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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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126 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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128 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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130 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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132 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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134 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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