Elevated Plus-maze Test Of Anxiety Research Articles

Recurrent Hypoglycemia Increases Anxiety and Amygdala Norepinephrine Release During Subsequent Hypoglycemia

Recurrent hypoglycemia (RH) is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp), a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and prefrontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e., less time spent in the open arms of the plus-maze). The results show that RH has widespread effects on subsequent brain function, which vary by neural system.

Dorsal hippocampus histaminergic and septum GABAergic neurons work in anxiety related behavior: Comparison between GABAA and GABAB receptors

Background: Integration of septum and hippocampus has an important role in anxiety modulation and inhibition. Our previous studies indicated that GABAergic system blockade in the medial septum (MS) attenuates anxiety-like behavior. Herein, we aimed to investigate the histaminergic and GABAergic associations between dorsal hippocampus and MS, respectively. Moreover, the present study compares the power of two kinds GABA receptors, GABA A and GABA B receptors, in MS in anxiety related behavior of male rats. Methods: In the present study we investigated the intrahippocampal CA1 (intra-CA1) microinjection of histamine and intra-septal GABAergic agents on anxiety-related behavior in rats, using elevated plus-maze test of anxiety. Results: Intra-CA1 administration of histamine increased open arm time (%OAT) and open arm entry (%OAE). Intra-septal administration of the GABA A agonist muscimol (10 ng/rat) increased %OAE and %OAT but not locomotor activity. Administration of muscimol (2.5 and 5 ng/rat) had no effect on anxiety, while co-administration of sub-effective dose of histamine (1 µg/rat) into CA1 and sub-effective dose of muscimol (2.5ng/rat) into medial septum area increased %OAE and %OAT. Administration of GABA A receptor antagonist confirmed GABA A function in the medial septum. In contrast, injection of GABA B receptor agonist decreased OAT and OAE percentage. Microinjection of GABA B receptor antagonist revealed that this GABA receptor increased the anxiety in the rats by a different mechanism. Conclusion: The effect of histamine on anxiety in CA1 may be modulating through septal GABAergic system and GABA A receptor is involved in the process

Endocannabinoid System and TRPV1 Receptors in the Dorsal Hippocampus of the Rats Modulate Anxiety-like Behaviors.

Fatty acid is amide hydrolase which reduce endogenous anandamide. Transient receptor potential vanilloid-1 (TRPV1) channels have been reported to have a role in the modulation of anxiety-like behaviors in rodents. In the present study, the effects of either endocannabinoid system or TRPV1 channels and their possible interaction on anxiety-like behaviors of the rats were explored. Elevated plus-maze test of anxiety was used to induce anxiety. Capsaicin and AMG 9810 as TRPV1 agonist and antagonist respectively were injected into the dorsal hippocampus. URB 597 as selective FAAH inhibitor and AM 251 as CB1 receptor selective antagonist were also injected into the dorsal hippocampus. The effect of AMG 9810 on the response of URB 597 was also examined. Intra-CA1 injection of URB 597 (0.001, 0.01 and 0.1 µg/rat) and AMG 9810 (0.003, 0.03 and 0.3 µg/rat) produced anxiolytic-like effects. Intra-CA1 infusion of capsaicin (0.003, 0.03 and 0.3 µg/rat) increased the anxiety-related behaviors and AM 251 (0.001, 0.01 and 0.1 µg/rat) did not significantly change the animals behavior. AMG 9810 at the dose of 0.003 µg/rat did not change the anxiolytic-like effect of URB 597. The results of the present study demonstrated that both endocannabinoid system and TRPV1 receptors may affect anxiety-like behaviors. In addition, it seems that TRPV1 receptors are not involved in the effects of anandamide on anxiety-related behaviors in the CA1 region.

Anxiogenic effect of CCK8s in the ventral hippocampus of rats: possible involvement of GABAA receptors

AbstractCholecystokinin (CCK) as an important neuropeptide in the brain has been implicated in the modulation of anxiety. The effects of this neurotransmitter on anxiety-like behavior in the ventral hippocampus have not been evaluated yet. Moreover, some evidences show a functional interaction between GABA and CCK in the nervous system. Bilateral injections of three doses of CCK8s (0.01, 0.05 and 0.1μg/rat) into the ventral hippocampus decreased percentage of open arm time (%OAT) and open arm entries (%OAE) that are representative of anxiogenic-like behavior in the elevated plus-maze test of anxiety. Bilateral injections of LY225910, a selective CCK2 receptor antagonist, at the doses of 0.01, 0.1 and 0.5μg/rat did not change anxiety-related parameters. Administration of muscimol, a selective GABAA receptor agonist, at the doses of 0.001, 0.005 and 0.01μg/rat produced dose dependent increase in %OAT and %OAE indicating an anxiolytic-like effect, while administration of bicuculline, a selective GABAA receptor antagonist, at the doses of 0.1, 0.2 and 0.5μg/rat decreased %OAT and %OAE showing that this drug promoted anxious behavior of the rats. Co-administration of bicuculline (0.2μg/rat) with CCK8s decreased the anxiogenic effects of CCK8s. Furthermore, co-administration of LY225910 (0.5μg/rat) with muscimol increased the anxiolytic effect of muscimol at the dose of 0.001μg/rat. The results of this study suggest that both CCK and GABAergic system have important and opposite roles in the modulation of anxiety-like behavior in the ventral hippocampus of rats and they may have a complex interaction in the ventral hippocampus to modulate anxiety-related behavior.

Anxiolytic-like Effect of Testosterone in Male Rats: GABAC Receptors Are Not Involved.

The effect of testosterone on anxiety-like behaviors has been the subject of some studies. There is evidence that testosterone modulates anxiety via GABA (gama aminobutyric acid) and GABAergic system. The involvement of GABAC receptors in those effects of testosterone on anxiety-like behaviors of the rats was investigated in the present study. A group of rats received subcutaneous injections of testosterone (5, 10 and 20 mg/kg). Two groups of rats received intracerebroventricular injections of either CACA (GABAC agonist, 0.125 μg/rat) or TPMPA (GABAC antagonist, 3 microg/rat) following administration of testosterone (5, 10 and 20 mg/kg). After the injections, the rats were submitted to the elevated plus-maze test of anxiety. The rats received testosterone alone, showed a decreased in anxiety-like behaviors (P< 0.01). Administration of either CACA or TPMPA did not modify animals' behavior compared to the rats received testosterone alone. The results of the present study showed that administration of testosterone induces anxiolytic-like behaviors in the rats and GABAC receptors possibly are not involved in the anxiolytic effect of testosterone.

Anxiolytic-like effect induced by the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA), in the rat amygdala is mediated through the D1 and D2 dopaminergic systems

In the present study the influence of the dopaminergic system(s) of the amygdala on the anxiolytic-like effect of the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA), in male Wistar rats was investigated. An elevated plus-maze test of anxiety was used to assess anxiety-like behaviors. The results showed that bilateral intra-amygdala injections of ACPA (0.125, 1.25 and 5 ng/rat) and the mixed dopamine D1/D2 receptor agonist, apomorphine, at different doses (0.001, 0.01 and 0.1 µg/rat) increased percentage open arm time (%OAT) and percentage open arm entries (%OAE), indicating an anxiolytic-like effect for both of the drugs. In contrast, intra-amygdala administration of the dopamine D1 receptor antagonist SCH23390 (0.5 and 1 µg/rat) and the dopamine D2 receptor antagonist, sulpiride (2 and 3 µg/rat) decreased %OAT and %OAE, suggesting an anxiogenic-like effect for both of the drugs. Interestingly, pretreatment with a sub-effective dose of apomorphine (0.0005 µg/rat) increased, while SCH23390 (0.25 µg/rat) and sulpiride (1.5 µg/rat) decreased the anxiolytic-like effect of ACPA. It can be concluded that the dopaminergic system of the amygdala may be involved, at least partly, in the anxiolytic-like effects induced by ACPA in the rat amygdala.

Role of Endocannabinoid System in the Ventral Hippocampus of Rats in the Modulation of Anxiety‐Like Behaviours

The effects of unilateral intra-ventral hippocampus injection of URB597, a fatty acid amid hydrolase inhibitor, and AM251, a selective CB(1) receptor antagonist, on anxiety-related behaviours using elevated plus-maze test of anxiety were evaluated in the present study. Possible involvement of GABAergic system in those effects of URB597 was also evaluated. Injection of URB597 at the doses of 0.01, 0.1 and 1 microg/rat showed significant anxiogenic-like effects at 0.1 and 1 microg/rat. However, intra-ventral hippocampus injection of AM251 at the doses of 0.001, 0.01 and 0.1 microg/rat did not produce any significant effect in the elevated plus-maze. The ineffective doses of selective GABA(A) receptor antagonist, bicuculline (2 microg/rat) and selective GABA(B) receptor antagonist, phaclofen (1 microg/rat) on anxiety-related behaviours were also injected with URB597 (0.1 microg/rat). The present data showed that neither bicuculline nor phaclofen affected the anxiogenic-like effects of URB597. The results showed that injection of URB597 into the ventral hippocampus may be anxiogenic and GABAergic system may not be involved in its anxiogenic-like effects.

The effects of cannabinergic agents in the central amygdala of rats in the elevated plus-maze test of anxiety

Materials and methods In the present study, we investigated the effects of intracentral amygdala microinjection of cannabinergic agents on anxiety-related behaviours in rats, using the elevated plus-maze test of anxiety. Intracentral amygdala administration of ACPA a cannabinergic potent agonist (0.125, 1.25,5 ng/0.5 μl bilateral) increased %open arm time and % open arm entries, but not locomotor activity, showing an anxilytic response. Intracentral amygdala microinjection of AM251 a potent CB1 antagonist (2.5, 25, 100 ng/ 0.5 μl bilateral) did not change anxiety-related parameters in our experiments.

Histaminergic H1 receptors mediate L-histidine-induced anxiety in elevated plus-maze test in mice

The central histaminergic system is reported to mediate behavioural, hormonal and physiological homeostasis of living organisms. Recent reports indicate its prominent role in various neurobehavioural disorders such as depression and psychosis. This study evaluated the effect of activation of the central histaminergic system in anxiety-like conditions, using the elevated plus-maze test in mice, and elucidated the role of different histaminergic receptors mediating such effects. Peripheral administration of L-histidine (L-His), in a dose-dependent manner, significantly decreased the exploration time in open arms and number of entries into open arms without modifying the number of entries into closed arms of the elevated plus-maze, indicating anxiogenesis. Further, such effects of central histamine were significantly attenuated, in a dose-dependent manner, by pretreatment with pyrilamine (H1 receptor antagonist). Pretreatment with either zolantidine (H2 receptor antagonist) or thioperamide (H3 receptor antagonist), however, failed to attenuate the L-His-induced anxiogenesis. Our results indicate that anxiogenic effects of central histaminergic system appear to be mediated prominently by activation of H1 receptors.

The effects of histaminergic agents in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety

High levels of histamine are found in the hippocampus. The central histamine system is involved in many physiological behavioural processes including anxiety-related behaviours both in animals and humans. In the present study, we investigated the effects of intra-hippocampal CA1 (intra-CA1) microinjection of histaminergic agents on anxiety-related behaviours in rats, using elevated plus-maze test of anxiety. Intra-CA1 administration of histamine (at the dose of 10 μg/rat) increased open arm time (%OAT) and open arm entry (%OAE) but not locomotor activity, thus showing an anxiolytic response. Intra-CA1 microinjection of pyrilamine (H 1 receptor antagonist; at the doses of 10, 20 and 40 μg/rat) in combination with histamine (10 μg/rat) showed a decrease in the %OAT and %OAE. Higher dose of the antagonist (40 μg/rat) by itself increased both %OAT and %OAE, but not locomotor activity, indicating an anxiolytic effect. Intra-CA1 microinjection of ranitidine (H 2 receptor antagonist), at the doses of 10, 20 and 40 μg/rat, also reduced the histamine response. Furthermore, the H 2 receptor antagonist by itself reduced %OAT and %OAE without affecting locomotor activity. The results may indicate an anxiogenic effect for the antagonist. Our results showed that histamine may modulate anxiety via H 1 and H 2 receptors in the CA1 region of hippocampus of the rat.

The effects of histaminergic agents in the ventral hippocampus of rats in the elevated plus‐maze test of anxiety

There are reports indicating that histamine & histaminergic agents can change anxiety-related behaviors both in animals and humans. Ventral hippocampus (VHC)is an important brain site in the modulation of fear or anxiety. In the present study, we have investigated the effects of intra-VHC microinjection of histaminergic agents on anxiety-related behaviors in rats, using elevated plus-maze test of anxiety. Intra-VHC administration of histamine at the doses of 2.5,5 and 7.5μg/rat decreased%OAT and %OAE but not locomotor activity, showing an anxiogenic response. Intra-ventral hippocampus microinjection of pyrilamine, a H1 receptor antagonist and ranitidine, a H2 receptor antagonist,(10,20 and 40μg/rat) decreased anxiety in our experiments. In another series of experiments, Histamine at doses of 2.5,5 and 7.5μg/rat was pretreatment with pyrilamine and ranitidine dose of 10μg/rat. The results showed that pyrilamine could significantly reverse the anxiogenic effect of histamine at doses of 5 and 7.5μg/rat and ranitidine could significantly reverse the anxiogenic effect of histamine at doses of 7.5μg/rat. Our results showed that histamine may modulate anxiety via H1 & H2 receptors in the ventral hippocampus of the rats.

The effects of histaminergic agents in the central amygdala of rats in the elevated plus-maze test of anxiety

Reports indicate that histamine and histaminergic agents can change anxiety-related behaviours in both animals and humans. The amygdala is an important brain site in the modulation of fear or anxiety. In the present study, we investigated the effects of intracentral amygdala microinjection of histaminergic agents on anxiety-related behaviours in rats, using the elevated plus-maze test of anxiety. Intracentral amygdala administration of histamine (0.01-0.5 microg/0.5 microl bilateral) decreased %open armtime and % open arm entries, but not locomotor activity, showing an anxiogenic response. Intracentral amygdala microinjection of pyrilamine (H1 receptor antagonist) and ranitidine (H2 receptor antagonist) (both at 1-20 microg/0.5 microl bilateral) did not change anxiety-related parameters in our experiments. In another series of experiments, histamine (0.5 microg/0.5 microl bilateral) was coadministrated with pyrilamine and ranitidine (both at 1-20 mg/0.5 microl bilateral). The results showed that pyrilamine but not ranitidine could significantly reverse the anxiogenic effect of histamine at doses of 10 and 20 microg/0.5 microl bilateral. The results suggest that histamine may modulate anxiety via H1 but not H2 receptors in the rat central amygdala.

Anxiolytic effect of estradiol in the median raphe nucleus mediated by 5-HT 1A receptors

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is evidence showing that estrogen modulates 5-HT 1A receptor functions. In the MRN, somatodendritic 5-HT 1A receptors control the activity of serotonergic neurones by negative feedback. The present study evaluated the effect of intra-MRN injection of estradiol benzoate (EB) (600 or 1200 ng/0.2 μl) on the performance of ovariectomised rats submitted to the elevated plus-maze test of anxiety and to the open-field test. Additionally, the same effect was evaluated with a previous intra-MRN injection of WAY 100635 (100 ng/0.2 μl), an antagonist of 5-HT 1A receptors. The results showed that both doses of EB increased the percentage of entries and the percentage of time spent into the open arms, suggestive of an anxiolytic effect. The highest dose of the drug also increased the number of entries into the enclosed arm and locomotion in the open field, indicating a stimulatory motor effect. WAY 100635 antagonised the effect of estradiol in the elevated plus-maze and in the open-field. The results show that estrogen receptors of the MRN are implicated in the regulation of anxiety-related behaviour. The results also support claims that the effect of estrogen involves a change in 5-HT 1A receptor function.

Cholecystokinin and GABA interaction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety

In the present study, we have investigated the effects and interaction of CCK and GABAergic systems in the dorsal hippocampus of rats using the elevated plus-maze test of anxiety. Bilateral injection of different doses of CCK 8s (0.01, 0.05 and 0.1 μg/rat) into the dorsal hippocampus (intra-CA1) decreased percentage of open arm time (%OAT) and open arm entries (%OAE) that are representative of anxiogenic-like behavior. The bilateral injection of three doses of LY225910, a selective CCK 2 receptor antagonist (0.01, 0.1 and 0.5 μg/rat) produced significant anxiolytic behavior. Although muscimol (GABA A +) (0.1, 0.5 and 1 μg/rat, intra-CA1) produced dose dependent increase in %OAT and a slight increase in %OAE, bicuculline (GABA A −), (1, 2 and 4 μg/rat, intra-CA1) failed to change the anxiety profile. Both muscimol (0.1 μg/rat) and bicuculline (1 μg/rat), when co-administered with LY225910, reversed the effect of latter drug on anxiety but when co-administered with CCK 8s (0.05 μg/rat) showed no effect on anxiety profile. In conclusion, it seems that both CCK and GABAergic systems not only play a part in the modulation of anxiety in the dorsal hippocampus of rats but also have demonstrated a complex interaction as well.

Possible anxiolytic effects of taurine in the mouse elevated plus-maze

The effects of taurine, an inhibitory amino acid, on the behavior of male mice were examined in the elevated plus-maze test of anxiety. Acute taurine treatment (60 mg/kg, PO) significantly increased the percentage of time spent in the open arms. Moreover, when taurine was administered daily for seven days and the plus-maze test was conducted 40 minutes after the last administration, a significant increase of the percentage of time in the open arms was observed even at dose of 2.5 mg/kg, however the open arm entries and the total entries were unaffected at any dose tested. In order to get a comprehensive profile of drug action, detailed behavioral analyses were further exerted. Single administration of 60 mg/kg taurine can significantly reduce the total rears. The results suggest that taurine have some anxiolytic-like properties, although its effects seem more limited and are not consistent with those presented by classic anxiolytics, such as diazepam.

The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety.

The aim of this study was to compare the effects of the genetic and pharmacological disruption of CB1 cannabinoid receptors on the elevated plus-maze test of anxiety. In the first experiment, the behaviour of CB1-knockout mice and wild-type mice was compared. In the second experiment, the cannabinoid antagonist SR141716A (0, 1, and 3 mg/kg) was administered to both CB1-knockout and wild type mice. Untreated CB1-knockout mice showed a reduced exploration of the open arms of the plus-maze apparatus, thus appearing more anxious than the wild-type animals, however no changes in locomotion were noticed. The vehicle-injected CB1-knockout mice from the second experiment also showed increased anxiety as compared with wild types. Surprisingly, the cannabinoid antagonist SR141716A reduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was only marginally affected. Recent evidence suggests the existence of a novel cannabinoid receptor in the brain. It has also been shown that SR141716A binds to both the CB1 and the putative novel receptor. The data presented here supports these findings, as the cannabinoid receptor antagonist affected anxiety in both wild type and CB1-knockout mice. Tentatively, it may be suggested that the discrepancy between the effects of the genetic and pharmacological blockade of the CB1 receptor suggests that the novel receptor plays a role in anxiety.

Strain-dependent effects of diazepam and the 5-HT2B/2C receptor antagonist SB 206553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze.

The 5-HT2B/2C receptor antagonist SB 206553 exerts anxiolytic effects in rat models of anxiety. However, these effects have been reported for standard rat strains, thus raising the issue of SB 206553 effects in rat strains displaying different levels of anxiety. Herein, the effects of SB 206553 in a 5-min elevated plus-maze test of anxiety were compared to those of the reference anxiolytic, diazepam, in two rat strains respectively displaying high (Lewis rats) and low (spontaneously hypertensive rats, SHR) anxiety. Diazepam (0.37, 0.75, or 1.5 mg/kg; 30 min before testing) increased in a dose-dependent manner the behavioral measures in SHR, but not in Lewis rats. On the other hand, SB 206553 (1.25, 2.5, or 5 mg/kg; 30 min before testing) failed to alter the anxiety parameters in both strains, whereas it increased closed arm entries in Lewis rats, suggesting that it elicited hyperactivity in the latter strain. Accordingly, the hypolocomotor effect of the nonselective 5-HT2B/2C receptor agonist m-chlorophenylpiperazine (1.5 mg/kg ip 20 min before a 15-min exposure to an activity cage) was prevented by the 1.25 and 2.5 mg/kg doses of SB 206553 in Lewis rats and SHR, respectively. Compared with SHR, Lewis rats may display a lower response to benzodiazepine-mediated effects and a more efficient control of locomotor activity by 5-HT2B/2C receptors.

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.

Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1, 5-benzodiazepine hydrogen sulfate in mice.

The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1, 5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P<0.05) and 1-10 mg/kg PTMB ip increased (F(5,98) = 3.26; P<0.01), whereas 2 mg/kg picrotoxin ip decreased (F(3,59) = 8.32; P<0.001) the proportion of time spent in the open arms, consistent with an anxiolytic action of both benzodiazepines, and an anxiogenic role for picrotoxin. In the holeboard, 1.0 mg/kg diazepam ip increased (F(3,54) = 2.78; P<0.05) and 2 mg/kg picrotoxin ip decreased (F(3, 59) = 4.69; P<0.01) locomotor activity. Rotarod assessment revealed that 1 mg/kg diazepam ip and 3, 10 and 30 mg/kg PTMB ip produced significant motor incoordination compared to vehicle control (F(4, 70) = 7.6; P<0.001). These data suggest that the recently synthesized PTMB compound possesses anxiolytic activity and produces motor incoordination similar to those observed with diazepam.

Tolerance to the anxiogenic-like effect of mCPP in the rat elevated zero-maze test after subchronic administration

In view of apparent commonalities in the aetiology, symptomatology, and pharmacotherapy of anxiety and depressive disorders, the present study compares the effects of the benzodiazepine, chlordiazepoxide (1.0–8.0 mg/kg), the selective noradrenaline (NA) reuptake inhibitor, maprotiline (0.5–10.0 mg/kg), and the serotonin (5-HT)-selective reuptake inhibitor, fluvoxamine (2.0–8.0 mg/kg), on the behaviour of mice in the elevated plus-maze test of anxiety. To more accurately reflect the clinical situation, subjects were treated daily for 21 days prior to testing, and comprehensive behavioural profiles were obtained through the application of an ethological scoring technique. Results show that subchronic treatment with chlordiazepoxide produced clear anxiolytic-like effects at the highest dose tested, coupled with an inhibition of risk assessment over the entire dose range. With the exception of risk assessment measures, anxiolytic-like effects were also seen with a low dose (0.5 mg/kg) of maprotiline; these effects were lost at higher doses. In contrast to these data, fluvoxamine produced minimal behavioural change under present test conditions. Findings are discussed in relation to the relative efficacy of selective monoamine reuptake inhibitors in the treatment of anxiety disorders, and the nature of anxiety evoked in mice by exposure to the elevated plus-maze.