Implication of 5-HT<Subscript>2</Subscript> receptor subtypes in the mechanism of action of antidepressants in the four plates test

Rationale The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants.Methods The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT).Results Paroxetine administered intraperitoneally (IP) (0.5, 2–8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT_2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT_2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT_2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2–16 mg/kg. This effect was reversed by the 5-HT_2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT_2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT_2A and 5-HT_2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT_{2A, 2B, 2C} receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration.Conclusion These results indicate that the co-administration of 5-HT₂ receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.     

Effects of S-21007, a potent 5-HT3 partial agonist, in mouse anxiety.

AIM: To study the effect of S-21007, a 5-HT3 partial agonist in different animal models of anxiety in mice. METHODS: S-21007 effects were evaluated in the behavior tests after intraperitoneal and oral acute treatment or in the light/dark test after both acute and chronic treatments. RESULTS: S-21007 presented anxiolytic-like properties after acute administration in the light/dark box test, the mirrored chamber test, and the elevated plus-maze at low doses 10 ng.kg(-1)-100 micrograms.kg-1, 1-100 micrograms.kg-1 and 10-100 micrograms.kg-1, respectively. In the light/dark box test, S-21007 was active orally after acute treatment at 100 ng.kg(-1)-10 mg.kg-1 and after chronic treatment (14 d) at 1-10 micrograms.kg-1. S-21007 was devoid of sedative or stimulatory effects. CONCLUSION: S-21007 exhibited anxiolytic-like properties. The mechanism of action may be a desensitization of 5-HT3 receptor or an antagonist activity on the 5-HT3 receptors.     

Influence of forced swimming-induced stress on the anxiolytic-like effect of 5HT<Subscript>1A</Subscript> agents in mice

RATIONALE: Stress has been related to both anxiety and mood disorders. Forced swimming (FS) is a type of stress that is able to modify the activity of serotonin (5-HT) and GABA in the central nervous system. 5-HT(1A) compounds have been shown to be anxiolytic in a variety of behavioral models and in clinical studies. OBJECTIVE: The main purpose of the present study was to analyze the effect of FS on the anxiolytic-like actions of three 5-HT(1A) compounds. METHODS: Stressed (ST) and unstressed (UST) mice were evaluated in the exploratory behavior test (EBT) or burying behavior test (BBT). In addition, the action of increasing doses of the 5-HT(1A) compounds buspirone, 8-OH-DPAT and indorenate in ST and UST mice was analyzed using the EBT. A spontaneous ambulatory behavior test was carried out immediately after the anxiety tests. RESULTS: One session of FS induced anxiolytic-like behavior in mice tested in both the EBT and the BBT. This effect of FS was blocked by a previous administration of either picrotoxin or WAY 100635. The 5-HT(1A) compounds produced a clear anxiolytic-like effect in UST animals. By contrast, with low doses of either 8-OH-DPAT (0.01 mg/kg), buspirone (0.03 mg/kg) or indorenate (0.3, 0.6 mg/kg) ST mice showed a decrease in the anti-anxiety-like effect observed after FS. No change in ambulation that could mask the results of the anxiety test was registered. CONCLUSIONS: The present data provide evidence that FS induces changes in the effect of 5-HT(1A) agents. The participation of the 5-HT and/or GABA systems in these stress-induced effects is discussed.     

Diazepam, but not buspirone, induces similar anxiolytic-like actions in lactating and ovariectomized Wistar rats

Previous reports indicate that the behavioural effects (including anxiolytic-like actions, hypothermia, "serotonergic syndrome," maternal behaviour and aggression and reduction in ambulation) of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), are completely blocked in lactating rats. The present study compares the behavioural effects of buspirone (1.25, 2.5 and 5.0 mg/kg) and diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg) between ovariectomized and mid-lactating rats. The study was carried out on Wistar female rats under inverted light/dark cycle conditions, by using the burying behaviour paradigm, the elevated plus maze and a general activity test. In both ovariectomized and lactating rats, diazepam produced a dose-dependent reduction in burying behaviour and an increase in the time spent in open arms, responses interpreted as anxiolytic. Buspirone at all doses (1.25, 2.5 and 5.0 mg/kg) produced clear motor impairments in lactating, but not in ovariectomized animals, indicating that the effects of this drug on the anxiety paradigms are unspecific. Diazepam, by contrast, at the highest dose (4.0 mg/kg) similarly inhibited ambulation in both conditions. In the elevated plus maze, control lactating subjects spent more time in the open arms compared with saline-treated ovariectomized subjects, suggesting an anxiolytic-like effect of lactation per se. The present results support the idea that some behavioural actions of drugs acting at the serotonergic system vary between ovariectomized and lactating rats.     

Alnespirone and buspirone have anxiolytic-like effects in a conflict procedure in rats by stimulating 5-HT(1A) receptors

We studied the anxiolytic-like activity of alnespirone and buspirone, two 5-HT(1A) receptor agonists, in a modified Geller-Seifter conflict model, and examined the role of 5-HT(1A) receptors by studying whether WAY-100635, a selective antagonist at these receptors, blocked their effects. Administered s.c. 30 minutes before testing, 0.5 and 1mg/kg alnespirone significantly increased punished responding, whereas lower doses (0.125 and 0.25 mg/kg) had no effect. At 1mg/kg, alnespirone significantly reduced the rates of unpunished responding. One dose of buspirone (1mg/kg) significantly increased punished responding and reduced unpunished responding. Lower doses were ineffective. Administered s.c. 40 minutes before testing, WAY-100635 had no effect on any parameter but completely antagonized the effects of alnespirone (1mg/kg) and buspirone (1mg/kg) on punished responding. The ability of buspirone to reduce unpunished responding was not antagonized by WAY-100635, probably reflecting a sedative effect of buspirone due to dopamine D2 receptor blockade. The results suggest that alnespirone and buspirone have anxiolytic-like activity in a conflict procedure by stimulating 5-HT(1A) receptors, presumably at a presynaptic level. Like buspirone, alnespirone may have useful effects in the treatment of anxiety disorders.     

Comparison of routes of administration and time course effects of zacopride and buspirone in mice using an automated light/dark test

The behavioral effects of zacopride and buspirone were assessed in mice in a fully automated 2-compartment light/dark test. A significant increase in time mice spent in the lit area was used as an indication of anxiolytic-like action. Doses of zacopride from 0.0001 to 17.8 mg/kg, IP, and buspirone from 3.16 to 17.8 mg/kg, IP, produced significant increases in time mice spent in the lit area of the chamber. In addition, zacopride and buspirone were compared for oral potency and for duration of action after IP and PO administration. Zacopride and buspirone produced anxiolytic-like activity between doses of 0.001 to 100.0 mg/kg, PO, and 10.0 to 56.2 mg/kg, PO, respectively. The duration of effect of buspirone was 2 to 4 h after IP or PO administration, while that for zacopride was ≥16 h by either route of administration. Thus, when compared for anxiolytic-like effects in this test, zacopride is a more potent and longer acting agent than buspirone.     

Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action

Milnacipran is a serotonin/noradrenaline reuptake inhibitor (SNRI) which has not yet been systematically studied preclinically or clinically for the treatment of anxiety disorders. In the four-plate test (FPT) which is known to predict anxiolytic-like activity in mice, milnacipran (4, 8, 16 and 32 mg/kg) demonstrated strong anti-punishment effects following acute administration. The anxiolytic-like effect of milnacipran was not reversed by the selective GABA(A) receptor antagonist, flumazenil (2 and 4 mg/kg), the selective alpha1-adrenoceptor antagonist, prazosin (0.5 and 2 mg/kg), the selective alpha2-adrenoceptor antagonist, idazoxan (1 and 4 mg/kg) or the selective 5-HT2B receptor antagonist, SB 206553 (0.1 and 1 mg/kg). In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 and 1 mg/kg), and the non-selective 5-HT2 receptor antagonist, ketanserin (0.125 and 0.5 mg/kg), completely abolished the anxiolytic-like effect of milnacipran in FPT. Neurochemical depletion of NA or 5-HT completely abolished the activity of milnacipran. These results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of milnacipran. On the other hand the lack of activity of milnacipran after depletion of NA or 5-HT is consistent with milnacipran acting on the locus coeruleus to induce 5-HT release. The present data suggest a strong connection between 5-HT2A receptors and NA neurotransmission.     

A fully automated light/dark apparatus useful for comparing anxiolytic agents

The effects of known anxiolytic agents and putative anxiolytic agents were assessed in mice in a fully automated 2-compartment light/dark test. Significant increases in lit area activities (e.g., time spent in the lit area, locomotor activity, rearing behavior) were used as possible indicators of anxiolytic-like action. The measurement found most consistent and useful for assessing antianxiety-like activity was the time mice spent in the lit area. The benzodiazepine, diazepam; the 5-HT1A agent, ipsapirone; and the 5-HT3 receptor antagonist, ondansetron, produced significant anxiolytic-like activity between doses of 1.0 to 10.0 mg/kg, 17.8 to 31.6 mg/kg, and 0.0001 to 1.0 mg/kg respectively. The 5-HT1A receptor agonist, 8-OH DPAT, also exhibited anxiolytic-like action between doses of 0.0005 to 3.16 mg/kg. In contrast, the peripheral 5-HT3 receptor agonist, N-phenylbiguanide; the antidepressant, imiprame; the neuroleptic, chlorpromazine; and the CNS stimulat, S(+)-amphetamine, did not display antianxiety-like activity. The positive results obtained for the three types of compounds (benzodiazepine, 5-HT1A, and 5-HT3) indicate that this fully automated light/dark apparatus may be useful for identifying known and putative anxiolytic agents.     

Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT(2A/2C) agonist) in the four-plate test in mice.

5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the four-plate test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT(2A) postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT(2A/2C) receptor agonists) with GABA(A) and GABA(B) receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.     

Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test

Rationale Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors demonstrated an anxiolytic-like effect in the four-plate test (FPT). (+/−)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; a 5-HT_2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT_2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the α-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the α₂-adrenoceptor agonists abolished the anxiolytic-like effect of antidepressants. Objectives The aim of the present study was to evaluate the role of noradrenergic system on the regulation of 5-HT₂ receptors implicated in the DOI anxiolytic-like activity in the FPT. Methods First, the effect of noradrenergic and serotonergic lesions on DOI anxiolytic-like activity was studied in the FPT. Second, the effect of co-administration of α-adrenoceptor ligands and DOI was evaluated in the same test. Results The noradrenergic and serotonergic lesions had no effect on DOI (1 mg/kg) anti-punishment activity in the FPT. Adrafinil 0.25 and 4 mg/kg (an α₁-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an α₁-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an α₂-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two α₂-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific α_2A-adrenoceptor agonist) completely abolished DOI-induced increase in punished passages. Conclusion These results indicate that the DOI seems to act on the 5-HT₂ receptors post-synaptically located. The effect of DOI is regulated by the α₂-adrenoceptors.     

The novel buspirone analogue, 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)[butyl]-8-azaspiro [4.5 ]decane-7,9-dione, with anxiolytic-like and antidepressant-like effects in rats

In the conflict drinking test, used as a model to examine anxiolytic-like activity, the novel buspirone analogue 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl)-8-azaspiro[ 4.5]decane-7,9-dione (MM199) (0.62-2.5 mg/kg) and buspirone (0.62-5 mg/kg), significantly increased the punished drinking in water-deprived rats, without affecting water consumption or perception of the stimulus. The anticonflict activity of MM199 (1.25 mg/kg) was blocked by (S)-WAY 100135 (20 mg/kg), a 5-hydroxytrypatmine1A (5-HT1A) receptor antagonist. In the forced swimming test, used as a model to examine the antidepressant-like activity, MM199 (5-20 mg/kg) reduced the immobility time, while buspirone (5-20 mg/kg) had no such effect. The reduced immobility induced by MM199 (20 mg/kg) was antagonized by (S)-WAY100135 (10 mg/kg). The above findings suggest that MM199 possesses potent anxiolytic- and antidepressant-like properties which are mediated by activation of 5-HT1A receptors.     

SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.     

Effects of buspirone, diazepam, and zolpidem on open field behavior, and brain [3H]muscimol binding after buspirone pretreatment

The effects of 5-HT(1A) receptor agonist buspirone, a nonselective (diazepam), and a selective (zolpidem) GABA(A) receptor agonist were compared in the open field test of neophobia. Unhabituated rats were pretreated with the drugs once, prior to a first exposure to the open field, and their behavior was recorded both during this test and during a second trial 24 h later. It has been hypothesized that the decrease in exploratory activity observed during the second test session may be considered an adaptive reaction to the first day aversive experience (neophobia). If so, a selective modulation of 5-HT and GABA systems activity during the test could bring about significant changes in animal behavior on the retest. Buspirone at the lowest dose of 0.3 mg/kg revealed anxiolytic-like properties on the first day, whereas the action of diazepam and zolpidem was modulated by the dose-related sedative effect. At the dose of 2.4 mg/kg buspirone elicited delayed in time anxiolytic-like action, i.e., produced the antithigmotactic effect during the retrial 24 h later. Diazepam and zolpidem failed to exhibit similar profile of action. Autoradiography of [3H]muscimol binding after pretreatment of rats with buspirone showed a significant increase in the selective radioligand binding within the frontal cortex and a similar, near-significant tendency in the dentate gyrus of the hippocampus. The behavioral data validate buspirone as important drug for the treatment of anxiety disorders, devoid of disruptive influence on motor and cognitive processes. The open field test, as modified by us, appeared sensitive in distinguishing the behavioral profiles of action of different anxiolytic compounds, including 5-HT(1A) receptor agonist. The present results support the assumption that reduced turnover of 5-HT due to stimulation of 5-HT(1A) autoreceptors, may bring about changes in GABA(A) receptor system activity, in some brain structures, leading to the anxiolytic effect.     

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.     

Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety

The activity of the novel antidepressant agomelatine was evaluated in three models of anxiety and compared with that of melatonin and two anxiolytics, diazepam and buspirone. All drugs were tested 2 h before and 2 h after the dark phase of the diurnal cycle. Morning and evening agomelatine (10-75 mg/kg) administration increased animals' responses in the elevated plus maze and Vogel tests. Melatonin (10-75 mg/kg) enhanced open arms exploration in the evening experiment and was inactive in the Vogel test. In the conditioned ultrasonic vocalization test, agomelatine, but not melatonin, was active in the morning and evening experiment. Melatonin antagonist, S22153 (20 mg/kg), enhanced the action of morning and evening agomelatine administration in the Vogel and conditioned ultrasonic vocalization tests, while in the elevated plus maze test, S22153 inhibited effects of evening but not morning melatonin and agomelatine administration. These results indicate the involvement of both the melatonin and the 5-HT2C receptors in the mechanism of anxiolytic-like action of agomelatine.     

1-(2-Pyrimidinyl)-piperazine may alter the effects of the 5-HT1A agonists in the learned helplessness paradigm in rats

The 5-HT1A agonists buspirone, gepirone and ipsapirone have been shown to possess antidepressive-like properties in several animal models of depression as well as in clinical studies. These compounds are metabolized to 1-(2-pyrimidinyl)-piperazine (1-PP) in rats and humans. In the learned helplessness paradigm, buspirone exhibits a biphasic action: at low or moderate doses it shows an antidepressant-like effect but this action progressively disappears as the doses are increased. In order to establish whether 1-PP affects the reversal of helpless behaviour induced by the 5-HT1A agonists at high doses in rats, we have investigated its role in the learned helplessness. Thus, 1-PP has been evaluated alone (0.06-4 mg/kg/day) or in combination with a selective 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg/day) which is not metabolized to 1-PP and buspirone (0.5 mg/kg/day). In addition, buspirone at a higher dose (2 mg/kg/day) has also been examined in the presence of proadifen which inhibits oxidative metabolism. Our results show that i) daily injections of 1-PP did not reverse helpless behaviour, ii) the reversal of helpless behaviour by 8-OH-DPAT or active dose of buspirone was antagonized by daily coadministration of 1-PP, iii) in rats pretreated with proadifen, the highest inactive dose of buspirone induces a reversal of helpless behaviour. These results strongly suggest that up to a certain concentration 1-PP can impair the effects of the parent drug in the learned helplessness.     

Anxiolytic-like effects of meprobamate. Interactions with an opiate antagonist in Swiss and BALB/c mice

Naloxone has previously been shown to block the effects of benzodiazepines in the Swiss but not in the BALB/c strain. We have also reported that naloxone potentiates subeffective doses of benzodiazepines in Swiss mice. In the present studies we first determined whether naloxone could block anxiolytic-like effects of meprobamate in Swiss and BALB/c mice. Then we evaluated if subeffective doses of meprobamate could be potentiated in Swiss as well as in BALB/c mice. The elevated plus-maze test and the light/dark choice procedure were used. The lowest dose of meprobamate with anxiolytic-like effects was 60 mg/kg in the BALB/c mice. This dose was effective in both the plus-maze and in the light/dark choice procedure. In Swiss mice the same dose was effective in the plus-maze, whereas 120 mg/kg was required in the light/dark choice procedure. When an effective dose of meprobamate was combined with naloxone, 10 mg/kg, no blockade of anxiolytic-like effects was obtained in any strain in any procedure. To the contrary, when a subeffective dose of meprobamate was combined with naloxone, 10 mg/kg, an anxiolytic-like effect was obtained in both strains in both procedures. The present series of experiment shows that the ability of naloxone to block anxiolytic-like drug effects do not apply to meprobamate. However, the naloxone-induced potentiation of subeffective doses previously observed after treatment with benzodiazepines or buspirone was present also after treatment with meprobamate. Moreover, although blockade of anxiolytic-like drug effects with naloxone has not been observed in BALB/c mice, potentiation was as evident in that strain as in the Swiss. This suggests that the mechanisms behind naloxone's blockade of anxiolytic-like effects are independent from those behind its potentiation of such effects.     

Behavioral effects of flibanserin (BIMT 17).

Flibanserin is a 5-HT1A agonist that, in contrast to other 5-HT1A receptor agonists, is capable of activating 5-HT1A receptors in frontal cortex. Flibanserin also behaves as an antagonist at 5-HT2A receptors. This compound has been described to be a putative fast-acting antidepressant owing to these properties. In the present study, the effect of flibanserin was investigated in several behavioral paradigms different from animal models of depression. Intraperitoneal flibanserin, at doses of 4-8 mg/kg, antagonized d-amphetamine- and (+)SKF-10047- induced hypermotility in mice and rats. At doses of 816 mg/kg, flibanserin exerted anxiolytic-like effects in the light/dark exploratory test and stress-induced hyperthermia in mice, and antagonized d-amphetamine- and apomorphine-induced stereotypy in rats. At the dose of 16 mg/kg, flibanserin reduced spontaneous motor activity in rats. At the dose of 32 mg/kg, flibanserin did not exert any clear effect on spontaneous motor activity in mice, or on the elevated plus-maze and the water maze in rats.     

Anxiolytic-like properties of melatonin receptor agonists in mice: involvement of mt1 and/or MT2 receptors in the regulation of emotional responsiveness

The anxiolytic-like properties of melatonin have been established in rodents. The present study investigated the possible involvement of melatonin receptors/binding sites in the regulation of emotional responsiveness in mice, using an mt1/MT2 receptor specific agonist (S 23478) and two specific ligands of MT3 binding sites with agonistic properties (N-acetylserotonin (NAS) and 5-methoxycarbonylamino N-acetyltryptamine (5-MCA-NAT)). We examined the behavioural effects of these compounds in C3H/He mice confronted with two anxiety models: the free-exploratory test, in which C3H/He mice present neophobic reactions ("trait" anxiety), and the light/dark choice test, which is an unconditioned conflict test (inducing "state" anxiety). Melatonin and S 23478 decreased anxious reactions in both the free-exploratory test (5-25 mg/kg) and the light/dark choice test (melatonin: 20 mg/kg; S 23478: 10-20-40 mg/kg). NAS exerted anxiolytic-like effects only at a dose of 35 mg/kg in the free-exploratory test and at a dose of 40 mg/kg in the light/dark choice test. Finally, 5-MCA-NAT was devoid of anxiolytic-like effects in both tests. These results suggest that the anxiolytic properties of melatonin could involve the activation of mt1 and/or MT2 receptors rather than of the MT3 binding site.     

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.