A review of 25 years of the social interaction test

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Abstract

The social interaction test of anxiety was developed 25 years ago to provide an ethologically based test that was sensitive to both anxiolytic and anxiogenic effects. It is sensitive to a number of environmental and physiological factors that can affect anxiety. It has detected anxiogenic effects of peptides such as corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and anxiolytic effects of neuropeptide Y and substance P receptor antagonists. It has successfully identified neuropharmacological sites of action of anxiogenic compounds and drug withdrawal. Effects of compounds acting on the γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) systems have been extensively investigated after both systemic administration and microinjection into specific brain regions. The use of this test has, thus, played a crucial role in unravelling the neural basis of anxiety. It is hoped that in the next 25 years, the test will play a crucial role in determining the genetic basis of anxiety disorders.

Section snippets

Background

The social interaction test was developed 25 years ago (File and Hyde, 1978) as the first animal test of anxiety that endeavoured to use ethologically relevant sources of anxiety, and to use a natural form of behaviour as the dependent measure. It, therefore, avoided the use of food or water deprivation and electric shock, and did not require extensive training of the animal. The dependent variable is the time spent by pairs of male rats in social interaction (e.g. sniffing, following or

Behavioural correlates

In the original validation of this test (File and Hyde, 1978), it was shown that the reduction in anxiety that resulted from a brightly lit or unfamiliar arena was not mediated by olfactory cues (anosmic rats showed the same pattern of decreases in social interaction across the four test conditions). It was also shown that reduced social interaction was not the result of the rats spending more time in other activities, such as walking round or exploring the unfamiliar test arena. In fact,

Mice

de Angelis and File (1979) showed that Swiss albino mice showed the same decrease in social interaction as rats when the light level was manipulated, but that the changes in response to the familiarity of the test arena were less reliable. Lister and Hilakivi (1988) found similar results, using male NIH Swiss strain of mice and, furthermore, drugs that have clear anxiolytic and anxiogenic profiles in the rat test did not have specific effects in the mouse test Lister and Hilakivi, 1988,

Corticotropin-releasing factor (CRF)

Because the social interaction test was not developed solely to detect the effects of the benzodiazepines, it is not surprising that it has proved to be sensitive to the effects of a wide range of drugs and neuropeptides. Intracerebroventricular injection of corticotropin-releasing hormone has an anxiogenic effect (Dunn and File, 1987), and this could be reversed by chronic, but not acute, treatment with fluoxetine (To et al., 1999). Combined infusions of CRF and arginine vasopressin into

Benzodiazepine receptor antagonists and inverse agonists

Although agonists at the benzodiazepine receptor have anxiolytic effects (see Section 7), the social interaction test was the first to show that some compounds acting at this receptor had opposite effects. The benzodiazepine receptor antagonist, flumazenil, had an anxiogenic action (File et al., 1982) that could be reversed by subchronic administration of chlordiazepoxide (File and Pellow, 1984). Another benzodiazepine receptor antagonist, ZK 93426, also had an anxiogenic action (File et al.,

Benzodiazepine withdrawal

Whilst the benzodiazepines have clear anxiolytic effects after subchronic treatment (e.g. 5 days), after longer treatment (e.g. 21 days), tolerance develops to this effect (Vellucci and File, 1979), and after even longer treatment (28 days) with a high dose, an anxiogenic effect can be seen (Fernandes et al., 1999). When rats are withdrawn from chronic treatment with benzodiazepines, an anxiogenic response is seen and this can be reversed by administration (in the drug-free state) of the

Benzodiazepines, barbiturates and ethanol

The benzodiazepines are still the most widely used and effective anxiolytic drugs, and many of these have been found to be effective in the social interaction test (see Table 1 for summary).

The social interaction test reflects well the difference between acute and chronic benzodiazepine treatment. With acute administration, the benzodiazepines have their usual sedative effect in all of the test conditions File et al., 1976, File, 1979b, File, 1982. In contrast, after 5 days of pretreatment,

Amygdala

The amygdala has long been considered to be an important structure mediating changes in anxiety and following injection of the specific neurotoxin 5,7-dihydroxytryptamine, resulting in 80% depletion of 5-HT, rats spent significantly less time in social interaction and had reduced locomotor activity (File et al., 1981). The lesion, therefore, seemed to be having a nonspecific effect of decreasing spontaneous behaviours. After direct injection into the amygdala, Higgins et al. (1991) observed

Conclusions

The social interaction test of anxiety has proved extremely useful in detecting both anxiolytic and anxiogenic effects of environmental factors and systemically administered drugs and peptides. It has also proved invaluable in unravelling the neural basis of anxiety. Most of the research over the past 25 years has been on the state of anxiety that is induced by the test itself. This is thought to mimic the state of anxiety most similar to that experienced in generalised anxiety disorder.

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