramatically in the
case of anesthetic drugs, which are effective in much lower dosages during the rats' normal
(daytime) quiet periods (Davis, 1962; see Figure 8.6). Higher doses are required during the
active periods, increasing the risk of overdose (Pauly & Scheving, 1964). Conversely, drugs that
specifically alter any of these physiological systems have the potential to disrupt the normal
rhythmicity and cause secondary problems.
Arousal as Reward
The level of arousal on a more local or moment to moment basis has been linked closely to the
phenomena of motivation and reward. One of the earliest and most influential statements about
this relationship is the Yerkes-Dodsen Law (1908) which states that an organism interacts most
efficiently with its environment when the level of stimulation is at some intermediate level; below
this level the arousal level is too low and the organism misses essential features of the
environment, while levels of arousal that are above the optimal result in exaggerated responses to
all elements and a decrement in performance. As shown in Figure 8.7, this relationship between
arousal and performance can be characterized as an inverted U-shaped curve.
The importance of this formulation is not just that behavior changes when the level of arousal
changes, but that behavior is also an important way to achieve a change in arousal. Butler
(1958), for example, found that monkeys would press a lever in order to open a small window
that would allow them to see the laboratory or hear the sounds of the monkey colony. Similarly,
Tapp (1969) showed that rats will press a lever to turn on a light for a brief period. These
exploratory behaviors, as well as several different types of locomotor activity (e.g., running wheel,
tilt cages, jiggle cages, open field, etc.) are all behaviors that cannot be explained by the
traditional motivators of hunger, thirst, or reproduction. Rather, these behaviors appear to be
reinforced simply by the feedback from the responses. Interestingly, a rat will run considerably
more if it has a food pellet in the running wheel. Not because it wants to eat it, but because it
makes more noise! A marble works as well.
The idea that a rat or monkey would perform a response out of "curiosity" or an "exploratory
drive", with the result being nothing more than a change in arousal level was a bold proposal. It
flew in the face of the very thorough and formal drive theory of Hull (1952) and Spence (1956.)
But even traditional drive theory assumes an important role for arousal. The drive state is said to
have two effects: (a) an energizing effect that increases the general behavior of the organism, and
(b) a directing effect that channels the behavior toward relevant goal objects. When
reinforcement is obtained, the drive and its resulting energy is reduced. When extinction or
nonreinforcement in encountered, the energy is intensified and the behavior is less channeled.
In summary, the brain systems that control arousal are subject to the same controls and
interactions that we have seen for other behaviors (cf., Fig. 8.8). The environment can adjust or
change the level of arousal, which results in changes in behavior. But changes in behavior also
produce changes in the level of arousal, and behaviors may occur for the purpose of changing
arousal levels. Furthermore, the behavior can actually change the environment, or at least move
the organism to a different part of the environment. Finally, drugs can rather directly enter into
this scheme by changing the level of arousal. It should not be surprising, therefore, that these
drugs have assumed considerable importance both in the practice of medicine and as a part of
human cultures. Because of their action on the very core of behavior, these drugs are often
overused or abused, having social consequences that may outweigh their effects on an individual.
We turn now to a discussion of some of the pharmacological and behavioral effects of these
Strychnine is an extremely potent drug that causes general excitation of the central nervous
system, especially the reflexes of the spinal cord. This bitter tasting substance is derived from an
extract of a tree that is native to India. It has a long history of medicinal use, as a general tonic,
to increase the appetite, to cure constipation, and as a general stimulant. Commercial forms of
the substance were once widely available as so-called "bitters" and can still be obtained in some
over-the-counter preparations. There is virtually no evidence that strychnine has any general
curative properties, and it is a very dangerous drug to use as a stimulant.
Strychnine has also been used (probably inappropriately) in more traditional medicine as an
antidote for the respiratory and cardiovascular depression that occurs with barbiturate or
anesthetic poisoning. Again, there is probably no rational basis for this, since the addition of the
second drug only complicates the already challenged physiology of the patient. It is usually more
advisable to use mechanical means of supporting the respiratory and cardiovascular deficiencies of
Currently, strychnine is used in some street formulations to add a stimulating effect to a variety of
different drugs. It is especially dangerous in this informal context, because of potentially lethal
overdoses or interactions with other drugs.
Strychnine has played an important role in research as a tool to help unravel some of the
mechanisms of brain and spinal cord circuits. High dosages of strychnine produce an
exaggeration of spinal reflexes that can result in tonic seizures with the limbs rigidly extended (an
interesting exception to this is the sloth, which shows extreme flexion owing to the reversed
organization of its anti-gravity muscles.) The most likely action of strychnine is that it excites
these actions by blocking the normal inhibitory effects (see Figure 8.9).
The Renshaw cell, an interneuron of the spinal cord, has long been of interest because of its
receptors. It was known that the alpha motor neurons release acetylcholine at the nerve-muscle
junction. Because of Dale's law (which may still be in effect in this instance) that any neuron
manufactures and releases only one neurotransmitter, the Renshaw cell was the first neuron within
the central nervous system that was known to be cholinoceptive. The transmitter substance
released by the Renshaw cell was not so easily determined, but electrophysiological studies
revealed that it had an inhibitory effect on the alpha motor neuron. More recent investigations
indicate that glycine is the transmitter substance, and both glycine and strychnine bind to the same
receptor sites on the alpha motor neuron. Thus, it would appear that strychnine stimulates
activity in spinal reflexes by blockade of the recurrent inhibition produced by the Renshaw cells.
Tetanus toxin, which causes similar convulsive activity, does so by blocking the release of the
transmitter, rather than blocking the receptor sites.
Another naturally occurring substance, picrotoxin, is derived from the seeds of the fishberry shrub
(so named because the berries were fed to fish so they would float to the surface). This drug also
stimulates nervous system activity by blocking inhibition, but apparently through different
mechanisms than strychnine. It appears to block the receptors that normally mediate the
inhibitory effects of GABA (see Figure 8.10); GABA refers to gamma amino butyric acid. In
fact, most of the evidence for GABA as a central neurotransmitter is based upon the experimental
effects of picrotoxin.
A third compound that has been widely used for research purposes is a synthetic drug called
pentylenetetrazol (Metrazol). It appears that this drug does not interfere with any particular
transmitter, but rather reduces the recovery time following action potentials. As indicated in
Figure 8.11, this is probably accomplished by increasing the permeability to potassium, leaving
the cell in a state of partial depolarization. Pentylenetetrazol has been used as a seizure inducing
drug in the process of screening drugs that may have anticonvulsant activities.
The Xanthine Derivatives
The xanthine derivatives are by far the most widely used stimulants, and appear to be safe in
moderate dosages (see Rall, 1980 for a review). The most common and most potent of these is
caffeine, with theophylline being somewhat less effective, and theobromine being considerably
less effective. All three substances are present to varying degrees in coffee, tea, cocoa and cola
(see Table 8.1):
Annual Consumption of Xanthine Derivatives
|Relative Caffeine Content|
|Coffee||10 pounds||1 cup coffee||2 cups tea|
|Cocoa||3 pounds||1 cup coffee||24 oz cola|
|Tea||1 pound||1 cup coffee||20 cups cocoa|
|1 cup coffee||5 oz chocolate|
(Cocoa contains much more theobromine.)
As in the case of pentylene tetrazol, these compounds have not been linked to a specific
transmitter. They appear to cause an increase in calcium permeability, and may increase cyclic
AMP production (see Fig. 8.12). These actions stimulate a wide range of physiological systems
and mood changes. The major psychological effects include a decrease in fatigue and drowsiness,
an increase in speed and efficiency, and a decrease in the number of errors (especially in an over-learned task such as typing). They increase the ability to do muscular work,
including an increase
in the action of the heart muscle. Peripheral vasodilation increases the perfusion of organs
(including the diuretic effect on the kidneys), except for the brain, which shows a decrease in
blood flow. This latter effect may account for the fact that coffee is effective in relieving
hypertensive headaches for some individuals. The increased gastric acid secretion can be a
liability, especially for those who may be prone to the development of gastric ulcers, but this
effect appears to be blocked completely by cimetidine (see Chapter 6). In general, these
compounds provide safe stimulating effects that do not appear to lead to serious abuse.
Nicotine is a powerful stimulant that is most commonly administered by smoking tobacco. It was
in widespread use throughout the Americas when the first European explorers arrived. Tobacco
use (chewing, smoking, and snuffing) has had many stormy periods in terms of cultural and legal
acceptance (and is in another right now), but for the most part, the use of tobacco has prevailed
(cf., Ray, 1978). In 1978, more than a decade after the Surgeon General's cancer warning, about
4,000 cigarettes were sold for every person over 18 in the United States. The health hazards are
legion, but for the present purposes we shall consider only those that relate to the direct
neuropharmacological effects and ignore the potentially more threatening effects of the associated
tars and additives.
Nicotine produces a bewildering array of influences, most of which occur by virtue of its ability to
mimic acetylcholine at certain receptor cites (e.g., Taylor, 1980). In fact, the categories of
acetylcholine receptors (muscarinic and nicotinic) are defined, in part, by their responsiveness to
nicotine (cf., Chapter 1). In the periphery, nicotine acts on the autonomic ganglia. This action
is complicated not only because it acts on both sympathetic and parasympathetic ganglia, but also
because of the biphasic action of the compound. At low dosages or during the initial stages of
higher dosages, the effect is one of stimulation, and expected changes in autonomic effector cells
can be observed. But unlike acetylcholine, nicotine is not rapidly inactivated by
acetylcholinesterase, and its long lasting effects on the receptors lead to prolonged depolarization.
This paralysis of ganglionic activity occurs not only while the cells are depolarized, but appears to
continue for some time after normal polarization has been restored. At moderate dosages, some
ganglia may be more affected than others, so heart rate (for example) could be increased either by
stimulation of sympathetic ganglia or by paralysis of the parasympathetic inhibitory effects.
Contrariwise, heart rate could be decreased by relative stimulation of the parasympathetic or
paralysis of the sympathetic ganglia. Some of these increases may be dangerous, because the
oxygen demands of the heart muscle may be increased while the oxygen supply remains the same.
This could trigger cardiac failure in certain individuals. Figure 8.13 summarizes the synaptic
effects that mediate these physiological changes.
Nicotine also acts on skeletal muscle receptors, but the initial stimulation phase is either very short
lived or nonexistent. The overall effect is, therefore, a relaxation of these muscles at low or
moderate dosages and paralysis at higher dosages.
Nicotine also influences neurons throughout the central nervous system, although the distribution
of these remains rather ill-defined. The drug appears to produce its central effects through both a
direct action on cholinoceptive cells, and indirectly through stimulation of dopaminergic fibers.
The administration of nicotine produces a rapid arousal of the EEG and an increase in the release
of norepinephrine and dopamine. Although the implications are not clear, it also increases the
release of growth hormone, antidiuretic hormone, and cortisol. Acute nicotinic poisoning can
lead to nausea, vomiting, diarrhea, and ultimately respiratory and cardiovascular collapse. In
lower dosages, the untoward gastrointestinal symptoms rather quickly disappear through
tolerance, but the EEG arousal effects continue. Although the mechanisms are not yet known, it
appears that the chronic administration of nicotine can lead to enzyme induction which facilitates
not only the metabolism of nicotine, but other apparently unrelated stimulants such as the xanthine
derivatives and various drugs that act on the catecholamine systems.
The sympathomimetic compounds mimic or otherwise increase the activity of neurotransmitters
associated with the sympathetic nervous system, namely, norepinephrine and dopamine(cf.,
Weiner, 1980b). The most widely used drugs within this class include the amphetamines and
cocaine. Although the mechanisms of action of these drugs differ, they act upon the same neural
substrates, and their effects upon mood and other behaviors are remarkably similar. These drugs
are powerful stimulants of the central nervous system, and in moderate dosages, they produce
EEG and behavioral arousal, decreased fatigue and boredom, increased psychomotor
performance, decreased appetite, and elevations in mood that are frequently described as
euphoria. At higher dosages they produce a variety of motor symptoms (twitching, restlessness,
stereotyped repetition), perceptual symptoms (distortion of time, tactile hallucinations or the
so-called "cocaine bugs"), mood distortions (fear, paranoia, psychotic symptoms), and the
possibility of convulsions and death.
The long term effects of the amphetamines may include some serious dangers to the motor
system. The symptoms include an increase in the startle response, twitching, and related
dyskinesias that may be due to a reduction of dopamine in the caudate. The most likely cause of
this decrease is a chronic decline in tyrosine hydroxylase activity, which is probably attributable to
erroneous feedback from the increased transmitter release.
Cocaine is present in the leaves of a shrub that grows high (so to speak) in the Andean mountains
of South America. The natives have chewed or sucked on these leaves for centuries (averaging as
much as four or five kilograms of leaves per year) for the elevation of mood that is produced. It
also produces a numbing sensation because of its local anesthetic actions, but was not used
clinically as a local anesthetic until Sigmund Freud made this suggestion. In the early 1900's
synthetic substitutes (e.g., procaine, lidocaine, xylocaine) began to be produced, but none is as
effective as cocaine in blocking pain, although all appear to have some euphoria producing effects.
Cocaine is still widely used and abused as a street drug, and also continues to be used clinically
because of its unparalleled strength and duration of local anesthesia for eye, nose and throat
Cocaine acts on the same neuronal systems as amphetamine, but enhances the effects of
catecholamines (primarily dopamine) by blocking reuptake (see Fig. 8.15) rather than stimulating
release (Ritz et al, 1987).
The local anesthetic properties of cocaine and the synthetic derivatives appear to be the result of
direct actions on the cell membrane. These changes block the transient change in sodium
permeability that is necessary for the propagation of the action potential. This action continues as
long as the drug is in contact with the cell, so most preparations include a solution of epinephrine
and norepinephrine to produce vasoconstriction that prevents the dispersion of the drug. One of
the reasons that cocaine is so effective is that it serves as its own vasoconstrictor through its
action on local sympathetic terminals.
The powerful behavioral effects of cocaine and the amphetamines are probably due to their effects
on two populations of brain cells. One effect is to increase the general level of arousal by
stimulating the catecholamine containing neurons that are involved in this system. The other is to
stimulate the catecholamine containing neurons that are involved in rewarded behavior. Together,
these effects are very potent: The organism is more responsive to the environment, and the
rewarding effects of that environment are amplified.
Both the benzodiazepines and the barbiturates reduce the activity of excitable tissues, but their
effects are much more pronounced on the central nervous system. Their action is widespread, but
appears to selectively influence polysynaptic pathways that involve small fibers (most notably,
cortical functions and the reticular formation). As indicated in Figure 8.16, these drugs
apparently lower arousal by virtue of their interaction with neurons that release the inhibitory
transmitter, GABA. This neurotransmitter is apparently involved with both presynaptic and
postsynaptic inhibition of a variety of different transmitters, but certainly includes those
transmitters that are involved with arousal systems. (Note that these effects are directly opposite
those produced by picrotoxin, cf., Figure 8.10).
In discussing the effects of the benzodiazepines, it was noted that these compounds bind rather specifically to receptor sites in the brain that do not appear to be involved with any known neurotransmitters. The conclusion was that there may be endogenous benzodiazepines which are involved in counteracting anxiety. Extending this model into the present context, it might be proposed that the GABA releasing neurons have receptors that are specific for the benzodiazepines. Further support for this indirect action is the observation that depletion of GABA prevents the sedative effects of the benzodiazepines.
Figure 8-16 summarizes the current model of the GABA receptor complex. This receptor
complex appears to have three separate, but interacting receptor sites: a sedative/hypnotic site, a
benzodiazepine site, and a GABA site. The inhibitory effects of the GABA neurotransmitter
appear to be mediated by the enlargement of the chloride (Cl-) channel. This effect is augmented
by the presence of either barbiturates or benzodiazepines, and blocked by convulsants.
One of the difficulties with the model shown in Figure 8-16, is that the benzodiazepines and
barbiturates have been classified as different types of drugs on the basis of their differing clinical
effects. In particular, the benzodiazepines are more effective in the reduction of anxiety, while the
barbiturates are much more effective as general anesthetics. One possibility is that these
compounds share the ability to enhance the activity of GABA, but that the barbiturates are less
specific in this regard and have additional effects as well. In particular, there has been evidence
that the barbiturates may block the reuptake of GABA and may be specifically involved in
blocking the activity of certain synapses that utilize norepinephrine or acetylcholine. The
barbiturates seem to produce a slower recovery time of neurons, which is of little importance in a
single synapse, but produces substantial impairment in pathways that involve multiple synapses.
Both the barbiturates and the benzodiazepines have been used to treat sleep disorders, but with
mixed results. These drugs make it easier to fall asleep, and may increase the total time spent
sleeping, but in many cases there is a reduction in the amount of REM sleep. As a result, the
sleep is less effective than normal and the patient becomes more sleep deprived. Dement (1974)
and other sleep researchers have cautioned against the use of so-called sleeping pills, because
many of them are more likely to cause insomnia than to cure it!
There is some evidence that the benzodiazepines may be useful in preventing the disruptive effects
of changing one's circadian rhythms (e.g., with shift work). Seidel and associates (1984)
imposed an abrupt 12-hr shift in the sleeping schedule of volunteers, delaying their bedtime from
midnight until noon. Over the course of the next three days, untreated subjects experienced a loss
of sleep and impaired function during the waking hours. Subjects treated with triazolam, a fast
acting benzodiazepine, did not show these disruptive effects.
Alcohol is one of the most ancient of drugs, with references to its use appearing in some of the
earliest recorded histories (cf., Ritchie, 1980). Alcohol use and abuse probably even preceded
the appearance of the human species, since it has been shown that a variety of animals (e.g, birds,
bees, wild pigs, and even elephants) have been known to partake of the naturally fermenting fruits.
The fermentation process can produce concentrations of ethyl alcohol in the range of 12 to 14
percent, at which point the reaction is self limiting because the alcohol kills the yeast that supports
the fermentation process. This limits the concentration of naturally fermented wines and beers
(mostly 4% in the United States). However, man was quick to increase the potential of this drug,
and the Arabs invented the distillation process some 1200 years ago to extract higher
concentrations of alcohol. This alcohol can be produced from a variety of different sources,
including fruits, grains, and even potatoes. Almost every known culture has contributed to the
science and the business of producing alcohol, and we now have a staggering array of
"preparations" of this compound from which to choose.
The mechanism of action of alcohol remained a mystery for many years despite the intense
research efforts that were aimed toward a better understanding of this drug. It is certainly a local
irritant, which can lead to the inflammation of tissues, especially the membranes. In sufficiently
high concentrations, it can even serve to coagulate protoplasm and kill the cells. These effects on
cell membranes can reduce the ability of peripheral nerves to conduct impulses (by decreasing the
permeability to both sodium and potassium), giving alcohol some local anesthetic properties.
All of the effects noted above occur in concentrations that are many times greater than the plasma
concentrations that are reached in the blood. As in the case of the benzodiazepines and
barbiturates, alcohol appears to selectively influence polysynaptic pathways, in part at least,
through the facilitation of GABA. Although the details of the interaction are not yet fully known,
alcohol can be very dangerous when taken in combination with a sedative compound such as
Librium or Valium. Normally safe dosages of each compound can combine synergistically to
produce coma or death.
The behavioral effects of alcohol are comparable in many respects to those produced by the
benzodiazepines and barbiturates. As shown in Figure 8.17, there is a selective depression of the
reticular activating system and a corresponding increase in EEG slow wave activity. Inhibitory
processes decline first and with smaller dosages, resulting in an exaggeration of spinal reflexes and
the appearances of behaviors (e.g., talkative, boisterous, aggressive, etc.) that are normally under
the influence of social inhibition. Hence, the mistaken notion that alcohol is a stimulant. These
effects precede or are accompanied by a marked decline in perceptual abilities (especially pain)
and psychomotor functions (especially previously trained responses). There is virtually no
evidence that alcohol can enhance motor or cognitive abilities beyond normal, except in those
cases where some aspect of the behavior is inhibited (e.g., it would probably greatly enhance the
ability to swim in the nude at one's in-laws). At very high dosages, alcohol has general anesthetic
effects, but it is not medically useful in this regard because the anesthetic dosage is very close to
the lethal dosage. In this regard, it should be pointed out that alcohol is a dangerous drug strictly
on the basis of its therapeutic ratio. Suppose, for example, that one considers two or three drinks
to be the effective dose for the "desired" effects of alcohol. A dosage of 12 to 15 drinks
represents a dangerous overdose that can lead to coma or death. This yields a therapeutic index
(LD/ED) in the range of about 6, which is much too low to be considered safe. It is for this
reason that hazing rituals, drinking contests, and so forth so frequently result in tragic death.
The behavioral effects of alcohol are accompanied by a variety of physiological changes which,
interestingly, fall into a pattern that is very much like that of a general stress response. The local
irritating effects on the oral membranes, gastrointestinal tract, and somatic muscles trigger
histaminic reactions. There is an increase in the release of ACTH and adrenal hormones. Lactic
acid and fatty acids are released into the bloodstream, the heart rate increases, and peripheral
vasodilation occurs. There is a decrease in antidiuretic hormone that increases urine outflow
which can result in the depletion of calcium, magnesium and zinc. These responses form an
important part of the general abuse syndrome, which will be discussed later in this chapter.
The behavioral and physiological effects of alcohol are closely related to the concentrations of the
drug that appear in the bloodstream. This is true for nearly all drugs (cf., Chapter 3), but has
assumed greater significance in the case of alcohol because the plasma level has become almost
synonymous (legally synonymous in many states) with the level of intoxication. There is a germ
of truth in some of the folklore concerning the effects of alcohol. Absorption is slower in the
stomach than in the intestine, so anything that helps to retard the progress of alcohol from the
stomach into the small intestine will also retard the climb in blood alcohol levels. Fatty foods,
milk, and meat all cause reflexive closing of the stomach valves to allow greater digestion at this
stage, and indirectly result in slower absorption of the alcohol. Meanwhile, the liver enzymes are
breaking down the alcohol as it enters the bloodstream, so the overall effect of a particular dosage
of alcohol will be prolonged, but the peak effect will be lower. Carbonated beverages enhance the
absorption process, highly concentrated drinks slow down absorption, and emotional changes can
either increase or decrease absorption. Finally, the effectiveness of a given blood level of alcohol
is greater on the ascending side of the curve than on the descending (especially when the rate of
ascent is rapid), presumably because some of the cells of the nervous system become somewhat
refractory to the alcoholic environment and resume some of their normal functions before the
blood alcohol concentrations begin to decline.
Regardless of these influences on absorption rates and other aspects of blood alcohol levels, the
alcohol is ultimately metabolized to produce energy. The first stage of this reaction converts the
ethyl alcohol into acetaldehyde. The acetaldehyde is poisonous, but the presence of the enzyme
acetaldehyde dehydrogenase normally results in the quick conversion of this compound into
acetic acid. The drug known as Antabuse (disulfiram) interferes with this enzyme and allows the
acetaldehyde levels to build up and cause illness following alcohol ingestion. Genetic variations in
this enzyme system may contribute to individual differences in the tendency to consume alcohol
(cf., Horowitz & Whitney, 1975).
The involvement of acetylcholine in arousal suggests that the anticholinergic compounds might
provide a powerful method of lowering arousal levels. The cholinergic blocking drugs such as
atropine and scopolamine compete with acetylcholine at muscarinic synapses throughout the
nervous system and especially in certain parts of the limbic system (see Fig. 8.18). When these
compounds were discussed for their potential antianxiety effects (cf., Chapter 4), it was noted
that one of the major drawbacks was that the compounds were too broad in their spectrum of
action. Their action within the parasympathetic system produces such undesirable side effects as
dry mouth, pupil dilation with blurred vision, rapid heart beat with palpitations, and others. These
same disadvantages apply to the potential use of these drugs for their hypnotic or sedative effects.
It is interesting, in this regard, that these compounds seem to have only modest potential for
abuse, despite their very real effects on the central nervous system.
Although atropine and scopolamine are not used routinely for their sedative effects (except as a
presurgical treatment), they have been important as a research tool. The effects of cholinergic
blockade have been used as an example of those uncommon situations in which the EEG seems to
be dissociated from behavior. Rinaldi and Himwich (1955) reported that atropine produces a
slow-wave EEG that is typical of sleep, but that the animal was still behaviorally awake. A more
accurate portrayal of this paradox might be that the animals show a slow-wave EEG while not
being behaviorally asleep--their state of wakefulness is somewhat questionable. High dosages of
cholinergic blocking agents greatly reduce the activity of rats in their home cage, and although
they appear to be awake (eyes open, upright), there also appears to be a lack of "voluntary"
attention to the environment (not unlike the state of college students during lectures). Yet, these
rats will show a greatly enhanced response when given the opportunity to explore a new
environment or when presented with specific external stimuli such as loud noises.
The effects of these drugs have been linked to the action of the septohippocampal system (cf.,
related discussion of behavioral inhibition in Chapters 1 & 4). It appears that the septum contains
cholinoceptive neurons that project to the hippocampus, producing the characteristic theta pattern
in the hippocampal EEG. This hippocampal theta activity is seen in a variety of
situations that involve attention to new aspects of the environment or to changes in the rewarding
contingencies of the environment (most notably, nonreinforcement or punishment). The blockade
of this system with cholinergic blocking agents results in a variety of deficits that can be
characterized as disinhibitory or failures of attention (see Gray, 1970).
The drugs that alter perception have been somewhat loosely classified on the basis of their ability
to produce distorted experiences of the environment. Descriptions of these effects allude to
dreamlike states, orgasmic feelings, florid visual imagery, a sort of distortion of time and space,
synesthesia (hearing visual stimuli, seeing odors, etc.), a feeling of oneness with the universe, a
feeling of separation from the universe, and so on. These experiences, which seldom occur with
other drugs or in the absence of drugs, have led to the terms hallucinogenic, psychedelic,
psychotomimetic, mind altering, or even mind expanding drugs.
A logical case can be made that all centrally active drugs alter perception. For example, the
stimulant and depressant drugs that were just discussed can produce changes in mood and level of
arousal. Since an individual's interpretation of the environment is heavily dependent on mood and
arousal, changes in perception certainly will occur. In fact, one of the major reasons for the
voluntary consumption of drugs like alcohol may be to reduce the perception of anxiety
provoking stimuli in the environment. (This is not to say which, if either, set of perceptions is
veridical; initially false perceptions fall prey to drug effects as easily as those that can be verified.)
In defense of a special category for the hallucinogenic drugs, the altered perceptions produced by
most other classes of drugs are much less profound. This does not mean that the drugs, as a
class, share a common mechanism. Their actions are diverse: Scopolamine and related
compounds block the cholinergic receptors, LSD and related compounds are serotonergic
agonists, the amphetamines and cocaine stimulate systems that use norepinephrine and dopamine,
the recently infamous phenylcyclidine (a.k.a. PCP, PeaCe Pill, angel dust, Hog) influences
several different transmitter systems, while the specific actions of the much studied marijuana
remain unknown. Any attempts to build an all encompassing theory forces one into complex
notions such as the balance among transmitter systems and the unsatisfying conclusion (already
made) that any drug would be expected to alter perceptions.
The lack of a common biochemical action is not the only problem encountered in the study of this
class of drugs. The behavioral effects have been equally difficult to study. Animal models seem
rather silly when one is talking about hallucinations, artistic creativity or oneness with the
universe. Nonetheless, there have been reports of monkeys grasping for apparently hallucinated
objects in empty space (at least it appeared empty to the investigators), of cats stalking
unobservable prey, and of spiders spinning unorthodox webs. This is not to say that animals do
not experience and perhaps even appreciate the effects of mind altering drugs, but simply that the
effects that are being championed by the users of these drugs are too close to the human
experience to make an animal model very useful. But the problem is not solved by turning to
human studies. Objective measures of performance (even creativity and imagery) can be obtained,
but many of the changes must rely on subjective reports, and when the drug is effective, these
reports must be obtained from an individual who has an altered interpretation of the environment.
The widespread use of drugs for the purpose of altering perception has led to an unwarranted
mystique about the properties of these drugs. A recurrent theme in the description of the drug
states is that the experience is unparalleled in the normal condition, except for dream states,
hypnotic or meditative trances, and religious rapture. While this is probably true, it should serve
to diminish rather than elevate the uniqueness of the drug effects. Hypnotic trances, for example,
have been viewed as something of the occult, with both the mind and the body under the direct
control of the hypnotist. Careful, objective studies reach less dramatic conclusions, and have
shown that the so-called trance includes the full range of normal EEG arousal and that the "feats"
of rigidity, induced sensory impairment, and even blister formation are all within the boundaries of
phenomena that can be done on command by many non-hypnotized individuals or by individuals
pretending to be hypnotized (cf., Dalal & Barber, 1972; Orne, 1979).
The normal non-drugged state may also be overrated in terms of its ability to provide a constant
and accurate view of the world. Illusions abound. One need only to lie down beside a church and
gaze skyward to see the tall spire apparently falling continuously as the clouds sweep by. If one
were to nurture this illusion in the same fashion as a drug induced effect, it might well turn into a
The misconception of all of these phenomena is that there is something inherent in the drug or
hypnotic induction that introduces these experiences. But it is not like bringing in a motion
picture reel from some mysterious external source. To borrow and paraphrase an old adage about
computer data processing, "crap in; crap out", the brain has only its own information to work on.
Altered states of consciousness induced by hypnosis, meditation, drugs, or sleep can do nothing
more than rearrange or reinterpret past experiences in the context of the ongoing environment. In
the normal, alert waking state, our nervous systems have a long history of selection that has
favored a slightly distorted (rocks really do fall faster than feathers) Newtonian interpretation of
the universe. The simplest conclusion from all of this appears to be the unsatisfying one that we
described earlier: The disruption of any of the major systems that are involved in arousal (ACh,
5-HT, NE and DA) can alter these perceptions in strange and sometimes rewarding fashion.
2. The EEG continues to be active during the daily periods of sleep. This EEG is characterized
by 90-min cycles that coincide with periods of REM and dream reports.
3. The ascending reticular activating system is an important brain structure for the maintenance of
4. Dopamine, norepinephrine and acetylcholine have all been related to arousal; serotonin has
been related to sleep.
5. Drug effects change dramatically as a function of the background level of arousal at the time of
6. Strychnine, picrotoxin and pentylenetetrazol produce CNS stimulation by blocking inhibition
or reducing recovery time between action potentials.
7. The xanthine derivatives increase arousal by increasing calcium permeability.
8. Nicotine mimics acetylcholine and produces arousal by acting on CNS neurons as well as
stimulation of autonomic ganglia.
9. Cocaine and amphetamines are sympathomimetic and increase arousal and the effects of
10. Cocaine and related local anesthetics block sodium channels and interfere with the
propagation of action potentials.
11. The hypnotic and sedative drugs reduce arousal and may induce sleep, but they may also
interfere with REM sleep. They probably act by facilitating the action of GABA.
12. Alcohol produces many of its effects by acting on the same polysynaptic systems that are
influenced by the sedative and hypnotic drugs, probably through the GABA receptor complex.
13. Anticholinergic drugs reduce arousal levels, but also interfere with behavioral inhibition and
14. Hallucinogenic drugs do not seem to fall into a class in terms of the cell population or
neurotransmitters that are affected.
GABA receptor complex