The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review
Introduction
Hall (1934) originally described the open field test for the study of emotionality in rats. The procedure consists of subjecting an animal, usually a rodent, to an unknown environment from which escape is prevented by surrounding walls (Walsh and Cummins, 1976). Hall's apparatus consisted of a brightly illuminated circular arena of about 1.2 m diameter closed by a wall 0.45 m high. He placed rats individually in the outer ring of the open field and observed the rat's behavior for 2 min, during daily repeated trials. Rats were sometimes tested after 24 or 48 h food deprivation. Hall observed that rats walked more when they were food deprived, but not all rats ate. Animals that did not eat were termed emotional. When compared to non-emotional rats, they had fewer entries in the central part of the arena and higher levels of defecation.
The open field test is now one of the most popular procedure in animal psychology (see Belzung, 1999 for a review). Different versions are available, differing in shape of the environment (circular, square or rectangular), lighting (lighting from above with a bulb above the open field or lighting from underneath with a bulb placed under a transparent floor, sometimes red light is used), presence of objects within the arena such as platforms, columns, tunnels (see for example Takahashi and Kalin, 1989), etc. The procedure generally usually involves forced confrontation of a rodent with the situation. The animal is placed in the center or close to the walls of the apparatus and the following behavioral items are recorded for a period ranging from 2 to 20 min (usually 5 min): horizontal locomotion (number of crossings of the lines marked on the floor), frequency of rearing or leaning (sometimes termed vertical activity), grooming (protracted washing of the coat). In such a situation, rodents spontaneously prefer the periphery of the apparatus to activity in the central parts of the open field. Indeed, mice and rats walk close to the walls, a behavior called thigmotaxis. Increase of time spent in the central part as well as of the ratio central/total locomotion or decrease of the latency to enter the central part are indications of anxiolysis. Some authors use a procedure in which the animals are allowed free access to the open field, from a familiar cage (see for example Kopp et al., 1997). In this case, the number of risk assessment postures directed to the open field may provide a good measure of the approach response toward novelty, that is, exploration.
The open field has become so popular that its use has been extended to a great number of species, including calves, pigs, lambs, rabbits, pullets, primates, bush babies, honeybees and lobsters. In fact, it has become a convenient procedure to measure not only anxiety-like behaviors, but also sedation or activity. In fact, anxiety behavior in the open field is triggered by two factors: individual testing (the animal is separated from its social group) and agoraphobia (as the arena is very large relative to the animal's breeding or natural environment). It is clear that these two factors may trigger anxiety behavior only in gregarious species and/or in species that show fear of open spaces into which they are forced. This is precisely the case with rodents that live in social groups and in small tunnels. This is of course not the case in species such as lambs or cows that live in large fields. For these reasons, in experiments involving rodents, observers are not measuring the effects of treatments on exploration, as is sometimes claimed, but the effects on the reaction of the subjects to a stressful event. Therefore, anxiolytic treatments do not themselves increase exploration in the open field but they decrease the stress-induced inhibition of exploration behavior.
Behavior of rodents in the open field depends mainly on the tactile sensory factors. Indeed, mice without vibrissae no longer show thigmotaxic behavior, as they lose tactile contact with the walls (unpublished data). They therefore display an increased percent of entries in the central area, which could be interpreted as anxiolytic-like behavior. One must thus emphasize the possibility of misinterpretation of data related to effects of some treatments on the sensory characteristics of the animals. It should also be noted that exploration can be increased by some factors such as food or water deprivation: it is therefore very important to verify that a given treatment does not act on such variables, before concluding about possible effects on anxiety-like behaviors. Finally, open field behavior also depends on lighting conditions and the light–dark cycle, so that it may be relevant to ensure that a treatment does not modify internal clock-related behaviors and to test the treatment under different lighting conditions.
The effects of many different drugs have been investigated in the open field, including compounds with effective or potential anxiolytic effects (benzodiazepines, serotonin ligands, neuropeptides) but also compounds with stimulant (amphetamine, cocaine), sedative (neuroleptic) or prostration-inducing (epileptogenic drugs) activity. An increase in central locomotion or in time spent in the central part of the device without modification of total locomotion and of vertical exploration can be interpreted as an anxiolytic-like effect while the contrary, that is a decrease of these variables, is associated with anxiogenic effects. Increased locomotion can be considered a stimulant effect while decreased vertical activity and locomotion are related to sedation or to post-ictal prostration. It should be said here that the decrease in vertical exploration appears at lower doses than does the decrease in rearing, so that this variable can be considered a more sensitive one. In this paper, we will focus on the effects of pharmacological treatment on anxiety measures in the open field and not on their sedative or stimulant effects. Therefore, this is not a general review on drugs in the open field, but a review of the effects of drugs on anxiety-like variables in the open field. The action of three classes of pharmacological compounds will be reviewed: the effects of compounds acting on the GABAA pentamer (mainly benzodiazepine receptor ligands but also GABAA receptor, barbiturate and neurosteroid ligands), the effects of drug acting like 5-hydroxytryptamine (5-HT) (ligands of the different 5-HT receptors as well as selective serotonin reuptake inhibitors, neurotoxins of 5-HT, etc.) and the effects of neuropeptidergic ligands (corticotropin releasing factor: CRF, cholecystokinin: CCK, neurokinin: NK, neuropeptide Y, etc).
Section snippets
Effects of compounds acting on the GABAA pentamer
Classical benzodiazepines are widely used for the clinical treatment of anxiety. They act via the benzodiazepine receptors which are present on the GABAA pentameric complex. The GABAA receptors can be allosterically modulated by compounds binding to at least six different sites: the benzodiazepine receptors, a binding site for barbiturates, a site for neurosteroids, a site for the convulsant drugs, picrotoxin and t-butylbicyclophosphorothionate, one for flurosemide and one for loreclezole (see
Effects of serotonin-like acting drugs
Considerable research has been undertaken since the early 1980s on the anxiolytic-like activity of drugs acting on serotonin (5-HT) neurotransmission, particularly compounds that bind selectively on 5-HT1A receptors (agonists, but also antagonists) or inhibit 5-HT reuptake (Selective Serotonin Reuptake Inhibitors) (see Griebel, 1995, Griebel, 1996, Griebel, 1999a, Belzung, 2001 for reviews). A summary of the studies investigating the effects of these compounds in animals tested in an open field
Effects of neuropeptide receptor ligands
Recently, the rapid advances in neuropeptide research have stimulated interest in the ability of some neuropeptides to act as anxiolytics (see Griebel, 1999b for an excellent review). Interest has focused on CRF receptor ligands, on cholecystokinin, neuropeptide Y, tachykinin (especially neurokinin) as well as on glucocorticoid and mineralocorticoid receptor ligands.
Studies investigating the effects of CRF receptor ligands are presented in Table 3. This table shows clearly that all the studies
Conclusion
Is the open field test suitable for screening anxiolytic activity of pharmacological treatments? To be a relevant model of human behavior, an animal test should fit three criteria: predictive, face and construct validity. Our review of the literature shows clearly that the open field cannot claim predictive validity for anxiety in general, as it is not sensitive to compounds (alprazolam and chronic Selective Serotonin Reuptake Inhibitors) effective in anxiety disorders such as panic,
Acknowledgements
The authors are thankful to Dr. G. Griebel for providing data from his personal database Table 2, Table 3, Table 4.
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