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causes pain or induces, e.g., nausea, this will affect behavior as well.

A final factor is that experimental conditions and handling will affect the outcome of an experiment. A stressed animal or an animal placed in an aversive experimental situation will necessarily exhibit a different behavior compared to a nonstressed or a nonanxious animal. These factors need to be controlled and what may constitute an aversive stimulus for that particular species needs to be considered. However, it is also possible to use aversive stimuli to control the types of behavior that the animals express and that are studied. For example, the light level in an arena will have considerable impact upon the behavior of a rat. High-light conditions will produce an anxiogenic state in the rat, which will reduce the level of active behaviors, whereas a low-light condition will increase the level of natural behaviors, e.g., explorative and social behaviors (Whishaw and Kolb 2005). The olfactory level in the arena and the number of repeated visits to the arena will affect the speed with which the animal begins to perceive the arena as a part of its territory and thereby the level of aggressive behaviors it expresses in order to defend its territory, if confronted with a conspecific. The level of aggressive behavior is also affected by the housing condition of the animals, e.g., in rats single housing will increase the aggression level. Light/ dark cycle will affect the sensitivity of the animals to drugs. If animals are tested during their normally active period, i.e., during the night for a rat, it will be more sensitive to drug effects compared to testing conducted in the day time, i.e., the rats inactive period. Finally, handling can have unexpectedly strong effects on behavior, e.g., handling a rat by the tail can stress it so much that it becomes impossible to study social interations, and the presence of a computer in the experimental room can affect behavior because the rats may be able to hear it.

Standard Test Paradigms

Social behavior can in principle be studied in any situation that involves two or more members of the same species. Complex situations involving many members living in a stable structure is likely to provide more detailed information on the effects of drugs on normal behavior or on behavioral abnormalities in animals carrying a disease, but it can be very difficult to standardize a test of this type to allow comparison of different drugs and the amount of time required to study drug effects may become so demanding that it in practice becomes impossible to compare drug series. For these reasons a number of simplified, standardized behavioral tests have been developed that allow the experimental observation of some aspects of social behavior thought to be relevant to human behaviors.

One of the most routinely used tests for social behavior is the ► social interaction test where two rats or mice are placed simultaneously into an arena and where their level of social behavior is recorded for 7-10 min (File and Seth 2003). The animals may be familiar with the arena and to each other. The test is usually performed in a highlight and a low-light configuration. For the high-light configuration, the arena is brightly illuminated and this will create an aversive environment since rats and mice in general avoid open, brightly lit areas. Their natural tendency will be to avoid the center of the arena and to stay in the periphery of the arena, where they usually remain inactive. Using this design, it has been shown by many researchers that anxiolytic drugs such as the ► benzodia-zepines, ► diazepam and ► chlordiazepoxide, will increase the level of social interaction, indicating a reduced level of anxiety in the animals, whereas drugs that lack ► anxiolytic effects are inactive. However, it should be noted that the avoidance of open spaces is a biologically appropriate response for a rat and a mouse, and the test therefore studies drug effects on natural behaviors and not on pathological anxiety, which is the type we seek to treat in human patients.

In the low-light configuration, the arena is only illuminated by dim red light to simulate a night-time situation, which is non-aversive to rats and mice, and they will typically explore the entire arena and engage in frequent social interactions, e.g., rats will typically investigate the novel area together. Under these conditions it is possible to evaluate manipulations that disrupt social behavior, e.g. to model a disease condition, or to determine if a drug causes side effects that affect normal behavior. An example of a disease model is phencyclidine-induced social isolation (Ellenbroek and Cools 2000). ► Phency-clidine (PCP) is an NMDA-antagonist that often is abused by humans and it has frequently been observed that PCP will induce a type of symptomatology, which resemble the negative symptoms of ► schizophrenia, i.e., the inability to engage in normal social relations. PCP will potently disrupt social behavior in rats, and this disruption can be reversed by ► antipsychotic drugs that in patients have an effect on the negative symptoms, e.g., ► clozapine and ► risperidone, whereas drugs that only affect the positive symptoms, e.g., ► haloperidol or that are not effective in the treatment of schizophrenia, e.g., ► citalopram and diazepam, are ineffective.

A different test paradigm is the ► social recognition test, which typically is performed in rats, where the level of social behavior or social interest is used as a measure of recognition. In this test, an adult rat is allowed, e.g., 5 min, to investigate a juvenile rat. The juvenile is removed and after a certain time period, e.g., 30 min, 2 h or 24 h, either the same juvenile or a different juvenile is presented to the adult rat. If the adult rat recognizes the juvenile it will spend less time investigating it compared to the situation where it is a novel juvenile. Drug studies have shown that ► nicotine, which is known to improve memory in humans, can prolong the time period in which the adult rat recognizes the juvenile, whereas ► scopol-amine, which interferes with memory, reduces the time period. The social recognition test is typically used in two configurations with either a long delay or a short delay until the re-introduction of the juvenile. The purpose of using a long delay is to identify drugs that can enhance memory, e.g., for symptomatic treatment of memory deficits in ► Alzheimer's disease, by demonstrating that a drug extends the time period in which the adult animal recognizes the juvenile. The purpose of using a short delay at which normal animals will recognize the juvenile is to determine whether a drug inhibits normal memory processes, e.g., caused by side effects, or to determine if animals display memory deficits, e.g., in connection with disease models, and whether drugs are able to reverse these deficits. Examples of the latter are scopolamine-in-duced memory deficits and cognitive deficits in disease-models of e.g., Alzheimer's disease, schizophrenia, and

► stroke. Finally, it is possible to administer the investigative drug at different time points in the testing sequence to determine which aspects of the memory process it affects, e.g. administering it after the first presentation of the juvenile to determine if it affects the ► consolidation of memory.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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