Memory animal tests

In recent years increasing attention has been paid to the possibility of delaying or even reversing the memory loss that accompanies old age or the more tragic loss of human capabilities associated with premature senility - Alzheimer s disease. Progress is hampered by the difficulty of identifying suitable animal tests, and there is presently no reliable therapy. 

Iversen (1991) stresses the need for some in vivo testing for neurotoxicity and emphasizes the value of sensitive behavioral tests. Behavioral tests are described for mice and rats, which provide measures of mood, posture, CNS excitation, motor coordination, sedation, exploration, responsiveness, learning, and memory function. Such assays can function as primary screens for neurotoxicity before adopting a stepwise scheme of in vitro tests to discover more about the initial site of action of neurotoxic compounds. It is argued that the requirement for animal testing can be drastically reduced by adopting structured in vitro protocols such as these. 

Teratological effects on passive avoidance behavior have been tested in a number of studies. It is often assumed that passive avoidance performance during the test session reflects memory capacity of the animal tested. However, such performance can also be considered a test of fear or arousal (ref. 138). 

Arylgermatranes were more active than hetaryl derivatives in memory improvement tests (Table 11). Phenylgermatrane, p-tolylgermatrane, p-fluorophenylethynylgermatrane, benzylgermatrane and o- and p-bromobenzylgermatranes completely prevented animals from retrogradal amnesia caused by electric shock. 

The running time score provides a measure of the intrinsic effects of the test substance on motor performance, and thereby permits an estimate of the selectivity of a drug effect on working memory . A test substance which markedly prolongs running time may also cause an increase in errors simply because the animal has to retain the required information (which arms were visited) over a longer period time. 

OR PEL PB-PK model RD50 REL SCE TOMM TWA UDS USAF odds ratio permissible exposure level physiologically based pharmacokinetic model respiratory depression in 50% of the animals tested recommended exposure limit sister chromatid exchange test of memory and motivation time-weighted average unscheduled DNA synthesis U.S. Air Force... 

The recent failure of Hemofilia B trials due to lack of efficacy raised other important issues. All animal tests using the AAV.fIX product showed positive results from mouse to subhuman primates. The lack of efficacy in humans is now attributed (at least in part) to a memory T-cell mediated immune response against the AAV vector, which is absent in animals. However, no human-specific immune response to Ad5 vectors has been identified to date. 

The preceding sections make It clear that none of the compounds presently In the limelight as potential memory enhancers has given reasonable evidence of positive effects In man. In addition, the animal results are all too often controversial. It Is of course true that those negative results which are available do not "prove" inactivity, but one must conclude that no reliable comparison standard Is available. It follows that animal tests cannot now be validated by the use of known actives. In the... 

The tests generally involve some form of maze but the simplest is the passive avoidance test. In this the animal learns that in a certain environment it will be punished with an electric shock for some particular action, like stepping onto a special part of the floor of the test chamber. The test of memory is how long the rat avoids (remains passive to) making the movement that will initiate the shock. Of course, drugs that reduce the animal s anxiety also modify the response. Using a maze in its simplest T shape, the animal is placed at the base of the vertical arm and a food reward at the end of one of the horizontal arms. Clearly the animal has to learn which arm contains the reward. Memory is assessed by the time taken for a food-deprived animal to reach the reward and the number of false arm entries. This simple system can be made more complex by introducing many more arms and branches but the principle is the same. 

In a radial maze a number of arms of equal length radiate from a central point, where the animal is placed. Initially food is placed at the end of each arm and the rat is expected to learn that fact by exploring and entering each arm. The test of memory is to see whether on re-exposure to the maze the rat remembers only to enter an arm not previously visited and so still containing food. 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

Initial evidence linking Hebb s coincidence detection rule to learning and memory. As the unique receptor in the brain with the coincidence-detection property, the NMDA receptor is an ideal candidate to gate the formation of memory at the synaptic level. Early observations demonstrated that infusion of NMDA receptor blockers into brain ventricles resulted in animals poor performance in the hidden-platform water maze. At first, this seemed to provide evidence for the role of hippocampal LTP in memory formation. Unfortunately, careful analyses revealed that poor performances in the water maze tests... 

To confirm their results and check for methodological problems, some studies have been carried out. As there was a probability that hypothermic conditions during temporary removal from dam may have affected the results, Pauluhn and Schmuck administered S-bioallethrin and deltamethrin to neonatal mice from postnatal day 10 to 16 under a hypo-, normo-, or hyperthermic environment, and measured the MAChR density at the age of 17 days [51]. Increase in MAChR in Cortex at PND 17 in animals treated with S-bioallethrin was observed. Meanwhile, no changes were observed in animals treated with deltamethrin. In addition, an enormous influence of environmental temperature on the density of MAChR receptors in the crude synaptosomal fraction of the cerebral cortex was ascertained. Tsuji et al. exposed mouse dams with their litters to D-allethrin by inhalation for 6 h from postnatal day 10 to 16. The inhalation administration method is the most relevant route of exposure for humans, including babies and infants, after indoor use of D-allethrin. The neonatal exposure to D-allethrin by inhalation did not induce effects either on the brain MAChR density or motor activity at 17 days and 4 months of age, or on performance in the leaming/memory test at 11 months of age [52]. Other unpublished studies with D-allethrin, S -bioallethrin, or deltamethrin were examined to confirm the results of Eriksson et al. and showed inconsistent results [53]. The reasons for discrepancy among these findings are unknown. 

Chlordecone causes a number of neurotoxic responses in humans and animals exposed to sufficiently high levels. Tremor that is accentuated by intentional acts, sustained postural movement, anxiety, or fatigue has been observed in workers exposed to high levels of chlordecone. Tremorograms have been used to objectively assess the tremor associated with chlordecone exposure in humans (Taylor et al. 1978). An infrared reflection technique and oculography have been used to assess the oculomotor disturbances caused by chlordecone (Taylor et al. 1978). Standard tests for memory and intelligence can be used to determine the presence of encephalopathy, but in the absence of baseline preexposure levels for individuals, subtle changes may be difficult to detect. 

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