Animal Models of Anxiety Disorders

In developing an animal model of diseases and disorders, scientists 

One of the most popular tests used to measure anxiety in animals are operant conflict tests. The word operant means that the subject, whether animal or human, must perform some task to bring about a specific result. In this kind of test, something that the animal likes or needs (such as food or water) is used as positive reinforcement to teach the animal to perform a task. For example, a rat might learn that pressing a lever brings the delivery of a food pellet. In this case, pressing the lever is the operant behavior and the food pellet is 

The elevated plus maze measures how rats and mice react in an apparatus that has two distinct environments, one a brightly lit and exposed runway and the other a dark and walled runway. The two runways intersect in the center (giving the maze the appearance of a plus sign) and are about 30 inches (76 cm) off the ground. Because rodents are nocturnal (active at night) animals and dislike open and well-lit places, the elevated plus maze is said to be a natural, or ethologically-based, test of anxiety. When a rat or mouse is placed in the elevated plus maze, it is free to go wherever it likes. This kind of approach/avoidance  

It is thought that this test for anxiety most closely resembles the behavior that accompanies a specific phobia. Because this burying behavior is consistent and does not decrease over time, it is also believed that this type of behavior resembles what is seen with obsessive-compulsive disorder. Benzodiazepines are an example of a drug that reduces both the avoidant and the burying behaviors in this test. 

Rats are usually social animals. When two rats that are unfamiliar with each other are introduced, they will spend the first few minutes sniffing and touching one another. However, when rats are in an unfamiliar environment or when there is something about the environment that makes rats uncomfortable, like bright lights or a wide open space, they will spend much less time investigating a new acquaintance. Therefore, the amount of time that two rats spend interacting with each other in a new or uncomfortable (for the rat) environment 

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These examples underline that in the search for animal models of anxiety disorders it is not sufficient to screen for anxiety-related behavioral characteristics. On the contrary, it is of fundamental importance to phenotype extensively and carefully each potential animal model, even the well-established inbred mouse strains. 

Liebsch G, Linthorst ACE, Neumann ID, Reul JMHM, Holsboer F, Landgraf R (1998) Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high and low anxiety-related behavior. Neuropsychopharmacology 19 381-396 Lister RG (1990) Ethologically based animal models of anxiety disorders. Pharmacol Ther 46 321-340... 

Griebel G (1995) 5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders more than 30 years of research. Pharmacol Ther 65 319-395 Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology (Berl) 148 164-170... 

Shekhar A, McCann UD, Meaney MJ, et al. Summary of a National Institute of Mental Health workshop developing animal models of anxiety disorders. Psychopharmacology (Berl) 2001 157 327-39. 

Uys JD, Stein DJ, Daniels WM, Harvey BH. Animal models of anxiety disorders. Curr. Psychiatry Rep. 2003 5 274-281. 

Ramboz S, Oosting R, Amara DA, Kung HP, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor lA knockout an animal model of anxiety-related disorder. ProcNatl Acad Sci U S A 95 14476-14481... 

Stress is thought to be an important factor in the pathophysiology of depression and anxiety disorders. It seems possible that the reduced stress reactivity of NKl receptor- and tael-deficient mice has contributed to the behavioral phenotypes observed in the animal models of anxiety and depression. 

The anxiolytic activity of several compounds in some, but not all, animal models of anxiety in fact suggests that different receptor subtypes may modulate different types of anxiety as discussed below. It would not be surprising if the specific serotonin links to disorders of anxiety also differ among the various disorders of anxiety such as generalized anxiety versus obsessive-compulsive disorder versus panic disorder versus social phobia versus mixed anxiety depression. Such studies are in progress, and much further research is necessary to clarify the potential links between subtypes of anxiety and subtypes of serotonin receptors. 

Many patients with anxiety disorders experience an increased susceptibihty to psychosocial stress. Behavioral sensitization may account for these cHnical phenomena, hi the laboratory model of sensitization, single or repeated exposure to physical stimuU or pharmacological agents sensitizes an animal to subsequent stressors (reviewed in Charney et al. 1993). For example, in animals with a history of prior stress, there is a potentiated release of NE in the hippocampus with subsequent exposure to stressors (Nisenbaum et al. 1991). Similar findings were observed in medial prefrontal cortex (Finlay and Abercrombie 1991). The hypothesis that sensitization is underlying neural mechanism contributing to the course of anxiety disorders is supported by clinical studies demonstrating that repeated exposure to traumatic stress is an important risk factor for the development of anxiety disorders, particularly PTSD (Table 1). 

Finally, chemicals aimed at relieving symptoms observed in psychiatric illnesses (e.g. anxiety, depression, schizophrenia) are studied in various animal models that reveal typical behaviours claimed to mimic those exhibited by patients. Animal tests are also needed to discover and develop drugs to treat cognitive decline. Recent studies of the effects of certain brain lesions on learning in rats or monkeys as animal models of Alzheimer s disease may go some way towards developing an experimental model for this disorder. 

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