Is co-administration of bupropion with SSRIs and SNRIs in forced swimming test in mice, predictive of efficacy in resistant depression?

UNLABELLED: The monoamine hypothesis based on the deficiency of one or several monoamines is commonly evoked to explain the physiopathology of depression. This hypothesis initially based on noradrenalin and serotonin deficiency has been extended to dopamine. The animal models of depression also suggest an implication of dopamine in the physiopathology of depression. The forced swimming test is an animal model used to predict the antidepressant activity of drugs. OBJECTIVES: The scope of this study was to investigate the antidepressant-like effect of a dopamine re-uptake inhibitor, bupropion, when combined with conventional antidepressants drugs SSRIs (selective serotonin re-uptake inhibitors), SNRI (selective serotonin-noradrenalin re-uptake inhibitors) and a NRI (selective noradrenalin inhibitor). METHODS: This study assessed the effects of co-administration of bupropion with SSRIs: sertraline, paroxetine, citalopram, fluvoxamine, SNRIs: venlafaxine and milnacipran and NRI: desipramine, using an animal model of depression, the forced swimming test in mice. Subactive doses of bupropion (4 and 8mg/kg) and antidepressants: sertraline (2mg/kg), paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran and desipramine (4mg/kg) were given i.p. 45 and 30min, respectively, before the test. RESULTS: Bupropion (4 and 8mg/kg) combined with inactive doses of antidepressants, decreased immobility time in the mice FST except with sertraline and desipramine. In conclusion, the antidepressant-enhancing effects of bupropion, in the present study, are in agreement with preliminary clinical evidence suggesting that bupropion may enhance the efficacy of therapeutic effect of SSRIs and SNRIs but not the therapeutic effect of NRI. These results suggest that bupropion enhances only the serotonergic system.

Antidepressant-like effect of lamotrigine is reversed by veratrine: a possible role of sodium channels in bipolar depression.

UNLABELLED: Lamotrigine has been found to be efficacious in the acute management of bipolar depression and long-term management of bipolar disorder, especially in delaying depressive recurrence, either as monotherapy or as adjunctive therapy. Lamotrigine is also an antiepileptic drug, and is efficient in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitivity sodium channels and stabilization of the neuronal membrane. OBJECTIVES: The scope of this study was to determinate if sodium channels are important for lamotrigine and other antidepressant to exert their antidepressant-like function. METHODS: This study assessed the effects of veratrine, a Na(+) channel opener on antidepressant effect of lamotrigine and others antidepressants: two tricyclic antidepressants (TCAs): imipramine, a mixed serotonergic noradrenergic reuptake inhibitor, desipramine, a specific noradrenergic reuptake inhibitor and a SSRI: paroxetine, the most potent selective serotonergic reuptake inhibitor, using an animal model of depression, the forced swimming test. Veratrine (0.125 mg/kg) and lamotrigine (16, 32 mg/kg) or antidepressants (16, 32 mg/kg) were given i.p. 45 and 30 min, respectively, before the test. RESULTS: We observed that when combined with veratrine the antidepressant-like effect of lamotrigine was reversed, but the antidepressant-like effect of the imipramine, desipramine and paroxetine was not changed, indicating that the mechanism of action of lamotrigine is different from that of antidepressants.

Anxiolytic-like effects of DOI microinjections into the hippocampus (but not the amygdala nor the PAG) in the mice four plates test.

Anxiolytic-like effects of DOI, a 5-HT(2A/2C) agonist have been observed in the four plates test (FPT) after intra-peritoneal administrations. In the present study, DOI (1 microg, 2 microg or 5 microg per mice) was directly injected to three brain structures, the hippocampus, the amygdala and the periaqueductal gray matter (PAG). Tests were carried out immediately after injections. In amygdala and PAG, DOI exerted an anxiogenic-like effect. In the hippocampus, a strong anxiolytic-like effect was found only when injecting 5 microg DOI/mice in the FPT, with a size effect comparable to the anxiolytic-like effect of diazepam 1mg/kg injected intra-peritoneally. DOI or vehicle injections did not affect locomotor activity. These results help us to understand mechanisms of action of DOI in animal models of anxiety, probably through an interaction with other neurotransmitter system, which may take place in the hippocampus.

Anxiolytic-like effect of 5-HT(2) ligands and benzodiazepines co-administration: comparison of two animal models of anxiety (the four-plate test and the elevated plus maze).

Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT(2A/2C) agonist DOI and the 5-HT(2B) agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT(2) ligands in the FPT and the EPM. Indeed, close distribution of GABA(A) and 5-HT(2) receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT(2A) ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.

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.

Animal models of anxiety in mice.

Among the multiple possibilities to study human pathologies, animal models remain one of the most used pathways. They allow to access to unavailable answers in human patients and to learn about mechanisms of action of drugs. Primarily developed with rats, animal models in anxiety have been adapted with a mixed success for mice, an easy-to-use mammal with better genetic possibilities than rats. In this review, we have focused on the most used animal models in anxiety in mice. Both conditioned and unconditioned models are described, to represent all types of animal models of anxiety. Behavioural studies require strong care for variable parameters, linked to environment, handling or paradigm; we have discussed about this topic. Finally, we focused on the consequences of re-exposure to the apparatus. Test-retest procedures can bring in new answers, but should be deeply studied, to revalidate the whole paradigm as an animal model of anxiety.

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-HT2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the alpha-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the alpha2-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 alpha-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 alpha1-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an alpha1-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an alpha2-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two alpha2-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific alpha2A-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 alpha2-adrenoceptors.

Implication of 5-HT2A subtype receptors in DOI activity in the four-plates test-retest paradigm in mice.

The four-plates test (FPT) is an animal model of anxiety which allows the detection of anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZDs anxiolytic compounds such as antidepressants (ADs). Furthermore, DOI, a 5-HT(2A/2C) agonist, has been shown to exert an anxiolytic-like effect in this model. Retesting mice in animal models of anxiety (test-retest paradigm) induces an anxiogenic-like and a loss of anxiolytic-like effects in response to BZDs and ADs. On the contrary, DOI has been reported to oppose the fear potentiation induced by trial 1 in the FPT. Despite DOI is considered as one of the most selective 5-HT(2A) available, it acts as agonist at all three 5-HT(2) receptor subtypes (5-HT(2A), 5-HT(2B) and 5-HT(2C)). The aim of this study was thus to investigate in the FPT test-retest paradigm, which 5-HT(2) receptor subtype(s) was involved in the DOI-induced effect in experienced mice. The effect of DOI (0.25-4 mg/kg) and the agonists, 5-HT(2B), BW 723C86 (1-16 mg/kg) and 5-HT(2C), RO 60-0175 (0.25-4 mg/kg) have also been studied. Then, antagonism studies were conducted combinating the 5-HT(2A) receptor antagonist SR 46349B, the 5-HT(2B/2C) receptor antagonist SB 206553 or the selective 5-HT(2C) receptor antagonist RS 10-2221 (at the doses of 0.1 and 1 mg/kg) with the DOI (1 mg/kg). Our study shows that the BW 723C86 had no effect on retesting mice, whereas it exerted an anxiolytic-like effect in naive mice. By contrast to DOI, the RO 60-0175 had no effect neither in naive nor experienced mice. Furthermore, only the SR 46349B antagonized the DOI-induced anti-punishment effect. Diazepam included as a positive control also increased in each case the number of punished passages in naive mice. Our findings altogether also suggest that DOI exerts its anxiolytic-like effect in the FPT test-retest paradigm through 5-HT(2A) receptors.

Light/dark cycle manipulation influences mice behaviour in the elevated plus maze.

The sensitization of animal models of anxiety is of great importance to detect potential anxiolytic drugs. Our goal was to evaluate the influence of manipulations of the light/dark cycle on the basal anxious behaviour of mice and the efficacy of two anxiolytic treatments in the mouse elevated plus maze (EPM). Male Swiss mice were exposed to different conditions of illumination for one week prior to testing. In the first experiment of the study, we evaluated the anxiolytic effects of diazepam, at the dose of 1 mg/kg, intraperitoneally (i.p.) administered 30 min before the test. In the second experiment, we examined the effects of WAY 100635, a 5-HT(1A) receptor antagonist, at the doses of 0.03 and 2 mg/kg, i.p. administered 30 min before the test. The locomotor activity of control mice and the anxiolytic efficacy of diazepam in the EPM were not affected by manipulation of the light/dark cycle. Conversely, the effects of WAY 100635, which were qualitatively different from those of diazepam, seemed to be influenced by the illumination conditions imposed before the test. We can conclude that diazepam's effect, which is characterized by a strong "disinhibition", was more robust than the 5-HT(1A) antagonist's effect, which was more anxioselective. Moreover, the light conditions imposed on mice before the test may be an important factor in the variability of the response to serotonergic but not to benzodiazepine treatments.

The four-plates test: anxiolytic or analgesic paradigm?

The four-plates test (FPT) is an animal model of anxiety in which the exploration of the novel surroundings is suppressed by the delivery of a mild electric foot shock. The anti-nociceptive system has been reported to be activated by a variety of stressful stimuli such as footshock. The present study was thus designed to compare effects of drugs in the FPT and in the hot-plate test (an animal model of pain), in order to disambiguate the drug-induced anti-punishment effects obtained in the FPT from alterations in pain sensitivity. Various compounds, known to be implicated in anxiety states as well as nociception, have been studied. Although morphine induced a strong anti-nociceptive effect, it did not modify the number of shocks received in the FPT. Alprazolam and diazepam induced an anxiolytic-like effect in the FPT, at doses that did not induce any effect in the hot-plate test. The antidepressants previously reported anxiogenic (desipramine, maprotiline) in the FPT were found to be analgesic at the same doses. Milnacipran, venlafaxine and paroxetine did not modify the pain threshold, whereas they have previously been shown to induce anxiolytic-like effects in the FPT. The dopaminergic antidepressant agent nomifensine was without effect on both tests. Our results suggest that the reported drug-induced anti-punishment effects in the FPT are not related to modifications of pain threshold but to a pure anxiolytic-like effect.

Implication of 5-HT2 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-HT2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT2B/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-HT2A 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-HT2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT2A and 5-HT2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT2A, 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.

The four-plates test-retest paradigm to discriminate anxiolytic effects.

RATIONALE: Animal models of anxiety such as the four-plates test (FPT) enable the detection of an anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZD anxiolytic compounds such as the antidepressants paroxetine and venlafaxine. Retesting mice in animal models of anxiety markedly alters the behavioural profile of various drugs. OBJECTIVES: The aim of this study was first to investigate the function of GABA(A)/BZD receptor and passive avoidance acquisition in the FPT "test-retest". The second aim of this study was to evaluate the capacity of the FPT to discriminate BZDs from other non-BZD anxiolytics in experienced mice. METHODS: The FPT was performed in naive and experienced mice (submitted to the test 24 h previously). The drugs studied were two BZDs, diazepam (1 mg/kg) and alprazolam (0.25 mg/kg); flumazenil, a GABA(A) receptor antagonist (8 mg/kg); atropine sulphate, a muscarinic cholinergic receptor antagonist (4 mg/kg) known for its amnesic properties; paroxetine, a selective serotonin reuptake inhibitor (4 and 8 mg/kg); venlafaxine, a serotonin and noradrenalin reuptake inhibitor (4 and 16 mg/kg); and DOI, a 5-HT2A agonist (1 mg/kg). RESULTS: Our results reveal an increase of anxiety (decrease of punished passages) in saline-experienced mice. Diazepam, alprazolam, paroxetine and venlafaxine did not prevent the increase in anxiety during retest, revealing a passive avoidance acquisition. Flumazenil did not modify the anxiogenic-like behaviour of experienced mice. In contrast, atropine seems to oppose the increase of anxiety; however, its effect is weak and disputable. DOI was the only anxiolytic compound able to oppose the decrease of punished passages of experienced mice. CONCLUSION: Anxiogenic behaviour on retesting indicates aversive learning. The protocol test-retest is unable to discriminate between the anxiolytic effect of BZDs from that of paroxetine or venlafaxine. However, this modified model may constitute a new tool to investigate other neural pathways implicated in anxiety.

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.

Role of GABA-ergic and serotonergic systems in the anxiolytic-like mechanism of action of a 5-HT-moduline antagonist in the mouse elevated plus maze.

5-HT-moduline is an endogenous tetrapeptide, which acts specifically as an antagonist of 5-HT1B auto- and heteroreceptors. HG1 is an ethyl arylmethyloxypiperidine acetate and an antagonist of 5-HT-moduline, which has no 5-HT-moduline agonist effect. In a pilot study, HG1 has demonstrated an anxiolytic-like profile in three mouse models of anxiety (elevated plus maze, light/dark, four plates). The aim of our study was to examine the mechanism of the anxiolytic-like effects of HG1 in the mouse elevated plus maze. Male Swiss mice were acutely administered HG1 at active doses in association with GABA antagonists such as flumazenil, bicuculline and picrotoxine, then, with 5-HT1A (NAN 190, WAY 100635) and 5-HT1B receptor antagonist (methiothepine). Finally, we tried to potentiate non-active doses of HG1 with 5-HT1A (8-OHDPAT) and 5-HT1B receptor agonists (anpirtoline) in the mouse elevated plus maze. Regarding GABA antagonists, only flumazenil antagonised active doses of HG1 in an incomplete manner. Moreover, non-active doses of HG1 were potentiated by low doses of WAY 100635 and by anpirtoline but not by 8-OHDPAT. Finally, the anxiolytic-like effects of HG1 at active doses were antagonised by all serotonergic antagonists (WAY 100635 at higher dose, NAN 190 and methiothepin). HG1 mechanism of action in the mouse elevated plus maze seems to associate a GABA-ergic component exerting a limited regulation of 5-HT neuronal activity and a major serotonergic component, which seems to implicate presynaptic 5-HT1A and 5-HT1B receptors.

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.

Antidepressant-like effects in various mice strains in the forced swimming test.

RATIONALE: Strain differences in mice have been reported in response to drugs in the mouse forced swimming test (FST), even if few antidepressants were examined. OBJECTIVES: The aim of the present study was to investigate the influence of genetic factors, using five antidepressants (imipramine, desipramine, citalopram, paroxetine and bupropion) in the mouse FST, in outbred strains (Swiss, NMRI) and inbred strains (DBA/2, C57BL/6J Rj). Moreover, whole brain levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) in vehicle treated animals, which were or were not subjected to the FST, were measured by HPLC analysis in an attempt to explain behavioural differences. METHODS: For each antidepressant, a dose range (1-16 mg/kg) was tested in the locomotor apparatus and only non-psychostimulant doses were then tested in the FST in order to detect antidepressant-like activity. RESULTS: No baseline differences among Swiss, NMRI, DBA/2 and C57BL/6J Rj strains were observed in our experiments, allowing the comparison of different antidepressants in each strain. Imipramine (16 mg/kg), desipramine, citalopram (4-16 mg/kg) and paroxetine (8 and 16 mg/kg) treatment decreased the immobility time in the Swiss strain and the size of the effect reached more than 20% for each of these antidepressants. C57BL/6J Rj was the only strain sensitive to bupropion (2 and 4 mg/kg). In the NMRI strain, only paroxetine treatment decreased the immobility time (16 mg/kg). CONCLUSION: Our study showed that drug sensitivity is genotype dependent. FST results have shown that Swiss mice are the most sensitive strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be limited, as an absence of antidepressant-like response was observed in the FST. The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due to high DA, NA and 5-HT whole brain concentrations.

Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety.

The behavioural effects of 5-HT(2) receptor agonists, 5-HT(2A) and 5-HT(2C) receptor antagonists were investigated in the mouse four plates test (FPT), light/dark paradigm (L/D) and the elevated plus maze (EPM), in order to elucidate the role of the 5-HT(2) receptor subtypes in these models and to address the inconclusive results previously reported using rat psychopharmacological models. All compounds were administered intraperitoneally 30 min before each test. DOI, a preferential 5-HT(2A) agonist (0.5-8 mg/kg) and BW 723C86, a 5-HT(2B) agonist (8 and 16 mg/kg) provoked an anxiolytic-like response in the FPT. In the EPM, an anxiolytic-like effect was observed for DOI (0.5, 1 and 2 mg/kg), BW 723C86 (0.5, 4, 8 and 16 mg/kg), RO 60-0175 a 5-HT(2C) agonist (4 mg/kg) and the non-selective 5-HT(2) receptor agonist mCPP (0.25 mg/kg.). Ketanserin, a 5-HT(2A/2C) non-selective receptor antagonist (0.015 and 0.03 mg/kg), induced an anxiogenic-like effect in the L/D paradigm. The 5-HT(2C) antagonists (RS 10-2221, SDZ SER082 and SB 206553) were without effect in all three tests. These behavioural results are indicative of an anxiolytic-like action of 5-HT(2) receptor agonists, an anxiogenic-like effect of 5-HT(2A) receptor antagonism, whereas the blockade of 5-HT(2C) receptors are without effect in the mouse models studied.

Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice.

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.

Antidepressant-like effects in various mice strains in the tail suspension test.

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

The mouse light/dark box test.

The light/dark test is based on the innate aversion of rodents to brightly illuminated areas and on the spontaneous exploratory behaviour of rodents in response to mild stressors, that is, novel environment and light. The test apparatus consists of a small dark safe compartment (one third) and a large illuminated aversive compartment (two thirds). The test was developed with male mice. The strain, weight and age may be crucial factors. The extent to which an anxiolytic compound can facilitate exploratory activity depends on the baseline level in the control group. Differences between the type and severity of external stressors might account for the variable results reported by different laboratories. The light/dark test may be useful to predict anxiolytic-like or anxiogenic-like activity in mice. Transitions have been reported to be an index of activity-exploration because of habituation over time, and the time spent in each compartment to be a reflection of aversion. Classic anxiolytics (benzodiazepines) as well as the newer anxiolytic-like compounds (e.g. serotonergic drugs or drugs acting on neuropeptide receptors) can be detected using this paradigm. It has the advantages of being quick and easy to use, without requiring the prior training of animals.