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

Rationale 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).Objectives 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.Methods 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.Results 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.Conclusions 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.     

The effect of glucocorticoids on the anxiolytic efficacy of buspirone

RATIONALE: The serotonergic system and the hypothalamus-hypophysis-adrenocortical axis reciprocally influence each other. Therefore, the interaction between stress and serotonergic anxiolytics should be of major concern for both laboratory investigations and clinical treatment. OBJECTIVES: We have studied the effects of the serotonergic anxiolytic buspirone in rats in which basal levels of glucocorticoids were low and stable, while acute stress reactions were inhibited or exogenously induced. METHODS: Rats were adrenalectomised. Subcutaneous corticosterone pellets maintained basal glucocorticoid concentrations while acute changes were mimicked by corticosterone injections. Anxiety was assessed by the social interaction test. Temporal changes were evaluated by submitting rats to the same manipulations three times at two-day intervals. RESULTS: Buspirone applied to animals with stable and low plasma glucocorticoid concentrations induced a dramatic increase in social interactions. A slight locomotor suppressive effect was also noticed. The effects of buspirone proved to be stable over time in these animals. Acute treatment with corticosterone doubled the locomotor suppressive effects of buspirone and reversed its anxiolytic effects: the buspirone-corticosterone combination was anxiogenic after the first application. During the second and third treatment, the impact of corticosterone on buspirone efficacy gradually decreased, but the combined treatment remained about half as effective in reducing anxiety as buspirone alone.     

Social isolation modifies nicotine's effects in animal tests of anxiety

1. These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal tests of anxiety, social interaction and elevated plus-maze tests. 2. In animals housed singly for 7 days, (-)nicotine (0.025 mg kg(-1) s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg(-1) (s.c.) significantly increased the time spent in social interaction, without changing locomotor activity, thus indicating anxiolytic actions. (-)Nicotine (0.45 mg kg(-1) s.c.) significantly reduced social interaction, indicating an anxiogenic effect. 3. However, in group-housed animals, (-)nicotine (0.025 mg kg(-1) s.c.) had a significant anxiolytic effect in the social interaction test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg(-1) were ineffective. (-)Nicotine (1 mg kg(-1)) reduced motor activity and social interaction in the group-housed animals. 4. In the elevated plus-maze, the time-course and the dose-response curve to nicotine were investigated. In both singly- and group-housed rats, (-) nicotine (0.1 - 0.45 mg kg(-1) s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects. 5. The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group-housed rats, and significant effects at 30 and 60 min in singly-housed rats. 6. In the social interaction test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus-maze. 7. These results provide further evidence that the two animal tests model distinct states of anxiety, and show how social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine.     

Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine

The purpose of these experiments was to explore the hypothesis that the effects of nicotine on anxiety depend on the time since administration and the duration of treatment. In the social interaction test of anxiety, acute nicotine administration (0.1 mg/kg, subcutaneously) decreased social interaction when rats were tested 5 min after injection, but increased it when they were tested 30 min after injection. Social interaction was also decreased 1 h post-injection, but levels returned to baseline between 3 and 30 h. As these changes were independent of any changes in locomotor activity, nicotine seemed to be having both anxiogenic and anxiolytic effects at different times after injection. An anxiolytic effect was also observed 30 min after the second nicotine injection, and the anxiogenic effect observed 5 min after injection remained after 4 days of nicotine administration. However, after 7 days of nicotine treatment, tolerance was observed to both these effects. When rats were tested 72 h after the last of 7 or 14 days of nicotine treatment, an anxiogenic withdrawal response was observed. Thus, an oppositional mechanism may underlie tolerance to the anxiolytic effects, whereas there is as yet no evidence for this type of mechanism mediating tolerance to the anxiogenic effects.     

Corticosterone Is Permissive to the Anxiolytic Effect That Results From the Blockade of Hippocampal Mineralocorticoid Receptors

The effects of RU 28318, a mineralocorticoid receptor antagonist (A-MR), and RU 38486, a glucocorticoid receptor antagonist (A-GR) on behavior in three animal models of anxiety were assessed after microinjection into the dorsal hippocampus. Significant anxiolytic effects were observed after intrahippocampal injection of 0.5, and 1 ng of A-MR in thigmotaxic behavior in the open field, in the elevated plus-maze, and in the defensive burying test. Lower (0.2 ng) or higher (5 ng) doses of A-MR were ineffective, as were comparable injections of A-GR or microinjections of combined A-MR and A-GR. The anxiolytic effect of intrahippocampal A-MR administration observed in the elevated plus-maze and in the open field was not observed in adrenalectomized animals or in animals pretreated with a systemic injection of dexamethasone (80 mg/kg). Intrahippocampal injection of 1 ng of A-MR or A-GR prevented the return to basal corticosterone levels observed 90 min after restraint stress. This effect was reversed in dexamethasone-pretreated animals. The results are discussed in light of recent findings implicating the role of the MR in the hippocampus in adaptive behavioral responses to an aversive or threatening environment, and further implicate the permissive role of corticosterone in A-MR-induced behavioral responses.     

The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam

Rationale: Chronic treatment with benzodiazepines results in tolerance to their sedative and anxiolytic effects and there is considerable evidence that different mechanisms underlie the development of tolerance to different behavioural effects. Objective: The purpose of the present experiment was to compare the behavioural effects of chronic treatment with diazepam (15 mg/kg per day) given as daily subcutaneous injections or by osmotic minipump. Both regimens resulted in continual receptor occupancy, but the daily injections also provided a period of higher brain concentrations. Methods: Rats were tested in the holeboard, which provides measures of exploration and locomotor activity, and in the elevated plus-maze and social interaction tests of anxiety. For those in the subcutaneous injection group the tests were 2 h after injection, when brain concentrations were highest. Results: Despite a higher brain concentration in the injected group, both groups showed tolerance to diazepam’s sedative effects, after 7 days of treatment. In contrast, in the elevated plus-maze, there was tolerance to the anxiolytic effects in the pump group after 14 days, but a persisting anxiolytic effect in the injected group at 14 and 28 days. Whilst higher brain concentrations could explain this result in the plus-maze, they cannot account for the pattern observed in the social interaction test, where the injection group showed a significant anxiogenic effect at 28 days. Conclusions: Whereas the mechanism underlying tolerance to the sedative effects of diazepam was insensitive to the different treatment regimens, the results suggest that different adaptive mechanisms were triggered in the two tests of anxiety with a differential sensitivity to the treatment regimen. The adaptive mechanism predominating in the social interaction test was favoured by the injection regimen which produced intermittent peak concentrations. This mechanism seems to be an oppositional one, leading to an anxiogenic response, which was manifest despite high brain concentrations of diazepam at the time of testing. Received: 12 July 1998 / Final version: 9 March 1999     

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 0.05 mg/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.     

Vigabatrin has an anxiolytic effect in the elevated plus-maze test of anxiety.

tau-Vinyl GABA (vigabatrin, GVG) is a novel antiepileptic drug that irreversibly inhibits GABA transaminase and elevates GABA levels in all parts of the brain. In the present study, we investigated the anxiolytic and behavioral effects of GVG in the elevated plus-maze and the hole board compared to diazepam. Doses of 500 and 1,000 mg/kg GVG were injected IP to different groups of male Wistar rats and animals were tested either 4 or 24 h after injection. Animals administered diazepam (1.5 mg/kg, IP) and saline (1 ml) were tested 20 min after injection. GVG and diazepam were found to decrease significantly the number of squares visited and rearing; both had a suppressant effect on locomotor activity. Neither drug had an effect on exploration (head dipping). GVG at a dose of 1,000 mg/kg was shown to have a similar anxiolytic activity either after 4 or 24 h as diazepam, while GVG at 500 mg/kg did not show any significant anxiolytic effect.     

Time course of ethanol's effects on locomotor activity,exploration and anxiety in mice

The time course of the effects of two doses of ethanol on exploration, locomotor activity and anxiety were investigated using the holeboard and plus-maze tests. In an 8 min holeboard test the lower (1.2 g/kg) dose increased both exploration and locomotor activity 0.5 h after ethanol administration whereas the higher (2.4 g/kg) dose decreased exploration but caused an even greater increase in locomotor activity. This activity increase was also seen 1 h postadministration. In the plus-maze test both doses showed an increased number of arm-entries 0.5 h and 1 h after administration but only the 2.4 g/kg dose caused anxiolytic effects persisting for over 2 h. The results add further support to the notion that the behavioral effects of ethanol vary with dose, time of administration and the behavioral measure taken.     

Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal

After 21 days of treatment with diazepam (2 mg/kg/day IP) rats were tested 24 h after the last injection in the social interaction and elevated plus-maze tests of anxiety. Compared with control-treated rats, they showed significant decreases in social interaction, in the % numbers of entries onto open arms of the plus-maze and in the % of time spent on the open arms, indicating an anxiogenic response on withdrawal from diazepam. Buspirone (200 µg/kg SC) significantly increased social interaction in diazepam withdrawn rats and in the plus-maze also this dose significantly reversed the anxiogenic effects of diazepam withdrawal. Buspirone (400 µg/kg SC) was without effect in the plus-maze, but buspirone (800 µg/kg SC) significantly decreased the % of time spent on open arms in control-treated rats, indicating an anxiogenic effect. In the social interaction test buspirone (800 µg/kg SC) was without significant effect. The contrasting effects of the 200 and 800 µg/kg doses are discussed in terms of the pre- and post-synaptic actions of buspirone. The findings are consistent with earlier proposals that the increased anxiety during benzodiazepine withdrawal is at least partly caused by an increased release of hippocampal 5-HT.     

Effects of taurine on rat behaviors in three anxiety models

In our previous studies using an elevated plus-maze test in mice, taurine was shown to present an anxiolytic-like effect after single and repeated administration. The aim of the present study was to investigate the anxiolytic and behavioral effects of taurine on rats in the open field, hole-board, and social interaction test compared to the positive control diazepam. Taurine (14, 42, and 126 mg/kg, i.p.) was administered 30 min before the tests. In the social interaction and hole-board tests, taurine (42 mg/kg) significantly increased social interaction time and the number and duration of head-dipping. In the open field test, taurine (126 mg/kg, i.p.) presented anxiolytic-like effects by increasing the number of center entries, time spent in the central area and the anti-thigmotactic score while having no effect on the locomotor activity. Results from these experiments suggest that taurine produces an anxiolytic-like effect in these animal models and may act as a modulator or anti-anxiety agent in the central nervous system.     

Measures of anxiety and stress in the rat following chronic treatment with yohimbine

Yohimbine (2.5 and 5 mg/kg) was investigated in two animal tests of anxiety and on baseline corticosterone plasma concentrations, following both acute and chronic administration. Acute treatment with yohimbine produced the following effects: a reduction in the percentage of total arm entries made onto the open arms and in the percentage of time spent on the open arms of an elevated plus-maze (indicating anxiogenic properties), an increase in baseline plasma corticosterone concentrations, and a reduction in locomotor activity (recorded in the social interaction test). No significant effects were observed on anxiety levels as measured by the social interaction test. Following chronic treatment, we saw no evidence for sensitization to the effects of yohimbine.     

Anxiogenic-like action of caerulein,a CCK-8 receptor agonist,in the mouse: influence of acute and subchronic diazepam treatment

Summary Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at nonsedative doses (100 ng/kg-1 µkg i. p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 antagonist (15 mg/kg i. p.), indicating the participation of CCK-8 receptors. Acute treatment with low doses (0.1–0.75 mg/kg i. p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i. p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i. p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers. Send offprint requests to: J. Harro at the above address     

The effects of angelica essential oil in three murine tests of anxiety

The effects of angelica essential oil in three assays predictive of anxiolytic activity in male mice were studied, with diazepam as a positive anxiolytic control. In the elevated plus-maze test, compared to the positive control diazepam, angelica essential oil (30.0 mg/kg, PO) had a modest anxiolytic-like effect (increased the percentage of open-arm time and reduced the percent protected head dips). In the light/dark test, angelica essential oil (30.0 mg/kg) prolonged the time spent in the light area without altering the locomotor activity of the animals. In the stress-induced hyperthermia test, 60 and 70 min after drug administration, rectal temperature was measured twice, angelica essential oil at the dose of 30.0 mg/kg inhibited stress-induced hyperthermia. Thus, these findings indicate that angelica essential oil, as does diazepam, exhibits an anxiolytic-like effect. Further studies will be required to assess the generality of the present findings to other species and behavioural paradigms.     

Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.

The anxiolytic effects of aniracetam have not been proven in animals despite its clinical usefulness for post-stroke anxiety. This study, therefore, aimed to characterize the anxiolytic effects of aniracetam in different anxiety models using mice and to examine the mode of action. In a social interaction test in which all classes (serotonergic, cholinergic and dopaminergic) of compounds were effective, aniracetam (10-100 mg/kg) increased total social interaction scores (time and frequency), and the increase in the total social interaction time mainly reflected an increase in trunk sniffing and following. The anxiolytic effects were completely blocked by haloperidol and nearly completely by mecamylamine or ketanserin, suggesting an involvement of nicotinic acetylcholine, 5-HT2A and dopamine D2 receptors in the anxiolytic mechanism. Aniracetam also showed anti-anxiety effects in two other anxiety models (elevated plus-maze and conditioned fear stress tests), whereas diazepam as a positive control was anxiolytic only in the elevated plus-maze and social interaction tests. The anxiolytic effects of aniracetam in each model were mimicked by different metabolites (i.e., p-anisic acid in the elevated plus-maze test) or specific combinations of metabolites. These results indicate that aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Thus, our findings suggest the potential usefulness of aniracetam against various types of anxiety-related disorders and social failure/impairments.     

The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard

In addition to possessing anti-anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4-benzodiazepines that have only anti-anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4-benzodiazepines. After acute administration, U-43,465 (16 mg kg-1) had a significant anxiolytic effect in the social interaction test. Neither adinazolam (1-3.5 mg kg-1) nor alprazolam (0.125-2 mg kg-1) had a significant effect. It is suggested that this is because, with adinazolam and alprazolam, doses at which anxiolytic effects can be observed are close to those at which sedative effects can be observed. U-43,465 (8-16 mg kg-1) and alprazolam (1-2 mg kg-1) had significant anxiolytic effects in the elevated plus-maze test of anxiety. U-43,465 (8-32 mg kg-1), adinazolam (0.5-5 mg kg-1) and alprazolam (0.2-2.0 mg kg-1) caused dose-related reductions in exploratory head-dipping, locomotor activity and rearing in the holeboard. In general the results seen in the three tests with the triazolobenzodiazepines alprazolam and adinazolam were similar to those seen with classical 1,4-benzodiazepines. With U-43,465, however, an anxiolytic effect was observed in the social interaction test after acute treatment; chronic treatment is required to see an effect with classical 1,4-benzodiazepines. In this U-43,465 resembles the effects of several novel non-benzodiazepine putative anxiolytic compounds that are believed to have less sedative potential than the benzodiazepines.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.     

Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic drugs including the involvement of group I metabotropic glutamate (mGlu) receptors. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), i.e. the most potent mGlu5 antagonist, was evaluated in established models of anxiety after single or repeated administration. We also studied if the anxiolytic effect of MTEP is mediated by mechanism involving the GABA-benzodiazepine (BZD) receptor complex. Experiments were performed on male Wistar rats or male Albino Swiss mice. The anxiolytic-like effects of MTEP were tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MTEP (0.3-3.0 mg/kg) induced anxiolytic-like effects in the conflict drinking test (after single and repeated administration) and in the elevated plus-maze test in rats. In the four-plate test in mice, it exerted anxiolytic activity at a dose of 20 mg/kg. MTEP had no effect on the locomotor activity of animals. The anxiolytic-like effect of MTEP was not changed by BZD antagonist flumazenil. Moreover, a synergistic interaction between non-effective doses of MTEP and diazepam was observed in the conflict drinking test. These data suggest that selective mGlu5 receptor antagonists mediated anxiolysis is not dependent on GABA-ergic system and that these agents may play a role in the therapy of anxiety.     

Behavioral reactivity to a noradrenergic challenge after chronic oral methylphenidate (ritalin) in rats

Methylphenidate (Ritalin) is routinely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is a psychomotor stimulant with pharmacodynamics similar to those established for cocaine and amphetamine with primary activation of the noradrenergic and dopaminergic systems. Long-term exposure to psychostimulants including methylphenidate (MPD) is believed to result in enduring functional changes along both these pathways and various behaviors mediated by these systems may be affected. In the present experiment, the effects of intermittent oral administration of methylphenidate (10 mg/kg) to rats over a 4-week period were subsequently (after a drug washout interval) assessed in three animal models sensitive to noradrenergic manipulation: the elevated plus-maze, predator odor avoidance, and social interaction tests. The behaviors of methylphenidate-experienced animals were compared with untreated controls. Thirty minutes prior to testing, half the animals with each of these histories received an injection of yohimbine hydrochloride (2.0 mg/kg), an alpha2-adrenoreceptor blocker intended to evoke noradrenergic system activation, while the remainder received a saline injection. Yohimbine was expected to reduce both exploration of novel stimuli and interaction with conspecifics, and it was predicted that methylphenidate would potentiate these effects. Relative to saline-tested controls, rats that received both the methylphenidate treatment and the yohimbine challenge exhibited the least exploration in the predator odor test and the lowest duration of interaction with an unfamiliar conspecific partner in the social interaction test. The behavior patterns observed in this group of rats suggest heightened emotionality and defensiveness that are typically seen when rats are administered drugs known to be anxiogenic in human subjects. In the plus-maze, exploratory locomotor activities remained unaltered by either drug while yohimbine decreased risk-assessment behaviors, an effect that remained uninfluenced by methylphenidate pretreatment.     

Chronic fluoxetine in tests of anxiety in rat lines selectively bred for differential 5-HT1A receptor function

Selective breeding for high and low sensitivity to the hypothermic response induced by the 5-HT1A receptor agonist 8- OH-DPAT has established two lines of rat (HDS and LDS, respectively) whose behavior differs in a model of depression and in the social interaction test of anxiety. The HDS line has a higher level of anxiety and, furthermore, does not display the usual anxiogenic response to intrahippocampal administration of 8-OH-DPAT. It was therefore hypothesized that this line of rat might be a useful model of high trait anxiety with a susceptibility to depression. We thus investigated whether chronic treatment with fluoxetine would result in an anxiolytic effect in the social interaction test in the LDS and HDS lines of rat. In both lines, acute fluoxetine (10 mg/kg) produced an anxiogenic effect in the social interaction test; when rats were tested 24 h after 14 days of fluoxetine treatment there were no anxiolytic effects in either line. In the social interaction test, chronic fluoxetine treatment did not change either the anxiogenic effect of 8-OH-DPAT (100 ng) injected bilaterally into the dorsal hippocampus in the LDS line or the lack of response in the HDS line. In the elevated plus-maze, chronic fluoxetine treatment resulted in a significant anxiogenic effect in the HDS line, but was without effect in the LDS line. Intrahippocampal 8-OH-DPAT was without effect in the plus-maze in either line. These results suggest that chronic treatment with fluoxetine did not modify the hippocampal 5-HT1A receptor in either line. The anxiogenic effects observed in the plus-maze in the HDS line after chronic fluoxetine might relate to line differences in 5-HT1A receptors in other brain regions.