Anxiolytic-like effects of 5-HT(1A) agonists in drug-naive and in benzodiazepine-experienced rats

The efficacy of two 5-HT(1A) receptor agonists in drug-naive and benzodiazepine-experienced rats was compared in two animal tests of anxiety, the social interaction and elevated plus-maze tests. Benzodiazepine-experienced rats were tested 48h after the last of 28 daily injections of diazepam (2mg/kg/day), a time at which there was no anxiogenic withdrawal response. S20499 (0.04, 0.2 and 1mg/kg) ((+)-8(4-[N-(5-methoxychroman-3yl)N-propylamine]butyl)-8-azaspirol[4,5]decane-7,9-dione) and buspirone (0.2mg/kg) significantly increased social investigation, indicating anxiolytic-like actions, and there was no significant modification in these effects as a result of the previous diazepam treatment. Both drugs also significantly reduced aggressive behaviours in both drug-naive and diazepam-experienced rats. An anxiolytic-like action in the elevated plus-maze was also indicated for S 20499 (0.04 and 0.2mg/kg) by an increase in the percentage of time spent on the open arms; this effect was not significantly changed by prior diazepam experience. Buspirone (0.2mg/kg) had no significant effects on the plus-maze. The results provide no evidence for reduced efficacy of 5-HT(1A) receptor agonists in animal tests of anxiety as a result of prior diazepam treatment.     

Cocaine-induced anxiety: alleviation by diazepam,but not buspirone,dimenhydrinate or diphenhydramine

Clinical reports and animal experiments indicate that both cocaine administration and cocaine withdrawal increase anxiety. We investigated the ability of a number of putative anxiolytic agents to alleviate these anxiety states using the elevated plus-maze. Rats in the cocaine condition received either saline or cocaine (20 mg/kg) 40 min prior to testing; those in the withdrawal condition were tested 48 h following a chronic treatment regime (saline or cocaine 20 mg/kg per day for 14 days). Prior to testing, animals received a benzodiazepine (1.0 or 2.0 mg/kg diazepam), a serotonergic agonist (0.5 or 1.0 mg/kg buspirone), an antihistamine (50 mg/kg dimenhydrinate or 27 mg/kg diphenhydramine) or a saline injection. All drugs were administered intraperitoneally. Cocaine administration and cocaine withdrawal reduced the percentage time spent on and the number of entries into the open arms. Diazepam dose-dependently alleviated cocaine withdrawal-induced anxiety and non-significantly attenuated cocaine-induced anxiety. Buspirone, dimenhydrinate and diphenhydramine did not consistently alleviate the anxiety caused by either cocaine pre-treatment regime; in the saline conditions, however, each of these treatments was anxiogenic. In summary, benzodiazepines alleviated cocaine-induced anxiety, while future research on the ability of serotonergic and antihistaminergic drugs to alleviate these anxiety states is warranted.     

Effects of DN-2327, a new anxiolytic,diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze

In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5–20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug. In conclusion, the present experiment revealed that the anxiolytic effect of DN-2327 in this test was clear, whereas buspirone showed no apparent effect.     

Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment?

Administration of 1-(3-chlorophenyl)-biguanide (mCPB), a 5-HT₃ receptor agonist (1 and 10 mg/kg IP), was found to be significantly anxiogenic in vehicle treated rats tested in the plus-maze, while having no significant effect in rats withdrawn for 24 h from 21 days diazepam treatment (2 mg/kg/day), suggesting a decreased agonist action at 5-HT₃ receptors following withdrawal from chronic diazepam treatment. In the social interaction test, diazepam withdrawn rats showed a significant decrease in social interaction when compared to the chronic vehicle treated group. This anxiogenic response was reversed by low doses of zacopride (0.0001–0.01 mg/kg IP); in the vehicle treated animals 0.1 mg/kg was significantly anxiogenic. The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT₃ receptors. The anxiolytic action of low doses is attributed to the R-isomer acting at the R-zacopride binding site and is enhanced in conditions of high 5-HT function, e.g. in the diazepam withdrawn rats. If this hypothesis is correct, then we would predict the R-isomer alone would be more effective in reversing the anxiogenic effects of diazepam withdrawal than the racemate, used here.     

Anxiety-like behavior in elevated plus-maze tests in repeatedly cold-stressed mice

To clarify the relationship between SART (specific alternation of rhythm in temperature) stress (repeated cold stress) and anxiety, the effects of various types of stress on the behavior of mice were studied in elevated plus-maze tests and then the effects of anxiolytics were evaluated. The percentage of time spent in the open arms of the plus-maze apparatus decreased in mice subjected to SART stress without change in the total number of arm entries. No change was noted in mice subjected to other stresses, such as 1-h, 2-day and 5-day cold stress and 1-h, 15-h and 5 x 15-h restraint stress. The reduction in the percentage of time spent in the open arms caused by SART stress was inhibited by single and repeated administrations of diazepam and alprazolam and by a single administration of buspirone, which have no influence on the percentage of time spent in the open arms in nonstressed mice, but not by flumazenil, WAY-100635 and chronic treatment with buspirone. The effects of diazepam and buspirone were antagonized by flumazenil and WAY-100635, respectively. The behavior of SART-stressed mice in the plus-maze would thus appear to arise from anxiety, to which benzodiazepine and serotonin receptors are related, but the diazepam binding inhibitor, an endogenous anxiogenic protein, is not. Thus SART-stressed animals may be useful for investigating the psychopharmacological and neuropharmacological basis of anxiety.     

Effect of valepotriates on the behavior of rats in the elevated plus-maze during diazepam withdrawal

The effect of a mixture of valepotriates on the elevated plus-maze performance of diazepam withdrawn rats was evaluated. The rats were chronically (28 days) treated with diazepam (doses increased up to 5.0 mg/kg) and then treated with control solution for 3 days to induce a withdrawal syndrome. Chronically vehicle-treated rats were used as control.The abstinent animals treated with vehicle showed a significant decrease in the percentage of time spent in the open arms when compared with the control animals. Diazepam and valerian 12.0 mg/kg reversed this anxiogenic effect. Valerian 6.0 mg/kg did not show any difference in relation to the others group.     

Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine

  Rationale: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (–)-nicotine in the social interaction test. Objective: To determine the effects of a wide dose range of (–)-nicotine on trial 1 and 2 in the plus-maze after systemic administration and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. Methods: (–)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze. Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 μl of artificial CSF or (–)-nicotine (0.1, 1, 4 or 8 μg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial 1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier. Results: Low doses of (–)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses (0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage entries onto the open arms. Infusion of (–)-nicotine (0.1, 1, 4 and 8 μg) bilaterally into the dorsal hippocampus was without effect on trial 1, but 1 μg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms. Conclusions: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2) showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to be identified. Received: 16 August 1998 / Final version: 10 December 1998     

Anxiety conditioned to nicotine in the elevated plus-maze is time dependent

Conditioning to the anxiogenic effects of nicotine has previously been demonstrated in the social interaction test and there was no generalization of conditioning between the social interaction and elevated plus-maze tests. Because the two tests generate distinct states of anxiety, the conditioning could have occurred to the cues associated with the test environment and/or to those associated with the type of anxiety generated by the test. The elevated plus-maze permits separation of these two factors, because quite distinct states of anxiety are generated on trials 1 and 2, whereas the apparatus cues remain the same. Rats that had been tested on day 1 in the plus-maze, 5 min after nicotine (0.45 mg/kg), showed a conditioned anxiogenic response when tested undrugged on day 2. This was shown by significantly lower percentages of open-arm entries and percentage of time spent on the open arms, compared with control groups. Thus, conditioning to apparatus cues is sufficient to mediate a conditioned anxiogenic effect. The importance of the timing of the nicotine-associated cues was demonstrated by the failure to obtain conditioned anxiogenic effects when rats were exposed to the plus-maze on day 1, 30 min after nicotine (0.45 or 0.1 mg/kg).     

Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen

After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase social interaction in the low light unfamiliar test condition of the social interaction test of anxiety. When they were tested 24 h after the last of 21 injections they showed significant decreases in social interaction, indicating an anxiogenic withdrawal response. However, the social interaction scores of rats tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased social interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in social interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABA_B sites in the hippocampus are involved or that the reversal of the decreased social interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.     

Anxiolytic-like profile of propofol, a general anesthetic, in the plus-maze test in mice

The present study was performed to investigate the effect of propofol on anxiety using the elevated plus-maze test. Groups of mice received propofol (20, 40, 60 mg/kg) or diazepam (2 mg/kg), caffeine (30 mg/kg), L-arginine (100 mg/kg), m-chlorophenylpiperazine (m-CPP, 2.5 mg/kg) and then were placed in an elevated plus-maze that was composed of two opposite closed arms and two opposite open arms. Propofol (20, 40, 60 mg/kg) and diazepam (2 mg/kg) significantly increased the percentage of time spent in the open arms compared to control. Caffeine (30 mg/kg) and m-CPP (2.5 mg/kg) decreased the percentage of time spent in the open arms and these effects were antagonized when propofol (40 mg/kg) was administered before the test. L-arginine (100 mg/kg) has also produced anxiogenic effect and this effect was not prevented by propofol. All drugs used in this study did not significantly change locomotor activity. These results suggest that propofol has anxiolytic effect in plus-maze test.     

Sodium phenobarbitone reverses the anxiogenic effects of compounds acting at three different central sites

Sodium phenobarbitone was tested for its ability to antagonise the anxiogenic effects of compounds acting at three different central sites. These compounds were: FG 7142, a beta-carboline which acts at the benzodiazepine binding site on the GABA-benzodiazepine receptor complex; pentylenetetrazole, which acts at the picrotoxinin site on the GABA-benzodiazepine receptor complex; and yohimbine which is an antagonist at the alpha 2-adrenoceptor. The experiments were carried out in two tests of anxiety using rats. In the social interaction test (the test arena was familiar and dimly lit), FG 7142 (5 mg/kg) and pentylenetetrazole (15 mg/kg) reduced the time spent in social interaction (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone decreased locomotor activity as measured in the social interaction test, which was reversed by pentylenetetrazole (15 mg/kg). In the elevated plus-maze, FG 7142 (6.7 mg/kg) pentylenetetrazole (20 mg/kg) and yohimbine (4 mg/kg) reduced the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone significantly increased the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiolytic activity). This study, together with previous studies using other clinically-effective anxiolytic drugs, suggests that the ability of a compound to antagonise the effects of anxiogenic agents may be a useful indirect means of predicting anxiolytic activity.     

The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models

VA21B7 (3-[2-(4-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential 5-HT₃ receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT₃ receptors as compared to other receptors studied, it was not a potent 5-HT₃ receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable anxiolytic-like effect was found at doses of 2–500 µg/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT₃ receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT_1A agent buspirone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25–0.5 mg/kg IP or 2–4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2–4 mg/kg. At variance with other studies, 5-HT₃ receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic action in the light/dark test was not flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2–4 mg/kg reduced the memory deficits induced in rats by scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an anxiolytic in humans.     

Anxiogenic properties of cocaine in the rat evaluated with the elevated plus-maze.

In previous work, we reported that cocaine (5, 10, and 20 mg/kg) failed to induce significant responses in naive rats in the elevated plus-maze test of anxiety. This study investigates the putative anxiogenic properties of cocaine in rats selected as "anxious" or "nonanxious" on the basis of their behavior in the plus-maze prior to drug treatment. In nonanxious rats, cocaine (10 mg/kg) increased the latency to the first entry into the open arms and reduced the number of entries into and time spent on the open arms. All these measures are indicative of an anxiogenic action of cocaine. In contrast, cocaine failed to modify the behavior of anxious rats. These findings demonstrate that rats with high exploratory activity in the plus-maze and regarded as nonanxious are more sensitive to cocaine's anxiogenic effects. Further, the present manipulation provides a useful procedure for investigating the anxiogenic effects of cocaine in rats.     

Tolerance to nicotine's effects in the elevated plus-maze and increased anxiety during withdrawal

In the elevated plus-maze test of anxiety, nicotine (0.1 mg/kg sc; 30 min after injection) had a significant anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open-arm entries. Tolerance developed to this anxiogenic effect after 7 days of nicotine treatment (0.1 mg/kg/day). Five minutes after an acute injection, nicotine (0.1 mg/kg) was ineffective, but after 7 days of treatment a significant anxiolytic effect, shown by specific increases in the percentage of time spent on the open arms and in the percentage of open-arm entries, emerged. After 14 days of nicotine treatment, tolerance developed to this anxiolytic effect. There was a complete dissociation between the effects of nicotine on the measures of anxiety, and on the locomotor activity as measured by closed-arm entries. No changes in closed-arm entries were found after acute administration of nicotine, but rats tested 30 min after their 7th injection made significantly fewer, and those tested 5 min after their 14th injection made significantly more, entries than their respective controls. Rats that were tested after 24 h withdrawal from six daily nicotine injections showed a significant anxiogenic effect. A low dose of nicotine (5 ng) injected into the dorsal hippocampus was without effect in vehicle pretreated rats, but it was able to reverse the anxiogenic effect found after 24 h of withdrawal from 6 days of nicotine treatment.     

Chronic exposure to noise modifies the anxiogenic response,but not the hypoactivity,detected on withdrawal from chronic ethanol treatment

Two groups of rats received chronic ethanol treatment in quiet or noisy housing conditions. Animals from both housing conditions were then withdrawn from ethanol for 12 h prior to testing in the social interaction and elevated plus-maze tests of anxiety. Both ethanol withdrawal groups showed marked hypoactivity (decreased motor activity and decreased closed arm entries in the plus-maze), but they differed in their anxiogenic response (decreased social interaction and percentage of time spent on the open arms), with only the group treated in quiet conditions showing a significant response. A similar pattern of results was found in rats tested 18 h after withdrawal and thus it is unlikely that the anxiogenic response was simply delayed in time. It therefore seemed that chronic exposure to noise during the chronic ethanol treatment modifies dependence, but only as assessed by measures reflecting anxiety. This implies that the adaptive changes are suppressed only in the neural pathways mediating anxiety; possible mediating factors are discussed.     

Influence of inflammatory nociception on the anxiolytic-like effect of diazepam and buspirone in rats

Rationale The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety.Objective The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs.Methods Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used.Results In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception.Conclusions These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.     

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K⁺-evoked release of [³H]5-HT and in⁴⁵Ca²⁺ uptake and both of these changes were reversed by the GABA_B agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT_1A receptor agonist/partial agonist; zacopride, a 5-HT₃ receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.     

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.     

Effect of buspirone on the behavioral regulation of rats in low versus high anxiety conditions

INTRODUCTION: Buspirone (CAS 33386-08-2) is reported to have anxiolytic effects in humans and is mostly described for mild anxiety. To further explore the effects of buspirone on different levels of anxiety, the effect of buspirone was evaluated in two different conditions of the open field which were distinguished as low and high anxiety (enclosed and exposed open field, respectively). MATERIALS AND METHODS: Twenty-eight albino Wistar rats (350-400 g) were tested in two different arena settings, an enclosed and an exposed open field. Fourteen animals were initially injected with 1 ml saline while the others (n = 14) received buspirone 3 mg/kg. RESULTS: The data showed clear differences in the two open-field settings, suggesting a higher anxiety level in the exposed open field. In addition, correlation analysis showed that the two anxiety tests measure different aspects of anxiety. Buspirone treatment reduced the behavioral activity in both the enclosed and exposed open-field, which is generally interpreted as an anxiogenic effect. However, buspirone increased the time in the center areas and decreased the frequencies in the outer regions. These behavioral changes are generally seen as an anxiolytic effect. Correlation analysis showed that buspirone treatment disrupted the relation between indices of anxiety. CONCLUSION: These results showed that in an open-field setting buspirone appears to have a dual effect. The reduced activity and increase in time spent in the center areas are indicative of both an anxiogenic and an anxiolytic effect, respectively. This was found in both open-field settings, suggesting that the effects of buspirone are independent of the anxiety level.