A review of central 5-HT receptors and their function

The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretched-attend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.

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The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

The mouse light/dark box test.

Despite or possibly by virtue of the fact that it is one of the most commonly used animal models of anxiety the Elevated Plus-Maze (EPM) results in a wide range of, often contradictory, results following pharmacological experiments. The responses from a questionnaire distributed to 65 groups that have published studies using the EPM in the past 3 years has, along with reference to published reports, enabled some conclusions regarding the influencing factors to be drawn. Some evidence for differential sensitivities between strains exists, with albino rats being more sensitive to the anxiolytic effects of 5-HT3 receptor antagonists and 5-HT1A receptor agonists than pigmented animals. Most important, however, is the manipulation of the animals prior to testing and the aversiveness of the test conditions themselves. Stressing animals before testing (e.g., by moving from holding to test room) or using more aversive test conditions (e.g., elevated light levels) increases sensitivity to potential anxiolytics. Animals that are habituated to gentle handling or tested in less aversive conditions (e.g., EPM with ledges) show reduced likelihood of anxiolytic responses with administration of 5-HT3 antagonists, 5-HT1A agonists, and benzodiazepines.

A review of the validity and variability of the elevated plus-maze as an animal model of anxiety.

5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively.

Contrasting behavioural effects of 8-OH DPAT in the dorsal raphé nucleus and ventral hippocampus.

Laboratory-bred rats can be divided into those showing clear innate behavioral responses to the odor of a predator (a cat) and those showing no response. However, these two groups did not differ in their responses to a neutral odor, or in the social interaction or elevated plus-maze tests of anxiety. This suggests a distinction between phobic anxiety (generated byt odor) and a generalized anxiety state (generated by novelty in the other test)). Trial 2 in the plus-maze generates a state of fear that is distinct from thet generated on trial 1, and one suggested to reflect phobic anxiety. Although the groups of cat responders and nonresponders did not differ in their scores on trial 2 in the plus-maze, two clear groups of responders and nonresponders could be identified on this trial 1 or not on trial 1 or in the social interaction test). This suggests that is possible to identify bimodal populations of rats in tests of both innate and acquired simple phobias.

Responders and nonresponders to cat odor do not differ in other tests of anxiety

In the first experiment male chicks were exposed to neutral and cat odours at days 4, 7, or 10 after hatching. Of the chicks tested at day 4, few made contact with either odour cloth, but those tested at day 7 made fewer contacts with the cat odour cloth, compared with the neutral odour, spent less time in contact with it, and spent more time in the zone furthest from the cloth. These clear differences were not seen in the group tested at day 10. In a second experiment, the behaviour of day 7 male chicks was compared in the presence of neutral, disinfectant, chick blood or cat odours, and the most extreme differences were between neutral and cat odours. In a third experiment, both male and female chicks were exposed to cat odour at day 7 and both showed similar avoidance. After exposure to cat odour both sexes showed significantly reduced GABA enhancement of benzodiazepine binding; which is a change associated with increased fear. However, after exposure to cat odour, they also showed significant decreases in 5-HT availability evidenced by lower basal and K + -evoked [ 3 H]-5-HT release and, in the male chicks only, by an increased [ 3 H]-5-HT uptake from archistriatal slices. These changes in 5-HT function are in the direction associated with reduced fear and would, therefore, seem to be adaptive and compensatory in function. Neither male nor female chicks showed any differences in [ 14 C]-GABA release or uptake as a result of exposure to cat odour. Although the pattern of response to cat odour was the same in both male and female chicks at day 7, there were significant sex differences in 5-HT and GABA tone and benzodiazepine binding; these sex differences were also found in day 10 chicks. The importance of these for sex differences in trait anxiety is discussed.

Sandy Hogg

Papers

A review of the validity and variability of the elevated plus-maze as an animal model of anxiety.

5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively.

Contrasting behavioural effects of 8-OH DPAT in the dorsal raphé nucleus and ventral hippocampus.

Responders and nonresponders to cat odor do not differ in other tests of anxiety

Behavioural and neurochemical responses of male and female chicks to cat odour