A review of 25 years of the social interaction test
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.
References (244)
- et al.
5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively
Eur. J. Pharmacol.
(1994) - et al.
Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors
Pharmacol. Biochem. Behav.
(1989) - et al.
Antagonistic effects of caffeine and yohimbine in animal tests of anxiety
Eur. J. Pharmacol.
(1989) - et al.
The differential activities of R(+)- and S(−)-zacopride as 5-HT3 receptor antagonists
Pharmacol. Biochem. Behav.
(1990) - et al.
Ketotifen and its analogues reduce aversive responding in the rodent
Pharmacol. Biochem. Behav.
(1990) - et al.
The interaction of R(+)- and S(−)-zacopride with PCPA to modify rodent aversive behaviour
Eur. J. Pharmacol.
(1992) - et al.
The functional significance of biochemical alterations in streptozotocin-induced diabetes
Physiol. Behav.
(1991) Anxiogenic activity of centrally administered scorpion (Mesobuthus tamulus) venom in rats
Toxicon
(1995)- et al.
Anxiolytic–antidepressant activity of Withania somnifera glycowithanolides: an experimental study
Phytomedicine
(2000) - et al.
Effects of chlorisondamine and restraint on cortical [3H]ketanserin binding, 5-HT2A receptor-mediated head shakes, and behaviours in models of anxiety
Neuropharmacology
(1994)
Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety
Prog. Neuropsychopharmacol. Biol. Psychiatry
In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats
Neuropsychopharmacology
Antagonism of the anxiolytic effect of nicotine in the dorsal raphe nucleus by dihydro-β-erythroidine
Pharmacol. Biochem. Behav.
Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils
Brain Res.
Interactions of Ginkgo biloba extract (EGb 761), diazepam and ethyl beta-carboline-3-carboxylate on social behavior of the rat
Pharmacol. Biochem. Behav.
Infundibular ACTH can be excluded as a critical mediator in social behaviours
Brain Res. Bull.
Selective neurotoxin lesions of the lateral septum: changes in social and aggressive behaviours
Pharmacol. Biochem. Behav.
Social and exploratory behaviour in the rat after septal administration of ORG 2766 and ACTH4-10
Psychoneuroendocrinology
The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam
Pharmacol. Biochem. Behav.
Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset
Pharmacol. Biochem. Behav.
Ondansetron inhibits a behavioural consequence of withdrawing from drugs of abuse
Pharmacol. Biochem. Behav.
Anxiolytic effects of CCK-B antagonists
Neuropeptides
The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety
Eur. J. Pharmacol.
The locus coeruleus noradrenergic system—evidence against a role in attention, habituation, anxiety and motor activity
Brain Res.
Behavioural effects in gerbils of the 5-HT3 receptor antagonists, BRL 43694 and ICS 205-930, under circumstances of high and low light intensity
Neuropharmacology
Behavioural effects in mice of subchronic buspirone, ondansetron and tianeptine: I. Social interactions
Pharmacol. Biochem. Behav.
Behavioural changes following lesions of the orbital prefrontal cortex in male rats
Behav. Brain Res.
Citalopram reduces social interaction in rats by activation of serotonin 5-HT2C receptors
Neuropharmacology
Corticotropin-releasing factor has an anxiogenic action in the social interaction test
Horm. Behav.
Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze
Eur. J. Pharmacol.
Activation of 5-HT2B receptors in the medial amygdala causes anxiolysis in the social interaction test in the rat
Neuropharmacology
Pathways linking the olfactory bulbs with the medial preoptic anterior hypothalamus are important for intermale aggression in mice
Physiol. Behav.
The anxiolytic-like effect of MCI-225, a selective NA reuptake inhibitor with 5-HT3 receptor antagonism
Pharmacol. Biochem. Behav.
The effects of separate or combined infusions of corticotropin-releasing factor and vasopressin either intraventricularly or into the amygdala on aggressive and investigative behaviour in the rat
Regul. Pept.
Effects of ACTH4-10 in the social interaction test of anxiety
Brain Res.
ACTH as a mediator in anxiety
The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs
J. Neurosci. Methods
Contrasting effects of Org 2766 and α-MSH on social and exploratory behavior in the rat
Peptides
Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test
Pharmacol. Biochem. Behav.
Intraventricular ACTH reduces social interaction in male rats
Pharmacol. Biochem. Behav.
Chemical lesions of both dorsal and median raphe nuclei and changes in social and aggressive behaviour in rats
Pharmacol. Biochem. Behav.
A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquilisers and of stimulants
Pharmacol. Biochem. Behav.
Interactions of ethyl-β-carboline-3-carboxylate and Ro 15-1788 with CGS 8216 in an animal model of anxiety
Neurosci. Lett.
The anxiogenic action of Ro 5-4864 is reversed by phenytoin
Neurosci. Lett.
Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions?
Neuropharmacology
The sensitivity of the rat corticosterone response to environmental manipulations and to chronic chlordiazepoxide treatment
Physiol. Behav.
Anxiogenic action of a convulsant benzodiazepine: reversal by chlordiazepoxide
Brain Res.
The anxiogenic action of Ro 15-1788 is reversed by chronic, but not by acute, treatment with chlordiazepoxide
Brain Res.
The effects of PK 11195, a ligand for benzodiazepine binding sites, in animal tests of anxiety and stress
Pharmacol. Biochem. Behav.
Triazolobenzodiazepines antagonize the effects of anxiogenic drugs mediated at three different central nervous system sites
Neurosci. Lett.
Cited by (623)
Social environment enrichment alleviates anxiety-like behavior in mice: Involvement of the dopamine system
2024, Behavioural Brain ResearchHow social information impacts action in rodents and humans: the role of the prefrontal cortex and its connections
2023, Neuroscience and Biobehavioral Reviews