Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions.

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (-)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT(2) receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT(2) receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.     

Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test. Taken together, the results of these experiments support the conclusion that the increase in immobility seen following chronic variable stress or repeated morphine exposure is modulated by the activation of an endogenous opiate mechanism, given that this effect is attenuated by naloxone administration.     

Animal model of menopausal depressive-like state in female mice: prolongation of immobility time in the forced swimming test following ovariectomy

Rationale The onset of menopause produces a depressive state in women, but the mechanism involved in menopause-induced depression is poorly understood.Objectives Building upon previous studies that used the duration of immobility in male rodents during the forced swimming test as a behavioral measure of the depression-like state, we investigated whether the duration of immobility in female mice was altered following bilateral ovariectomy. We also evaluated the chronic effects of estradiol, antidepressants, scopolamine, and diazepam on both the duration of immobility and uterine weight.Methods We bilaterally resected the ovaries of ICR albino female mice at 9 weeks of age. The day after the surgery, drug treatment was started once per day for 2 weeks, after which, the behavioral test was administered. The duration of immobility was measured during the last 4 min of the 6-min trial.Results Bilateral ovariectomy significantly increased the duration of immobility. Chronic treatment with estradiol (15–30 μg kg⁻¹ day⁻¹) prevented the prolongation of immobility following ovariectomy and produced a significant increase in uterine weight. Chronic treatment with imipramine, fluvoxamine, and milnacipran at 5, 10, and 15 mg kg⁻¹ day⁻¹, respectively, significantly reduced the duration of immobility, whereas treatment with scopolamine or diazepam (0.5, 1.0, and 2.0 mg kg⁻¹ day⁻¹ for both) was ineffective.Conclusion Based on these results, we suggest that the prolongation of immobility in female mice following ovariectomy may be a useful tool for investigating menopausal depression.     

Neuropsychopharmacological study on an animal model for negative symptom of schizophrenia induced by repeated phencyclidine treatment

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 receptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.     

Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test

RATIONALE: Opiate-dependent subjects experience severe depression as one of the subjective symptoms during withdrawal. No experimental work, however, has focused on the ability of opiate-withdrawal to produce depression-like behavior in dependent animal. OBJECTIVES. We therefore investigated whether withdrawal from chronic morphine treatment affects immobility in forced swimming test in rats. METHODS: Morphine was administered in a dose escalation fashion using doses ranging from 20 to 140 mg/kg twice daily for 14 days, followed by 1-6 days of withdrawal, and their duration of immobility was assessed. RESULTS: After the last morphine treatment. an increase in immobility occurred late on day 3 and persisted to at least day 6 of withdrawal without any change in ambulatory activity. CONCLUSIONS: The results suggest that the morphine withdrawal resulted in prolonged enhancement of depression-like behavior in drug-dependent laboratory animals.     

Involvement of central opioid systems in human interferon-alpha induced immobility in the mouse forced swimming test

1. We investigated the mechanism by which human interferon-alpha (IFN-alpha) increases the immobility time in a forced swimming test, an animal model of depression. 2. Central administration of IFN-alpha (0.05 - 50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner. 3. Neither IFN-beta nor -gamma possessed any effect under the same experimental conditions. 4. Pre-treatment with an opioid receptor antagonist, naloxone (1 mg kg(-1), s.c.) inhibited the prolonged immobility time induced by IFN-alpha (60 KIU kg(-1), i.v. or 50 IU per mouse. i.cist. ). 5. Peripheral administration of naloxone methiodide (1 mg kg(-1), s. c.), which does not pass the blood - brain barrier, failed to block the effect of IFN-alpha, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked. 6. The effect of IFN-alpha was inhibited by a mu(1)-specific opioid receptor antagonist, naloxonazine (35 mg kg(-1), s.c.) and a mu(1)/mu(2) receptor antagonist, beta-FNA (40 mg kg(-1), s.c.). A selective delta-opioid receptor antagonist, naltrindole (3 mg kg(-1), s.c.) and a kappa-opioid receptor antagonist, nor-binaltorphimine (20 mg kg(-1), s.c.), both failed to inhibit the increasing effect of IFN-alpha. 7. These results suggest that the activator of the central opioid receptors of the mu(1)-subtype might be related to the prolonged immobility time of IFN-alpha, but delta and kappa-opioid receptors most likely are not involved.     

Effect of presynaptic dopaminergic agonism on the immobility of mice in the forced swimming test]

Administration of 0.05 mg/kg (i.p.) of apomorphine (APO) or of the two dopamine (DA) lipoamides, DA steatamide (S-DA) or DA palmitamide (P-DA), at doses of 10 or 30 mg/kg (i.p.), induced an anti-immobility effect, in the forced swimming test in mice, of the same order as those of imipramime (30 mg/kg, i.p.). At the aforementioned doses APO, S-DA or P-DA could be acting on the dopaminergic autoreceptors and cause a decrease of the turnover and/or the release of the brain DA in the striatum. In contrast, DA linoleamide (L-DA), which has no action on the brain DA, did not exhibit anti-immobility effect. It is suggested that the decrease of turnover and/or release of the brain DA, induced by APO, S-DA or P-DA, could constitute a clue of the extent of the extrasynaptic action developed by these drugs whose antiglutamatergic incidence could cause the anti-immobility effect, observed with these derivatives, as well as their possible antidepressive action.     

Effect of Withania somnifera on forced swimming test induced immobility in mice and its interaction with various drugs

The objective of the present study was to evaluate the antidepressant action of Withania somnifera (WS) as well as its interaction with the conventional antidepressant drugs and to delineate the possible mechanism of its antidepressant action using forced swimming model in mice. Effect of different doses of WS, fluoxetine and imipramine were studied on forced swimming test induced mean immobility time (MIT). Moreover effect of WS 100 mg/kg, i.p. was observed at different time intervals. Effect produced by combination of sub therapeutic doses of WS with imipramine (2.5 mg/kg, i.p.) as well as fluoxetine (2.5 mg/kg, i.p.) were also observed. Effect of WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) were observed in mice pretreated with reserpine (2 mg/kg, i.p.) and clonidine (0.15 mg/kg, i.p.). Effects of prazosin (3 mg/kg, i.p.) or haloperidol (0.1 mg/kg, i.p.) pre-treatment were also observed on WS induced decrease in MIT. WS produced dose dependent decrease in MIT. Maximum effect in MIT was observed after 30 min of treatment with WS 100 mg/kg, i.p. Combination of WS (37.5 mg/kg, i.p.) with imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) also produced significant decrease in the MIT. Clonidine and reserpine induced increase in MIT, was significantly reversed by treatment with WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.). Pre-treatment with prazosin but not haloperidol, significantly antagonized the WS (100 mg/kg, i.p.) induced decrease in MIT. It is concluded that, WS produced significant decrease in MIT in mice which could be mediated partly through a adrenoceptor as well as alteration in the level of central biogenic amines.     

Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice: role of serotonin

We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.     

Enhancement of the anti-immobility action of antidepressants by risperidone in the forced swimming test in mice

The aim of the present study was to examine the effect of antidepressants (ADs) belonging to different pharmacological groups and risperidone (an atypical antipsychotic drug), given separately or jointly, on immobility time in the forced swimming test in male C57BL/6J mice. The antidepressants: citalopram, fluvoxamine, sertraline, reboxetine, milnacipran (5 and 10 mg/kg), or risperidone in low doses (0.05 and 0.1 mg/kg) given alone did not change the immobility time of mice in the forced swimming test. Co-treatment with reboxetine or milnacipran (10 mg/kg) and risperidone in a lower dose of 0.05 mg/kg or with sertraline, reboxetine (5 and 10 mg/kg), citalopram, fluvoxamine, milnacipran (10 mg/kg) and risperidone in a higher dose of 0.1 mg/kg produced antidepressant-like effect in the forced swimming test. WAY100635 (a 5-HT(1A) receptor antagonist) inhibited the effects induced by co-administration of ADs and risperidone. Active behavior in the forced swimming test was not a consequence of an increased general activity, since the combined treatment with ADs and risperidone failed to enhance the locomotor activity of mice. The obtained results indicate that a low dose of risperidone enhances the activity of ADs in an animal model of depression, and that, among other mechanisms, 5-HT(1A) receptors may play a role in these effects.     

Long-lasting effects of chronic chlorimipramine treatment of rats on exploratory activity on a hole-board, and on immobility in the forced swimming test

The study concerned the effects of acute and chronic clomipramine administration to male rats on exploratory activity in a novel environment (hole-board) and on immobility in the forced swimming test. Acute clomipramine administration did not alter either exploratory activity on a hole-board as measured 3 or 20 h after drug administration, or immobility in the forced swimming test as measured 20 h after drug administration. Approximately 20 h after the last injection of clomipramine, the rats chronically treated with the drug showed reduced exploratory activity on the hole-board. In contrast, chronic clomipramine treatment significantly increased the activity in the forced swimming test. The effects of the drug on exploratory and forced swimming activities persisted for 14 days after the cessation of clomipramine administration. These data indicate that chronic clomipramine administration exerted profound and long-lasting effects on central nervous system function. The long-lasting action of the drug on behaviour in the forced swimming test might explain the long-term beneficial effect of antidepressant drugs in counteracting behavioral depression.     

Effects of co-treatment with mirtazapine and low doses of risperidone on immobility time in the forced swimming test in mice

The aim of the present study was to examine the effect of mirtazapine (MIR) and risperidone (an atypical antipsychotic drug), given separately or jointly, on immobility time in the forced swimming test in male C57BL/6J mice. Fluoxetine (FLU) was used as a reference drug. MIR (2.5, 5 and 10 mg/kg) and FLU (5 and 10 mg/kg), or risperidone in low doses (0.05 and 0.1 mg/kg) given alone did not change the immobility time of mice in the forced swimming test. Joint administration of MIR (5 and 10 mg/kg) or FLU (10 mg/kg) and risperidone (0.1 mg/kg) produced antidepressant-like activity in the forced swimming test. WAY100636 (a 5-HT(1A) receptor antagonist) inhibited, while yohimbine (an α(2)-adrenergic receptor antagonist) potentiated the antidepressant-like effect induced by co-administration of MIR and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined administration of antidepressants and risperidone failed to enhance the locomotor activity of mice. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of MIR and that, among other mechanisms, 5-HT(1A)-, and α(2)-adrenergic receptors may play a role in this effect.     

Neonatal treatment with clomipramine increased immobility in the forced swim test: an attribute of animal models of depression.

The forced swimming test in rats has been identified as a suitable model for detecting antidepressant activity of several drugs regardless of their mode of action. On the other hand, a number of animal models of human endogenous depression have been proposed. Recently, it has been reported that perinatal administration of clomipramine in rats elicits behavioral changes in adulthood that resemble human endogenous depression. In the present study, we showed that in this new animal model of depression immobility was increased when animals were submitted to the forced swimming test. This finding supports the notion that the amount of immobility during the forced swimming test is directly proportional to a depressive state in the rat.     

Antidepressant effects of apocynum venetum leaves in a forced swimming test.

An extract of the leaves of Apocynum venetum L. (Apocynaceae) markedly shortened the immobility time of male rats in a forced swimming test (FST) in a dose range of 30-125 mg/kg, indicating a possible antidepressant activity. This effect was comparable to that of the tricyclic antidepressant imipramine (20 mg/kg). Neither imipramine (20 mg/kg) nor the Apocynum extract in various doses (30, 60, 125 mg/kg) produced any overt behavioural change or motor dysfunction in the open field test. This result confirms the assumption that the antidepressant effect of an Apocynum extract in the FST is specific. Further, it can be speculated that this effect might be related to hyperoside and isoquercitrin which are major flavonoids in the extract.     

Availability of learned helplessness test as a model of depression compared to a forced swimming test in rats

This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5-20 mg/kg), clomipramine (0.1325-1.25 mg/kg, p.o.) and fluvoxamine (0.3125-1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats.     

Effects of anxiogenic drugs in rat forced swimming test.

The effect of antidepressants and anxiogenics in the forced swimming (Porsolt') test was investigated in rats. On the second day of an experiment, desipramine (10 mg/kg), pentylenetetrazole (20 mg/kg), picrotoxin (2.5 mg/kg), and clonidine (1.0 mg/kg) shortened while buspirone (1.0 mg/kg), yohimbine (2.5 mg/kg), DMCM (1.0 mg/kg), and Ro-15-4513 (1.0 mg/kg) prolonged the time of immobility or behavioral despair; fluoxetine (10 and 20 mg/kg), citalopram (10 mg/kg), and flumazenil (10 mg/kg) were ineffective. While clonidine, given in a subeffective dose (0.1 mg/kg), augmented the effect of desipramine (10 mg/kg), buspirone (1.0 mg/kg) had an opposite effect. The picrotoxin (2.5 mg/kg) challenge prominently shortened the time of immobility after desipramine (10 mg/kg) or citalopram (10 mg/kg) treatment. In conclusion, our results indicate that pharmacologically enhanced anxiety interacts with the effects of acute drug treatment in the forced swimming test.     

The 5-HT2 receptor antagonist reduces immobility of mice treated with the atypical antidepressant mianserin in the forced swimming test

Effects of co-administration with the 5-HT(2) receptor antagonist LY 53857 and the antidepressant mianserin on immobility time in the forced swimming test were investigated in mice. Mianserin did not affect the immobility time at ranges from 1-10 mg/kg, although it elicited anti-immobility effects at 20 mg/kg. Co-administration of the 5-HT(2) receptor antagonist LY 53857 and a subactive dose of mianserin induced apparent anti-immobility effects. Since mianserin facilitates noradrenaline (NA) release from nerve terminals via inhibition of alpha(2) receptors, the blockade of the 5-HT(2) receptor may increase the antidepressant effect of drugs modifying NA levels in the synaptic cleft.     

Effect of potassium channel modulators in mouse forced swimming test.

1. The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. 2. Tetraethylammonium (TEA; 5 microg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 microg per mouse i.c.v.) and gliquidone (6 microg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg(-1) s.c.) and imipramine (30 mg kg(-1) s.c.). 3. By contrast pinacidil (10-20 microg per mouse i.c.v.), minoxidil (10-20 microg per mouse i.c.v.) and cromakalim (20-30 microg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. 4. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. 5. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. 6. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test.