Social Interaction Test Of Anxiety Research Articles

Cocaine- and amphetamine-regulated transcript peptide (CART) in the central nucleus of amygdala potentiates behavioral and hormonal responses of the rat exposed to its predator

Since cocaine- and amphetamine-regulated transcript peptide (CART) regulates anxiety and stress in amygdala, we hypothesized that the peptide may also process negative psychological experience like fear. During acute exposure to a cat, the rat showed freezing behavior and subsequently, profound signs of anxiety in social interaction test, and elevated serum cortisol concentration. While these behavioral effects were potentiated by the intracerebroventricular (icv) and intra-central nucleus of amygdala (intra-CeA) administration of CART peptide, they were blocked by CART antibody. On the other hand, chronic exposure for 7 days resulted in a steady reduction in freezing, increase in social interaction index and restored cortisol levels. In these rats, the behavior resembled with that of the time matched control rats suggesting habituation. However, CART peptide treatment, via the icv or intra-CeA route, chronically for 7 days, prevented habituation; significant freezing behavior and anxiety were noticed in these rats. The results suggest that CART peptide, in the framework of CeA, may process predator triggered innate fear in acute time scale, while chronic exposure might down-regulate the system and produce habituation.

Corticosterone -- an anxiogenic or an anxiolytic agent?

Corticosterone (3--12 mg kg-1, i.p., giving rise to plasma corticosterone concentrations from 26.7 to 89.0 micrograms/100 ml) failed to have a significant anxiogenic action. Instead, corticosterone (3 mg kg-1) had a significant anxiolytic effect in the social interaction test of anxiety. Adrenalectomized rats had very low levels of social interaction; but adrenalectomized rats that had been given replacement corticosterone therapy did not differ from the sham-operated controls. Thus, corticosterone appears to have the opposite effect to that previously reported for ACTH. Possible mechanisms for the observed results are discussed.

The effects of p-chlorophenylalanine and ethanolamine-O-sulphate in an animal test of anxiety.

p-Chlorophenylalanine, which produces a depletion of brain 5-HT concentration, had effects qualitatively similar to those previously found with chronic chlordiazepoxide and with acute ethanol in the social interaction test of anxiety. This result is compatible with the idea that a reduced turnover of 5-HT is important in anxiety reduction. On the same test, ethanolamine-O-sulphate, which raises brain gamma-aminobutyric acid, was without effect, suggesting raised concentrations of this acid are not essential for anxiety reduction.

Antidepressant-like effects of the vasopressin V1b receptor antagonist SSR149415 in the Flinders Sensitive Line rat

There is an increased interest in the potential of vasopressin receptor antagonists as antidepressants because of the involvement of vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective vasopressin V1b receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22–24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 °C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats. In contrast, SSR149415 did not alter the lower immobility of the FRL rats. The social interaction test of anxiety was also examined in the FSL rats, at 20–22 h after the last of the 14 injections. Results showed that the 10 and 30 mg/kg doses of SSR149415 increased the time spent in social interaction in the FSL rats, suggesting anxiolytic effects. These findings confirm the antidepressant-like potential of SSR149415 and suggest that it may also have anxiolytic effects. It is likely that the strategy of testing selective vasopressin V1b receptor antagonists will be fruitful.

The effects of angelica essential oil in social interaction and hole-board tests

In our previous studies, we have demonstrated the anxiolytic effects of angelica essential oil in three anxiety models using mice. This study aimed to characterize the similar behavior effects of angelica essential oil in the social interaction test of anxiety and the hole-board test of exploration and locomotor activity in rats. These results indicate that angelica essential oil possessed a wide range of anxiolytic properties. In the social interaction test, angelica essential oil decreased aggressive behaviors at the doses of 21 and 42 mg/kg, while the doses of 21 and 42 mg/kg significantly increased social interaction time of the high light, unfamiliar test condition and 21 mg/kg could also prolong social interaction time of the high light, familiar test condition. In the hole-board test, angelica essential oil at 10.5 mg/kg significantly increased head-dipping counts and duration. Thus, our findings suggest the potential usefulness of angelica essential oil against various types of anxiety-related disorders and social failure.

Sociability trait and serotonin metabolism in the rat social interaction test

Social behaviour is the basis of one of the most generally accepted independent dimensions of personality. The purpose of the present study was to find out whether the social activity of individual rats, expressed in the social interaction test of anxiety, is consistent, and associated with monoamine levels. Four social interaction tests with 10 days intervals were carried out in 20 rats, and the animals were decapitated 4 days after the last test. There was no consistent correlation between performances in single tests, but the social interaction time in each test correlated strongly with the mean values of social activity in all or the other three tests. Social interaction time of rats correlated moderately but significantly with their partner’s social activity in the test. The average social interaction time correlated strongly with 5-HIAA levels in the frontal cortex ( r=−0.67, P<0.01). Neither exposure of rats singly to the social interaction test box nor the test procedure had any effect on monoamine levels. When animals were decapitated immediately after a single social interaction test, there was a negative correlation between the social interaction time and 5-HIAA and 5-HT levels in the septum, but not in the frontal cortex or hippocampus. Thus, social behaviour is a stable trait, expression of which depends in part upon the partner’s social behaviour. This trait is negatively associated with 5-HT metabolism in the frontal cortex. Social activity of rats in a particular test situation may rather be related to 5-HT metabolism in the septum.

Social instability in female rats: effects on anxiety and buspirone efficacy.

Buspirone produces inconsistent effects in laboratory rodents. Individual housing increases the efficacy of buspirone in male rats, suggesting that the effects of this (and other) compounds become conspicuous in animals showing anxiety-like states. The effect of individual housing was, however, weak, and evident only when the locomotor suppressive effects of buspirone dissipated (i.e. 4 h after treatment). The effects of social instability, a recently developed model of social stress in female rats, was investigated on both anxiety and the anxiolytic efficacy of buspirone. Female rats were exposed to alternate days of isolation and moderate crowding for 2 weeks. Group composition was changed for each crowding phase. Basal anxiety and the anxiolytic efficacy of buspirone were assessed by the social interaction test of anxiety 24 h after the last crowding phase. Crowding appeared stressful, as it increased plasma glucocorticoid levels in less than 1 h. Anxiety-like behaviours were increased by social instability compared with stable group housing. In group housed controls, buspirone markedly suppressed locomotion, without clear effects on anxiety-related behaviours. Social instability attenuated the locomotor suppressive effects of buspirone, but made the anxiolytic effects of the compound more conspicuous. The effects of individual housing (assessed earlier) and social instability (assessed here) on buspirone efficacy appear qualitatively different. Buspirone abolishes stress-induced anxiety, but has no anxiolytic effects in controls. This is consistent with clinical findings, as the drug decreases anxiety in anxious patients but not in healthy humans. Laboratory models involving stress-induced anxiety-like states can improve our understanding of drug effects and efficacy.

Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats

The effect of angiotensin-converting enzyme (ACE) inhibitor enalapril (EPL) (2 and 4 mg/kg), angiotensin (AT) II receptor antagonist losartan (LRN) (5 and 10 mg/kg), and anxiolytic drug diazepam (DZP) (0.5 mg/kg) on anxiety parameters were evaluated in experimentally induced renal hypertensive rats (RHR). Renal hypertension was induced in Wistar strain male albino rats weighing 200–250 g by following the method of Goldblatt. The animals having systolic blood pressure more than 180–210 mm Hg were subjected to open-field exploratory behaviour, elevated plus maze behaviour, and social interaction tests of anxiety. The RHR showed hyperactivity in open-field behaviour and anxiogenicity in elevated plus maze and social interaction tests. Losartan (5 and 10 mg/kg) and DZP (0.5 mg/kg) significantly attenuated the hyperactivity and anxiogenic behaviour in experimentally induced hypertensive rats and induced anxiolysis in normotensive rats (NTR). Enalapril reversed the hypertension-induced alteration only at higher dose (4 mg/kg) and failed to show any effect in NTR. It can be concluded that renin angiotensin aldosterone system (RAAS) has a significant role on behaviour, and LRN has shown better effect in reversing the hyperactivity and anxiogenicity in the experimentally induced hypertensive rats, indicating a possible role of AT receptor in the mediation of anxiolysis.

A review of 25 years of the social interaction test

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.

Age-associated sex differences in response to food deprivation in two animal tests of anxiety

The effects of mild food deprivation (7 days of food restricted to once daily feeding to maintain body weights at 85% of free-feeding weights) were examined in adult male and female and adolescent female rats tested in the elevated plus maze and social interaction tests of anxiety. In adult male rats, food deprivation appeared to have an anxiolytic effect in the plus-maze as it significantly increased the percentage of entries onto open arms and the percentage of time spent on the open arms, without changing the number of closed arm entries. There were no effects of food deprivation in adult females, although in adolescent females food deprivation significantly increased the percentage of open arm entries rats. Adolescent female rats have female brains, but do not have circulating gonadal hormones and thus these results suggest that circulating female gonadal hormones are able to suppress some of the effects of mild food deprivation in the plus-maze. In the social interaction test, there were no effects of food deprivation in any group on the time spent in social interaction. There were opposite effects on locomotor activity in the adult male and female rats, with deprivation increasing activity in males and decreasing it in females. There were no effects of food deprivation on locomotor activity in the adolescent females, suggesting that circulating gonadal hormones were responsible for the bidirectional effects in the adult rats. In both tests there were age-associated differences in the female rats, with the adolescent females being less anxious (higher percentage of open arm entries and increased social interaction) than the adults.

Accentuated Decrease in Social Interaction in Rats Subjected to Repeated Ethanol Withdrawals

Background Previous work has shown that repeated withdrawals from chronic ethanol exposure can kindle seizures in rodents. In this article, the effects of a three-cycle model of ethanol exposure and withdrawal on the social interaction test of anxiety are summarized. Methods Rats were exposed to ethanol (7% or 4.5%) diets over three periods of 5 days, with 2 days of withdrawal between cycles. Between 5 and 6 hr after the ethanol was removed, pairs of rats were placed in open field chambers for the assessment of social interaction behavior and locomotor activity. Results After the third cycle of ethanol (7%) presentation, both male and female rats exhibited lower social interaction behavior (more anxiety) and activity than after a single cycle. Rats exposed to a similar amount of ethanol but tested while ethanol was still available did not exhibit a reduction in social interaction. The decrease in social interaction was still present for up to 24 hr but had disappeared by 48 hr after ethanol was withdrawn. When rats were allowed 8 or 16 days to recover from the effects of the three-cycle protocol, a further exposure to 5 days of 7% ethanol diet resulted in a reduction in social interaction on withdrawal similar to that seen from the three-cycle protocol. In contrast, rats exposed continuously to 7% ethanol diet for 15 consecutive days exhibited higher levels of social interaction when maintained on control diet for 8 or 16 days and then reexposed to ethanol. Rats that were exposed to the three-cycle protocol and allowed 32 days to recover before being reexposed to ethanol still had a partial deficit in social interaction. Finally, animals subjected to repeated withdrawals from 4.5% ethanol exhibited a reduction in social interaction without a change in activity after the final withdrawal from ethanol, whereas rats exposed continuously to a 4.5% ethanol diet did not exhibit a reduction in social interaction or activity. Neither blood ethanol concentrations nor changes in body weight could account for these behavioral differences. Conclusion Repeated withdrawal from ethanol can lead to accentuated or more persistent anxiety-like behavior in rats, as indicated by a decrease in social interaction. The withdrawal-induced decrease in locomotor activity is not accentuated by repeated withdrawals. This model of repeated withdrawals from ethanol may prove useful in defining the neurochemical basis of this accentuation.

Antagonism of the anxiolytic effect of nicotine in the dorsal raphé nucleus by dihydro-β-erythroidine

Nicotine has been reported to reduce anxiety in humans and in a number of animal tests. In the social interaction test of anxiety, administration of low doses of nicotine into the dorsal raphé nucleus (DRN) increases the time spent in social interaction without producing accompanying changes in locomotor activity, suggesting that nicotine acts specifically to reduce anxiety in this brain region. The present study examined the ability of the high-affinity competitive nicotinic receptor antagonist dihydro-β-erythroidine hydrobromide (DHβE) to antagonise the anxiolytic effect of nicotine following intra-DRN infusion using the social interaction test. The increase in social interaction observed after administration of nicotine (5 ng) into the DRN was completely reversed by coadministration of 100 ng DHβE. DHβE (100 ng), when administered alone into the DRN, did not modify the time spent in social interaction. However, it did significantly increase locomotor activity, and this effect was not antagonised by coadministration of nicotine (5 ng) into the DRN. Because of the pharmacological profile of DHβE, our results suggest that the anxiolytic effect of nicotine in the DRN is mediated by the α4β2 nicotinic receptor subtype.

In Adolescence, Female Rats Are More Sensitive to the Anxiolytic Effect of Nicotine Than Are Male Rats

Anxiety may play an important role in the onset of smoking, particularly in young girls. This study examined whether there were sex differences in the effects of nicotine on anxiety in adolescent rats and whether social isolation modified these effects. Male and female adolescent rats were housed in groups of the same sex or in social isolation for seven days prior to testing in the social interaction test of anxiety. Nicotine increased social interaction in both males and females, and because there was no concomitant change in locomotor activity, this indicated anxiolytic effects. However, there was a 5-fold sex difference in the lowest dose required to enhance social interaction, with an anxiolytic effect in females at 0.05mg/kg, but in males only at 0.25mg/kg. Furthermore, in males the anxiolytic effect was seen only in socially isolated animals, whereas in the females it was present in both housing conditions. The depressant effect of nicotine on locomotor activity also depended on both the sex of the animal and on their housing conditions, with greater effects in singly housed animals and in males. This sex difference in sensitivity to nicotine's anxiolytic effects suggests there may be sex differences in the factors initiating and maintaining teenage smoking.

Different treatment regimens and the development of tolerance to nicotine's anxiogenic effects

The effects of different treatment regimens were investigated on the development of tolerance to the anxiogenic effect of nicotine (0.45 mg/kg) in the social interaction test of anxiety. Rats received nicotine (0.45 mg/kg/day) by intravenous injections (5 days/week), subcutaneous injections (5 or 7 days/week) or continuous infusion by osmotic minipump. In all groups, 4 days of nicotine treatment resulted in significant decreases in social interaction compared with the vehicle control groups, without changes in locomotor activity, indicating a specific anxiogenic effect. These significant anxiogenic effects persisted even after 4 weeks of treatment although they were less marked, indicating development of partial tolerance. No significant changes in the time spent in social interaction were found when rats were tested undrugged 24 and 72 h after the termination of nicotine treatment. There was no evidence that the treatment regimen affected the rate of development of tolerance, despite very different peak plasma nicotine concentrations.

Tolerance to midazolam's anxiolytic effects after short-term nicotine treatment

In the social interaction test of anxiety, microinjections of midazolam (2–8 μg) into the dorsal hippocampus or dorsal raphé nucleus significantly increased the time spent in active social interaction, without changing locomotor activity, thus indicating specific anxiolytic effects. However, tolerance developed to these effects in rats that had been pre-treated for 6 days with (−)-nicotine (0.1 mg/kg/day; subcutaneous). Thus, cross-tolerance to the anxiolytic effects of midazolam develops rapidly following a short period of treatment with a low dose of nicotine, which contrasts with the more slowly developing tolerance (about 3 weeks) that develops after benzodiazepine treatment. Following 6 days of nicotine treatment there was a significant reduction in [ 3H]flunitrazepam binding at 2 and 10 nM in the hippocampus, but no change in the midbrain. The decrease in benzodiazepine binding could explain tolerance to the effects of midazolam when administered to the dorsal hippocampus, but other mechanisms, such as indirect effects on the serotonergic (5-HT) system, might be involved in tolerance to the effects of dorsal raphé nucleus administration.

Development of tolerance to nicotine’s anxiogenic effect in the social interaction test

The purpose of the present experiment was to explore the role of the dorsal hippocampus in mediating the development of tolerance to the anxiogenic effect of nicotine in the social interaction test of anxiety, and to determine whether tolerance develops to the effects of nicotine on [ 3H]-5-HT release in this area. Nicotine (1 μg) administered bilaterally into the dorsal hippocampus significantly reduced the time spent in social interaction in vehicle pre-treated rats, indicating an anxiogenic effect, but tolerance to this effect was seen in the rats pre-treated for 6 days with s.c. nicotine (0.1 mg/kg/day). In rats that had been pre-treated with vehicle for 6 days, nicotine (50–200 μM), significantly stimulated [ 3H]-5-HT release from dorsal hippocampal slices. This stimulation was significantly reduced in rats pre-treated with nicotine (0.1 mg/kg/day) for 6 days, indicating the development of tolerance to the effects of nicotine on 5-HT release. This suggests that tolerance to the anxiogenic effect of nicotine administered into the dorsal hippocampus could be mediated by a reduction in the nicotine enhancement of 5-HT release in this area.

The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses.

Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking, and this may be one factor which contributes to nicotine dependence. The aim of this study was to investigate the role of the dorsal raphé nucleus (DRN) in mediating the acute anxiolytic effect of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5-4000 ng) following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN nicotine (2.5-7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5-10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100-1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 micrograms). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic 5-HT1A autoreceptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and because there is an anxiogenic response 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.

Diazepam and nicotine increase social interaction in gerbils: a test for anxiolytic action

The effects of two drugs with anxiolytic actions, diazepam (0.1, 0.3 and 1 mg/kg) and nicotine (0.1 and 0.5 mg/kg) were examined on the time spent in social interaction by pairs of male gerbils. In a test arena lit by high light, diazepam (0.1 mg/kg) increased social interaction, without changing locomotor activity. Diazepam (0.3 and 1 mg/kg) produced a dose-related increase in locomotor activity, which reached significance at the higher dose. Nicotine produced a dose-related increase in social interaction, which reached significance at 0.5 mg/kg, but was without effect on locomotor activity. The specific increases in social interaction observed with diazepam and nicotine are similar to those seen in the well-validated social interaction test of anxiety in rats and suggest that social interaction in gerbils may also be used to screen for anxiolytic action of novel compounds.

NKP608, an NK1 receptor antagonist, has an anxiolytic action in the social interaction test in rats.

Evidence is starting to accumulate that NK1 receptor antagonists might have anxiolytic effects in animal tests and in patients. To examine the effects of NKP608, a substance P antagonist acting at NK1 receptors, in various conditions of the social interaction test of anxiety and to determine its effects after 3 and 6 weeks of treatment. Rats were tested after vehicle, 0.01 or 0.1 mg/kg PO in three conditions of the social interaction test that varied in the level of anxiety generated. Thus pairs of rats were tested in an arena with which they were unfamiliar that was lit by high (HU) or low (LU) light and in the condition that generated the lowest level of anxiety, i.e. an arena with which they were familiar, lit by low light (LF). They were also tested after 3 and 6 weeks of treatment with 0.03 mg/kg and after 24 h withdrawal from these chronic treatments. NKP608 had significant anxiolytic effects at 0.01, 0.03 and 0.1 mg/kg PO in the HU and LU test conditions, but was without effect in the LF condition, except for an increased incidence of bite attacks at 0.1 mg/kg. The anxiolytic effect of 0.03 mg/kg remained after 3 weeks of chronic treatment and there was no anxiogenic effect after 24 h of drug withdrawal. Following 6 weeks of chronic treatment (0.03 mg/kg per day), tolerance had developed, but no anxiogenic withdrawal effect was seen 24 h after the last dose. These results provide further evidence that substance P may play a role in mediating states of anxiety and suggest that the selective NK1 receptor antagonist NKP608 may prove a useful anxiolytic compound.

Enduring effects of prenatal cocaine administration on emotional behavior in rats

The present studies sought to determine whether prenatal cocaine administration (15 mg/kg b.i.d. between gestational ages 1–20) had enduring effects on emotional behavior of rats. Rats prenatally treated with cocaine interacted less with other rats in the social interaction test of anxiety at both 30 and 120 days of age. However, there were no differences in the elevated plus maze test of anxiety. Rats prenatally treated with cocaine were significantly more immobile in the forced-swim test at 60 and 120 days of age. In addition, animals exposed to prenatal cocaine were more sensitive to the enhancing effect of phencyclidine (2.0 mg/kg) on startle responses to an acoustic stimulus. The cocaine-treated animals tested at 50 to 60 days of age showed higher levels of prepulse inhibition, in comparison to the saline group, after vehicle pretreatment, but not after phencyclidine. Although there were gender differences in the expression of some of these behavioral tasks, there were no gender differences in the effects of cocaine. These findings indicate that when emotional behavior is altered by prenatal cocaine administration, the effects are enduring.