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OCR for page 124
Animal Models of Dementia:
Their Relevance to Neurobehavioral
Toxicology Testing
David H. Overstreet and Elaine L. Bailey
There is a wealth of evidence from clinical and epidemiological
research to document the fact that a wide variety of exogenous chemicals
are capable of producing dementia. Dementia involves declines in
learning memory and other cognitive processes, (e.g., problem solving),
all of which are necessary for normal adaptations to changing physi-
cal and psychosocial environments. The development of animal mod-
els of dementia is making it possible to supplement knowledge gained
from clinical and epidemiological approaches with information obtained
by experimental manipulations of the variables involved. The mate-
rial that follows, briefly reviews the research designs, procedures,
and specific paradigms used in such experimental studies.
ANIMAL MODELS OF DEMENTIA
With the increasing recognition of the significance to individuals,
and to society generally, of the primary degenerative dementias, interest
in the development of animal models of dementia has been growing
rapidly. Although some skepticism has been expressed about the
possibility of constructing such models, a generally optimistic view
has prevailed (Heise, 1984; Overstreet and Russell, 1984~. For ex-
ample, several investigators have used neurotoxins such as ibotenic
acid, an excitotoxic amino acid, or AF64A, a putatively specific cholinergic
neurotoxin, as tools for creating morphological lesions in the central
nervous system (CNS), thereby producing cholinergic deficits analo-
124
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ANIMAL MODELS OF DEMENTIA
125
gous to those characteristic of Alzheimer's disease (Bailey et al., 1986;
Hepler et al., 1985~. There have been approaches using neurochemi-
cal methods (see chapters by Michalek and Pintor, and Russell). These
studies have routinely shown that treatments which interfere with
normal cholinergic neurotransmission lead to disruption in measures
of learning and memory, thereby providing support for the "cholinergic
hypothesis of memory" (Bartus et al., 1982; Coyle et al., 1983~. There
is also a growing appreciation that the behavioral measures used in
these studies are applicable to the detection of the neurobehavioral
effects of suspected environmental toxicants (e.g., Walsh and Chrobak,
1987~.
Learning and memory are theoretical constructs that cannot be
measured directly. They are inferred from observations of behavior
under certain specified conditions. Learning is manifested by systematic
changes in behavior as a consequence of repeated exposures to the
same stimulus environment; memory, as the preservation of learned
behavior over time (Heise, 1984~. Any manipulation of an animal's
performance may confound the interpretation of the possible effects
of that manipulation on learning. As a consequence, an investigator
studying animal models of dementia should examine a range of tasks
from which learning and memory measures may be extracted, as well
as observing, for comparison, other behavioral parameters that are
definitely not related to learning and memory. For example, if, dur-
ing the course of an experiment, food or water is used as a reinforcer,
the investigator should measure the effect of the experimental
manipulation on the food or water directly. Without elaborating
further, it is clear that in order to specify toxic effects on cognitive
processes, it is desirable to use batteries of measures rather than to
depend upon single assays.
Requirements that animal models of dementia must meet and the
characteristics of research designs in which they are put to work
have been discussed in detail elsewhere (Heise, 1984; Hepler et al.,
1985; Kennett et al., 1987; Olton, 1983; Overstreet and Russell, 1984;
Russell and Overstreet, 1984; Tilson and Mitchell, 1984; Willner, 1984~.
They are mentioned here only very briefly as a general setting within
which to project the more detailed discussion to follow. Specifications
for the development of animal models and for safeguards in the use
of them have been established by international organizations (e.g.,
World Health Organization, 1975), by national scientific bodies (e.g.,
Xintaris et al., 1974), and by individual investigators (e.g., Weiss and
Laties, 1975~. These specifications include systematic manipulation of
independent variables, while eliminating effects of other potentially
confounding factors; precise measurement of dependent variables by
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DAVID H. OVERSTREET AND ELAINE L. BAILEY
using reliable measuring instruments; attention to the validity of ani-
mal models for generalizations to other species, including human;
and strict adherence to today's scientific ethics in the care and treat-
ment of animal subjects. With these general points in mind, the use
of environmental or pharmacological "challenges" as methodologies
in neurobehavioral toxicology is considered.
ENVIRONMENTAL CHALLENGES
MacPhail et al. (1983) have given several examples of the use of an
environmental challenge to uncover a debilitating effect of an
environmental toxin. They define environmental challenges as "variables
that are either known or suspected to affect a baseline of behavior.'!
In effect, the various tasks described above for measuring learning
and: memory are environmental challenges because they place some
demand on the organism. It is precisely for this reason that they may
be likely to reveal some effect of the environmental toxin, whereas
standard neurobehavioral toxicology testing would not. It is also
possible to infer that a limited number of brain regions might be
affected if the treatment results in a disruption of memory.
Among other environmental challenges that can be used in an attempt
to uncover an effect of a suspected environmental toxin are manipu-
lations of schedule-controlled behavior (MacPhail et al., 1983~. As
indicated above, spatial or temporal alternation tasks can be used to
infer the working memory of an animal. Some years ago, we reported
that rats treated chronically with the anticholinesterase diisopropyl
fluorophosphate (DFP) did not develop tolerance to its effects on
alternation behavior (Overstreet et al., 1974~. This finding correlates
with the observation of memory disturbances in humans exposed to
organophosphate pesticides (Russell and Overstreet, 1987~.
A final group of environmental challenges that might be consid-
ered for studying neurobehavioral toxicology are paradigms involving
stress. As far as we know, no investigator has used this approach as
yet, although it has been widely used on animal models of depression
(e.g., Willner, 1984) and to study the effects of some drugs (e.g., Weiss
et al., 1961~. Among the possibilities are the forced swim test (Porsolt,
1982), the inescapable shock ("learned helplessness") paradigm (Mater,
1984), and restraint (e. g., Kennett et al., 1987~. After the animals are
exposed to these various forms of stress (sometimes, during exposure),
measures of their ability to move are taken. It is reasonable to hy-
pothesize that animals exposed to environmental toxicants would be
more susceptible to these stressful conditions and would exhibit greater
reductions in activity than control animals. This approach has been
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ANIMAL MODELS OF DEMENTIA
127
used to differentiate between two lines of rats that have been selec-
tively bred for varying responses to the anticholinesterase DFP (Overstreet,
1986; Overstreet et al.,l988b).
PHARMACOLOGICAL CHALLENGES
The use of pharmacological challenges to uncover changes in an
organism chronically exposed to chemical agents is a recent development
in neurobehavioral toxicology testing (see Zenick, 1983~; as far as we
know, this design has been used only rarely in studies of animal
models of dementia. However, the principles underlying these chal-
lenges were well known to some investigators much earlier. In our
early work on the development of tolerance to DFP, for example, we
showed that rats could "become tolerant without acute behavioral
changes" (Chippendale et al., 1972~. These rats, which received daily
low doses of DFP, had reductions in brain acetylcholinesterase activity
comparable to other rats treated with higher dosages and showed
comparable increased sensitivity to the muscarinic antagonist scopolamine
(Chippendale et al., 1972~. ~
In a subsequent study using a daily, low-dose paradigm of DFP
treatment and a challenge design, it was found that rats developed
subsensitivity to muscarinic agonists within five days of starting treatment.
The subsensitivity was complete within nine days, at about the time
brain acetylcholinesterase activity was at its lowest (Overstreet, 1974~.
In still another study using the challenge design, we determined that
the muscarinic subsensitivity which follows anticholinesterase treatment
can be observed after a single, acute treatment; it first appears at
about 48 hours and lasts for about two weeks (Overstreet et al., 1977~.
In fact, it was these challenge studies which led to the notion that
decreases in muscarinic receptor concentrations might be a primary
mechanism underlying tolerance development to anticholinesterases
(Russell and Overstreet, 1987; Schiller, 1979~. Zenick (1983) also called
attention to this advantage of the challenge design: by using appropriate
challenge agents, some hint of the adapting changes taking place in
the central nervous system can be obtained.
The challenge design has also been very useful in understanding
the changes that have occurred in our two selectively bred rat lines-
the Flinders Sensitive Line (FSL) and the Flinders Resistant Line (FRL).
These rats were selectively bred to differ in their responses to DFP
(Overstreet et al., 1979~. Subsequently, it was found that the FSL rats
were more sensitive to muscarinic agonists (Overstreet and Russell,
1982), which correlated with increased concentrations of muscarinic
receptors in the hippocampus and striatum (Overstreet et al., 1984~.
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DAVID H. OVERSTREET AND ELAINE L. BAILEY
More recently, it has been found that the FSL and FRL rats differ in
their sensitivity to agents acting upon other neurotransmitter receptors
(Russell and Overstreet, 1987; see Overstreet et al., 1988b, for reviews).
Thus, selective breeding for differences in sensitivity to anticholinesterases
has led to changes in sensitivity to a range of other drugs. These
findings suggest that investigators should challenge their treated ani-
0 — _ ~ __ _ _ _O _ __ _
~ . . ~ ~ ~ ~ . ~ . .
malS With a range ot compounds; otherwise, they may make conclu-
sions that are not accurate (i.e., a neurobehavioral toxicant may in-
duce adaptive changes in a number of neurochemical systems).
As far as we know, the challenge approach has not been used with
much purpose by investigators studying animal models of dementia,
even though it is reasonable to expect adaptive changes in the lesioned
animals (Finger, 1978~. We would like to describe some of our recent
work in which the challenge design has been very useful in exploring
the time-dependent changes that occur in rats after hippocampal ad-
ministration of the neurotoxin AF64A. The challenge approach was
used to help answer the question whether AF64A has both pre- and
postsynaptic effects at cholinergic synapses because the suggestion
has been made that it works mainly presynaptically (Hanin, 1984~.
If AF64A destroys cholinergic axons in the hippocampus, one would
expect a supersensitivity to develop as an adaptation to the lost cho-
linergic input. We approached this question by challenging the rats
with scopolamine, a muscarinic antagonist, and oxotremorine, a
muscarinic agonist, and measuring locomotor activity by direct
observation of line crossing in a open field chamber. We were sur-
prised by the initial results, carried out three months after surgery,
which showed the AF64A-treated rats to be subsensitive to oxotremorine
and supersensitive to scopolamine. These data are consistent with
receptor decreases, not increases. Intrigued by these results, we sacrificed
the rats and carried out receptor binding assays on the hippocampal
homogenates. There was a significant 30 percent reduction in the
number of muscarinic receptors in the AF64A-treated rats (Schiller et
al., 1990~.
In a subsequent experiment we decided to challenge the rats much
sooner after the hippocampal administration of AF64A. At three
weeks after treatment, the rats were subsensitive to scopolamine, the
antagonist, and supersensitive to oxotremorine, the agonist, which
suggests that a supersensitivity had developed. These animals were
then left for several months and rechallenged. At this time they were
supersensitive to scopolamine and subsensitive to oxotremorine, con-
firming our earlier results. Thus, there are time-dependent changes
in cholinergic mechanisms in response to hippocampal injections of
AF64A. The early changes are consistent with the expected supersensitivity;
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ANIMAL MODELS OF DEMENTIA
129
however, a subsensitivity later occurs which is associated with a loss
of muscarinic receptors (Schiller et al., 1990~.
From this it should be clear that a challenge design may be useful
in establishing that changes in sensitivity have occurred as a consequence
of some treatment or manipulation. Therefore, information about
adaptive changes in animals exposed to neurobehavioral toxicants
and the mechanisms underlying these adaptive changes can also be
gathered by using similar designs. Zenick (1983) gives a number of
examples of how the pharmacological challenge design has been used
to uncover an effect of a neurobehavioral toxicant. The use of this
design should increase in frequency as more investigators become
aware of its utility.
In closing this section, we wish to offer a few words of caution
about the pharmacological challenge design. Once one has selected a
compound to use, there are still problems about the choice of parameters.
Locomotor activity is a useful parameter that is sensitive to a range
of compounds, whereas operant responding requires more effort to
establish but is more sensitive to drug effects. Another problem is
the possibility of choosing only one or a limited range of compounds,
which might give the investigators a false picture of the mechanisms
underlying the adaptive changes. Whenever possible, a wide range
of compounds should be selected. A consequence of multiple compounds
is multiple testing; therefore, operant responding is favored over locomotor
activity as the dependent variable because it is less subject to shifts in
baseline.
MEASURING BEHAVIORAL EFFECTS:
SPECIFIC PARADIGMS
It has been said that there is a finite number of measurable behav-
iors, but that the number is very large. Examination of the research
literature on neurobehavioral toxicology indicates that certain paradigms
have been favored in studies involving animal models, favored at
least in part because of their analogies to human behaviors. The
categories in which these paradigms are included is discussed below
in some detail.
Inhibitory (Passive) Avoidance
The typical experimental environment in which passive avoidance
is generated is a two-compartment box. The animal is placed in the
lighted compartment on the first day and given a foot shock upon
entering the dark compartment. Memory is inferred from the length
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DAVID H. OVERSTREET AND ELAINE L. BAILEY
of time the rat remains in the lighted compartment when put there 24
hours later; the longer the stay, the better is the memory. This task
can be a particularly useful one because parameters such as strength
of shock, its duration, and the time between testing and retention can
be varied to search for differences between groups. Large numbers
of animals can also be tested in a short space of time. However,
because this task uses aversive stimulation, a number of potentially
confounding variables must be checked before a firm conclusion can
be reached. For example, a drug (e. g., vasopressin) that has intrinsic
aversive properties may appear to enhance the memory of this task.
Similarly, any manipulation that makes the animal more "fearful" or
alters its sensitivity to shock will influence its performance on the
passive avoidance task. These potential effects must therefore be
tested by independent means.
Active Avoidance Tasks
There are a number of variations to test environments used in
active avoidance testing. Runways and two-compartment boxes with
either one-way or two-way avoidance tasks have been used. It is
also possible to alter the conditioned stimulus, which is usually either
a tone or a light. The basic procedure is to place the animal in the
apparatus and, after a brief interval (30 s), give the conditioned stimulus.
This stimulus is followed in 5-10 s with the shock, if the animal has
not moved beforehand. Thus, measures of both avoidance and escape
are recorded. If a treatment has a general debilitating effect on the
animals, then both avoidances and escapes should be affected. If the
treatment influences learning only, then only avoidances will be affected.
The active avoidance tasks require more effort because most animals
require 50 or more trials to reach some criterion of learning. Although
the escape measure provides an index of the motor effects of a treat-
ment, there are other problems of interpretation. For example, drugs
that stimulate motor activity, such as scopolamine and amphetamine,
are known to facilitate active avoidance responding (Barrett et al.,
1974~. At the same time, scopolamine disrupts passive avoidance
performance, and some investigators have used the scopolamine-treated
animal as a model for dementia (Flood and Cherkin, 1986~. Another
problem with these tasks is that aversive stimuli are used. In conclusion,
although active avoidance tasks can be used to measure learning in
animals, many other tests must be conducted before other confound-
ing variables can be ruled out.
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ANIMAL MODELS OF DEMENTIA
13
Operant Conditioning
Operant conditioning tasks require the animal to press a bar to
deliver a reward (food or water). A wide range of schedules can be
used, varying from the simple continuous reinforcement schedule to
the m-ore complex delayed reinforcement of low rates of responding
(DRL). It is not our intention here to summarize all of the possible
schedules that may be used. Rather, a couple of them will be discussed
to give an indication of their usefulness as well as their limitations.
In all cases, however, it must be remembered that one is working
with a deprived animal. Any manipulation that influences food or
water intake will influence performance on the task. Similarly, any
manipulation that dramatically alters motor capabilities could also
influence the task.
The continuous reinforcement schedule or various fixed ratio schedules
(e.g., FR5 five presses per reward) can be very useful in testing the
acute effects of various agents, but they are not particularly useful in
studying learning and memory measures per se. If a treatment that
disrupted passive avoidance did not have any influence on either
acquiring or performing an operant task, then a more specific argument
could be made about its effects. We have found the FR5 schedule of
operant responding to be more sensitive to the effects of cholinergic
agonists than open field activity (Overstreet, unpublished observations,
1988~.
The DRL schedule of reinforcement involves rewarding the animal
for responding at low rates. If the animal responds before a set time
(e.g., 20 s), a timer is reset and it must wait another 20 s to obtain a
reward. This schedule has been particularly useful for looking at
disinhibition, which can be produced by lesioning the hippocampus
or injecting cholinergic antagonists such as scopolamine. The reader
will note that the two treatments mentioned above are also well known
to disrupt memory. Whether the DRL task is a useful measure of
memory function in animals is debatable (Heise, 1984~. One problem
is that classical stimulants such as amphetamine, which can enhance
memory under a range of conditions (McGaugh, 1973), may produce
a disinhibition of DRL responding similar to scopolamine. Another
limitation of the DRL task is the long time required for the animal to
reach an acceptable criterion before manipulations can be attempted.
The last operant tasks to be discussed are the alternation para-
digms. The one we have used to study the effects of cholinergic
agents and anticholinesterase tolerance is the single alternation task
(Overstreet et al., 1974~. The rats are initially trained to bar-press
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DAVID H. OVERSTREET AND ELAINE L. BAILEY
whenever a light comes on; then, only on every other trial. Any
presses during the dark period or during the - trials are counted as
errors of commission (i.e., disinhibition), whereas a failure to press
during the + trials is an error of omission. Thus, the task can simul-
taneously obtain measures of general motor function as well as disin-
hibition or "memory." We found that anticholinesterases not only
reduced general motor function, but also produced disinhibition.
Although tolerance development was complete for the former effects,
it was incomplete for the latter (Overstreet et al., 1974~. Spatial alternation
tasks, rather than temporal, can also be examined. However, despite
their usefulness, they require considerable effort.
Maze Learning
Mazes have been used to test rodents for a very long period of
time, and most readers would be aware of the Tryon maze-bright
and maze-dull rats obtained by selective breeding. There was a con-
troversy in the 1930s about the ability of mazes to measure "intelligence"
or learning, and the controversy continues today. Of the many mazes
available to test rodents, this discussion is confined to just two: the T
maze and the radial arm maze.
The T maze can be used under a variety of conditions. It has often
been used in normal rats to examine spontaneous alternation behav-
ior (e.g., Overstreet et al., 1988a; Scheff and Cotman, 1977~. Heise
(1984) has reviewed the effects of drugs on this task and has concluded
that the task more likely measures short-term memory than habitua-
tion. Both cholinergic agonists and antagonists can modify rates of
alternation, depending on the conditions of the experiment (Squire,
1969~. The T maze can also be used under conditions of food or
water deprivation; a common paradigm is rewarded alternation, where
the rewards on successive trials are in opposite arms of the T maze
(e.g., Karpiak, 1983~. Others have used even more sophisticated ap-
proaches in order to separate working (short-term) from reference
(Iong-term) memory (Hepler et al., 1985; Olton, 1983~.
The radial arm maze has been used extensively by Olton and col-
leagues to study the effects of hippocampal lesions initially, and lesions
to other cholinergic systems later, on spatial learning and memory
(e.g., Olton, 1983; Olton et al., 1979~. Other investigators have now
used it to study quite a number of manipulations of the cholinergic
system. Typically, all eight arms of the radial arm maze are baited
and a trial continues until the rat consumes seven of the eight rewards.
During the trial the rat may return to an alley it has already visited,
thus making an error (working memory). Normal rats tend to reach
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ANIMAL MODELS OF DEMENTIA
133
error-free performance within a few days, but rats with lesions in the
nucleus basalis, for example, take much longer. Thus, the task has
been particularly useful in detecting the memory-disruptive effects
of treatments that affect the cholinergic system.
Recently, we have become dissatisfied with the standard radial
arm maze paradigm, as have others (Olson, 1983) because it does not
provide a measure of long-term or reference memory. One approach
to this problem has been the construction of a sixteen-arm maze,
with only nine of the arms baited. Another approach has been to
remove the rat from the maze after several rewards and return it
after a delay of varying intervals. Our approach has been to bait
only three of the eight arms of a standard maze. Such a procedure
has allowed us to measure both reference memory (entry into never-
baited arms) and working memory (reentry into an arm that was
baited) during performance. We have found that administration of
AF64A into the hippocampus produced a significant effect on work-
ing memory, but not on reference memory (Schiller et al., 1990~.
The baiting of only three arms of the eight-arm maze permits other
procedural manipulations. For example, once both groups have reached
asymptotic levels of performance, the location of the rewards can be
changed and the ability of the animals to relearn the task can be measured.
Such a manipulation also differentiated control rats from AF64A-treated
rats. In addition, however, the procedure allowed us to observe the
effects of physostigmine, a cholinesterase inhibitor often used experimentally
in the treatment of Alzheimer's disease. Both the control and the AF64A-
treated rats exhibited improved performance in the maze during daily
treatment with 0.15 mg/kg of physostigmine, with the performance of
the physostigmine-treated AF64A group resembling the saline-treated
control group (Schiller et al., 1990~.
In conclusion, both the T maze and the radial arm maze have been
extremely useful in detecting disturbances of higher brain function
produced by various treatments. Their main limitations are that food
or water deprivation is often necessary and that they are time-consum~ng,
requiring daily running in the mazes for up to several weeks. Most
investigators using these tasks would agree that the outcome more
than makes up for these limitations. They could be useful additions
to a behavioral battery designed to detect the neurobehavioral toxicology
of a particular agent (see Walsh and Chrobak, 1987~.
Other Measures
Some of the paradigms that might be used by neurobehavioral
toxicologists to examine the potential effects of a toxin on cognitive
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DAVID H. OVERSTREET AND ELAINE L. BAILEY
processes have been summarized above. This section includes some
other measures that investigators have found useful in assessing be-
havior under toxic conditions which produce dementia.
A commonly employed measure is locomotor activity. Its uses
and limitations have been thoroughly reviewed by Reiter and McPhail
(1979~. We have found that hippocampal AF64A treatment induces
hyperactivity, as well as disrupts memory (Bailey et al., 1986~. A
measure of the effects of a treatment on locomotor activity would be
particularly useful as a simple nonmanipulative task, if an investigator
used a limited number of tasks to assess memory (e.g., Dunnett et al.,
1982~. As indicated above, it is common for drugs that stimulate
activity to disrupt passive avoidance behavior.
Among other tasks that might be used by both neurobehavioral
toxicologists and those studying dementia in animals are measures of
reactivity such as startle reactions, measures of food or water intake,
and measures of sensory sensitivity. Tilson and Mitchell (1984) have
recently reviewed these and commented on their advantages and
limitations. The point we wish to make is that, too often, cognitive
psychologists overlook these less complex tasks when they study ef-
fects of changes in brain structures or functions on learning and memory.
CONCLUSION
Clinically the essential feature of dementia is ". . . a loss of intellec-
tual abilities of sufficient severity to interfere with social or occupational
functioning" (American Psychiatric Association, 1980~. Such losses
are multifaceted, being reflected in a variety of behavioral abnormalities.
In the preceding discussion, paradigms have been described which
provide measures of analogous behavioral abnormalities in animals
exposed to environmental toxicants. It has been suggested that studies
involving such animal models can generate information of importance
in supplementing knowledge in behavioral toxicology based upon
clinical and epidemiological research. Animal models provide means
of varying exposures to toxic substances and of controlling potentially
confounding variables to extents not usually available in research
involving human subjects. They also provide unique approaches in
the search for mechanisms and sites of action of such substances.
ACKNOWLEDGMENTS
This work was supported in part by a grant from the Flinders
University Research Budget to D. Overstreet. Elaine Bailey was sup-
ported by a Flinders University Postgraduate Research Scholarship.
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ANIMAL MODELS OF DEMENTIA
135
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Representative terms from entire chapter:
neurobehavioral toxicology
