Effects of combined treatment with imipramine and metyrapone in the forced swimming test in rats. Behavioral and pharmacokinetic studies

In the present study, we examined the effects of imipramine (IMI) and metyrapone (MET) given alone or in combination of IMI and MET in the forced swimming test in rats. We also measured pharmacokinetic parameters: the level of IMI and its metabolite, desipramine (DMI), in the rat plasma and brain (1 h after the forced swimming test). The present studies indicate that MET (50 mg/kg) reduced immobility time. Combined treatment with MET (50 mg/kg) and IMI (5 or 10 mg/kg) produced stronger antidepressant-like effect than either of drugs given alone. Sulpiride (dopamine D2/3 antagonist), or WAY 100635 (5-HT1A antagonist) but not prazosin, (alpha1-adrenergic antagonist), at doses ineffective in the forced swimming test, inhibited an antidepressant-like effect induced by co-administration of IMI with MET. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and MET failed to alter the locomotor activity of rats, measured in the open field test. MET elevated the concentrations of IMI and DMI in plasma, and the total drug concentration (IMI + DMI) was doubled by MET. In the brain, MET enhanced the concentration of IMI, but decreased that of DMI, consequently, the brain IMI/DMI ratio increased twice. The total drug concentration in the brain (IMI + DMI) was not changed significantly by MET treatment. The obtained results suggest that dopamine D2/3 and 5-HT1A receptors may contribute to the mechanism of synergistic action of IMI and MET in the forced swimming test in rats, and that pharmacokinetic interaction should not have a substantial impact on the MET-induced potentiation of IMI effect, observed in vivo. These findings may be of particular importance to pharmacotherapy of drug-resistant depression.     

Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioral and pharmacokinetic studies

Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptor, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either of drugs given alone. Since it has been suggested that, in addition to their other functions, dopamine and alpha(1)-adrenergic receptors may play a role in behavioral response in the forced swimming test, in the present study we examined the effect of sulpiride (dopamine D(2/3) receptor antagonist) and prazosin (alpha(1)-adrenergic receptor antagonist) on the effect of AMA given alone or in combination with IMI in the forced swimming test in rats. We also measured the level of IMI and its metabolite, desipramine, in the rat plasma and brain, 1 h after the forced swimming test. Joint treatment with IMI (5 or 10 mg/kg) and AMA (20 mg/kg) produced stronger antidepressant-like effect than either of agents given alone. Sulpiride (10 mg/kg) or prazosin (1 mg/kg) (ineffective in the forced swimming test) inhibited an antidepressant-like effect induced by co-administration of IMI and AMA. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and AMA failed to enhance the locomotor activity of rats, measured in the open field test. Also sulpiride and prazosin did not decrease the exploratory activity induced by co-administration of IMI and AMA. The above result suggests that the dopamine D(2/3) and alpha(1)-adrenergic receptors may contribute to the mechanism of synergistic action of IMI and AMA in the forced swimming test in rats. The pharmacokinetic interaction can be excluded, since AMA did not change significantly the antidepressant level in the rat plasma and brain, measured 1 h after exposure to the forced swimming test.     

Synergistic effect of pramipexole and sertraline in the forced swimming test

The authors studied the effect of sertraline, one of selective serotonin reuptake inhibitors (SSRIs), and pramipexole, administered jointly, to male Wistar rats in the forced swimming test. Both those drugs were injected three times (24, 5 and 1 h before the test): sertraline at doses of 5 and 10 mg/kg ip, pramipexole at doses of 0.05, 0.1 and 0.3 mg/kg sc. Sertraline given separately was inactive in the test used. Pramipexole reduced the immobility time only at a dose of 0.3 mg/kg. Joint administation of both those drugs distinctly shorted the immobility time, that effect.being particularly strong at pramipexole, 0.3 mg/kg, and sertraline, 5 or 10 mg/kg. The obtained results indicate that sertraline--like the previously tested citalopram and fluoxetine--shows a synergistic effect when given with pramipexole in the forced swimming test.     

Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test

Antidepressant medications are indicated in a variety of sustained mood disorders, including depression, and in epileptic patients. On the other hand, some antiepileptics are also used in the treatment of affective disorders. Therefore, some interactions may appear between antiepileptics and antidepressant drugs. The aim of the present study was to investigate the influence of the treatment with antiepileptic drugs on the antidepressants' activity in mice (forced swimming test or assessment of locomotor activity). The animals received intraperitoneally (ip) antiepileptics: phenytoin (PHT) at 6 or 12 mg/kg, valproate (VAL) at 50, 100, 200 or 300 mg/kg, carbamazepine (CBZ) at 4, 6 or 9 mg/kg, vigabatrin (VGB) at 50, 100, 200 or 300 mg/kg or lamotrigine (LTG) at 12.5 or 25 mg/kg, 30, 60 or 90 min before the injection of antidepressants: imipramine (IMI, 20 mg/kg) amitriptyline (AMI, 10 mg/kg), maprotiline (MAP, 10 mg/kg), mianserin (MIA, 15 mg/kg), fluoxetine (FLX, 40 mg/kg) or fluvoxamine (FLV, 20 mg/kg). It was shown that the acute administration of antidepressant drugs significantly reduced the immobility time in forced swimming test in mice. Antiepileptics, given in a single dose, caused did not change the behavior of mice in this test, however, they abolished the characteristic effect of antidepressant drugs. Each antidepressant, given at a single dose, shortening the immobility time in forced swimming test and reduced the locomotor activity of mice. This sedative effect of antidepressants was intensified by antiepileptics. The present results suggest that antiepileptics can reduce the activating effect of antidepressant drugs of different groups.     

Antidepressant-like activity of ipsapirone, buspirone and gepirone in the forced swimming test in rats pretreated with proadifen

The antidepressant-like activity of ipsapirone, buspirone and gepirone was studied in rats in the forced swimming test (behavioural despair test). lpsapirone and buspirone administered in single doses (5-20 mg/kg) did not affect the immobility time in this test. When administered in the same doses in a three-injection course in 24 h, buspirone was also inactive, while ipsapirone slightly but significantly reduced the immobility time only after a dose of 5 mg/kg. On the other hand, gepirone administered both in single doses (2.5-20 mg/kg) and in a three-injection course (5-20 mg/kg) potently and dose-dependently shortened the immobility time. 1-(2-Pyrimidinyl)-piperazine (1-PP; 5-20 mg/kg), a common metabolite of all the three drugs, administered in single doses or in a three-injection course, was inactive in the forced swimming test. In rats pretreated with proadifen (50 mg/kg), a non-selective drug metabolism inhibitor, both ipsapirone and buspirone administered in single doses (5-20 mg/kg) reduced the immobility time in a dose-dependent manner. Proadifen also potentiated the anti-immobility effect of gepirone (5 and 10 mg/kg). The anti-immobility effect of single doses (20 mg/kg) of ipsapirone, buspirone and gepirone in proadifen-pretreated animals was completely abolished by 1-PP (4 mg/kg). These results indicate that the antidepressant-like activity of the examined drugs in the behavioural despairtest is masked (ipsapirone, buspirone) or attenuated (gepirone) by their metabolite 1-PP.     

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.     

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.     

Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia.

1. Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces such negative symptoms in humans. 2. Repeated treatment with PCP (10 mg kg-1 day-1, s.c., once a day for 14 days) prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment; the effect was not obtained by single or 5 treatments with PCP (10 mg kg-1, s.c.), or by repeated treatment with methamphetamine (0.5 and 1 mg kg-1 day-1, s.c., once a day for 14 days). 3. The enhancing effect of PCP (10 mg kg-1 day-1, s.c.) on the immobility persisted for at least 21 days after the withdrawal of the drug. 4. Haloperidol (0.3 and 1 mg kg-1, p.o.), ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.1-1 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.) failed to attenuate the immobility induced by the forced swimming in mice repeatedly treated with saline when the drugs were administered 1 h before the forced swimming test. However, ritanserin (30 mg kg-1) and clozapine (30 mg kg-1) did attenuate this immobility. 5. The enhancing effect of PCP on the immobility was attenuated by ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.3 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.), whereas haloperidol (0.3 and 1 mg kg-1, p.o.) had no effect. 6. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia. This effect of PCP appeared to be mediated, at least in part, via 5-HT2A receptors.     

Combined treatment with imipramine and metyrapone induces hippocampal and cortical brain-derived neurotrophic factor gene expression in rats

The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. Recently it was shown that joint administration of imipramine (IMI) and metyrapone (MET), an inhibitor of glucocorticoid synthesis, produced a more potent "antidepressant" effect in the forced swimming test than did treatment with either drug alone. Our studies also showed that co-administration of IMI and MET to drug-resistant, unipolar depressed patients effected a clinical improvement. In addition, recent studies indicated a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present research we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and MET (50 mg/kg), given separately or jointly (twice daily for 14 day), on the BDNF mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last dose of IMI and MET. The obtained results showed that in the hippocampus IMI (10 mg/kg) and cerebral cortex IMI (5 mg/kg) and MET (50 mg/kg) significantly elevated the BDNF mRNA level. Joint administration of IMI (10 mg/kg) and MET (50 mg/kg) induced a more potent increase BDNF gene expression in both the examined brain regions (compared to the treatment with either drug alone). Moreover, the obtained results suggested that BDNF may be involved in the mechanism of the synergistic antidepressant effect of IMI and MET in drug-resistant depressed patients.     

Omega-3 fatty acids have antidepressant activity in forced swimming test in Wistar rats

Forced swimming test is used to induce a characteristic behavior of immobility in rats, which resembles depression in humans to some extent. We evaluated the effect of omega-3 fatty acids alone as well as compared it with the standard antidepressant therapy with fluoxetine in both acute and chronic studies. In both the studies, rats were divided into 4 groups and subjected to the following drug interventions - Group 1- control: Group 2- fluoxetine in dose of 10 mg/kg subcutaneously 23.5, 5 and 1 h before the test: Group 3- omega-3 fatty acids in dose of 500 mg/kg orally; Group 4- fluoxetine plus omega-3 fatty acids both. In acute study, omega-3 fatty acids were given in single dose 2 h prior to the test while in chronic study omega-3 fatty acids were given daily for a period of 28 days. All animals were subjected to a 15-min pretest followed 24 h later by a 5-min test. A time sampling method was used to score the behavioral activity in each group. The results revealed that in acute study, omega-3 fatty acids do not have any significant effect in forced swimming test. However, in chronic study, omega-3 fatty acids affect the immobility and swimming behavior significantly when compared with control (p < 0.01) without any significant effect on climbing behavior and the efficacy of combination of omega-3 fatty acids and fluoxetine is significantly more than that of fluoxetine alone in changing the behavioral activity of rats in forced swimming test. It leads to the conclusion that omega-3 fatty acids have antidepressant activity per se, and the combination of fluoxetine and omega-3 fatty acids has more antidepressant efficacy than fluoxetine alone in forced swimming test in Wistar rats.     

Alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test

The influence of alpha 2-adrenoceptor blockade on the activity of desipramine in an experimental model of depression was studied by using idazoxan and 1-(pyrimidinyl)piperazine (1-PP). The two drugs antagonists at these receptors, were studied for their ability to modify the effect of repeated treatment with the antidepressant, desipramine in the forced swimming test. Idazoxan (0.03, 0.3 and 3 mg/kg s.c.) and 1-PP (0.3 and 3 mg/kg p.o.) given with the last dose of a 7-day schedule of 10 mg/kg i.p. desipramine significantly reduced the effect of the latter on immobility. On its own neither drug modified the immobility time of rats at any dose. Infusion of various concentrations of idazoxan (1.6, 8 and 40 ng/microliters) in the rat locus coeruleus (LC), dose dependently antagonized the effect of desipramine without causing any appreciable change in motor behavior or immobility. The effect of idazoxan (8 ng/microliters) infusion in the LC was completely prevented by administering 6 micrograms 6-hydroxydopamine in the same region 12 days earlier. It thus appears that alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test, presumably by an effect on noradrenaline-containing cells in the LC. The question of how blockade or activation of alpha 2-adrenoceptors, both in the LC and in other sites, could influence antidepressant activity is discussed.     

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.     

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.     

Effects of neuroleptics displaying antidepressant activity on behavior of rats in the forced swimming test

Levomepromazine, thioridazine and cis-chlorprothixene, neuroleptics with antidepressant activity, trans-chlorprothixene, the therapeutically inactive isomer of chlorprothixene, clozapine, an atypical neuroleptic, and imipramine, a classical antidepressant, were studied in the forced swimming test in rats after single or chronic administration. Levomepromazine (1.5 mg/kg), clozapine (2.5 and 5.0 mg/kg) and imipramine (10 mg/kg) after single administration, 1 hr before the test, shortened the period of the immobility. After chronic administration only imipramine (10 mg/kg orally, twice daily, for 10 days) diminished the immobility. Levomepromazine, thioridazine, cis-chlorprothixene and trans-chlorprothixene (1.5 mg, orally, twice daily, for 10 days), 15-18 hr after the last dose did not influence the immobility, although the behavioral parameters in the open field test were not depressed. It is concluded that the forced swimming test is not a suitable pharmacological model for revealing antidepressant activities of certain neuroleptics that are useful in treating certain forms of human depression.     

Allopregnanolone reduces immobility in the forced swimming test and increases the firing rate of lateral septal neurons through actions on the GABAA receptor in the rat

Since allopregnanolone reduces the total time of immobility in rats submitted to the forced swimming test, we decided to explore whether this neuroactive steroid shares other antidepressant-like actions, such as increasing the neuronal firing rate in the lateral septal nucleus (LSN). In order to discard the influence of the oestrous cycle on immobility and on the firing rate of LSN neurons, all Wistar rats used in the study underwent ovariectomy before treatments. A group of rats received different doses of allopregnanolone (0.5, 1.0, 2.0 and 3.0 mg/kg, i.p.) 1 hour before being forced to swim in order to identify the minimum effective dose diminishing immobility. None of the tested doses of allopregnanolone produced significant changes in motor activity in the open-field test. The minimum dose of allopregnanolone producing a significant reduction in the total time of immobility (p<0.05) against the vehicle was 1.0 mg/kg, while 2.0 mg/kg and above also increased the latency to the first period of immobility (p<0.05). The minimum effective dose of allopregnanolone reducing immobility in the forced swimming test (1.0 mg/kg) significantly (p <0.05) produced a higher (twofold) neuronal firing rate in LSN neurons, but did not produce any change in septofimbrial nucleus neurons, which fired at a rate similar to that of vehicle-treated rats. The pretreatment with the non-competitive GABAA receptor antagonist, picrotoxin (1.0 mg/kg), blocked the aforementioned actions of allopregnanolone on both immobility and LSN firing rate. In conclusion, allopregnanolone produces an antidepressant-like effect in the forced swimming test, associated with an increase in the LSN neuronal firing rate, seemingly mediated by the GABAA receptor.     

Effects of histamine H3 receptor ligands in experimental models of anxiety and depression

Histamine H₃ receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H₃ receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated IP with the histamine H₃ receptor agonist R-α-methylhistamine (10 mg/kg) or the histamine H₃ receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the IP administration of R-α-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H₃ receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-α-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-α-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2–10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H₃ receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H₃ receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied. Received: 1 July 1998/Final version: 8 September 1998     

Cholinergic drug effects on antidepressant-induced behaviour in the forced swimming test

The contribution of anticholinergic effects to the action of desipramine and nomifensine was investigated in the forced swimming test in rats. The immobility time was reduced by high doses of atropine (10-25 mg/kg i.p.) and scopolamine (1.5 mg/kg i.p., 1 and 0.5 h before the test, respectively) and was unaffected by physostigmine (0.25-0.5 mg/kg i.p., 1 h before the test). Unlike atropine (25 mg/kg), scopolamine (1.5 mg/kg) increased motor activity (open-field). The anti-immobility effect of i.p. desipramine (20 or 30 mg/kg) and nomifensine (2.5 or 5 mg/kg), administered 24, 5 and 1 h before the test, was potentiated by scopolamine (0.5-1.0 mg/kg) and antagonized by physostigmine (0.25-0.5 mg/kg). The brain levels of desipramine and nomifensine were unaffected by scopolamine or physostigmine. Motor performance was impaired in rats treated with physostigmine and desipramine whereas hypermotility was observed in rats treated with scopolamine and nomifensine. The anti-immobility effect of atropine (25 mg/kg) and scopolamine (1.5 mg/kg) was not antagonized by physostigmine (0.5 mg/kg). These results indicate that anticholinergic mechanisms alone are not sufficient to influence immobility time and suggest that the cholinergic system may control, the neural circuitry upon which desipramine and nomifensine act to reduce immobility time.     

Clonidine causes antidepressant-like effects in rats by activating alpha 2-adrenoceptors outside the locus coeruleus.

Clonidine, 0.05, 0.1 and 0.5 mg/kg administered i.p. as a three-injection course but not as single doses, significantly reduced the immobility of rats in the forced swimming test. Doses of 0.1 and 0.5, administered the same way, significantly reduced activity in an open field. The effect of 0.05 and 0.5 mg/kg clonidine on immobility was prevented by 1 mg/kg idazoxan, an alpha 2-adrenoceptor antagonist, but not by 3 mg/kg prazosin, which blocks alpha 1-adrenoceptors. An infusion of 6 micrograms/microliters 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, did not modify the effect of 0.05 and 0.5 mg/kg clonidine on immobility. Chronic treatment with 5 mg/kg i.p. desipramine or 0.1 mg/kg i.p. clonidine, twice daily for 15 days, did not modify the effect of a three-injection course with 0.1 mg/kg clonidine. It is suggested that clonidine exerts antidepressant-like effects on rats in the forced swimming test by acting on central alpha 2-adrenoceptors outside the locus coeruleus and presumably postsynaptically to noradrenaline-containing neurons. No tolerance or sensitization of the clonidine effect was found after chronic treatment with desipramine or clonidine. These findings are of significance for the effects of clonidine in subgroups of depressed patients.     

Anti-depressant action of melatonin in chronic forced swimming-induced behavioral despair in mice, role of peripheral benzodiazepine receptor modulation

The possible antidepressant effect of physiological and pharmacological doses of melatonin was investigated in the Porsolt forced swimming-induced behavioral despair test. The duration of immobility period of BALB/c and C57BL/6J mice during a 6-min swim test was measured at noon (11:00–12:00 h), early dark (20:00–21:00 h) and at midnight (1:00–2:00 h), respectively. The circadian time cycle did not alter the duration of immobility in either strains of mice. Similarly, exogenously administered melatonin (10–1000 μg/kg50 nM to 5 μM/mouse), a dose that could act on high affinity melatonin receptors, did not modify the duration of immobility period at any of the time intervals studied in either strains of the mice. This suggested that neither circadian variation influenced the duration of immobility period of BALB/c and C57BL/6J mice nor at physiological doses melatonin showed any anti-depressant action. Acute administration of higher doses of melatonin (2.5–10 mg/kg) failed to induce any anti-depressant activity in mice which were subjected to forced swimming test for the first time. However, daily administration of melatonin (2.5–10 mg/kg) prior to swimming test significantly reversed the increase in immobility period that was observed on chronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAergic drugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test. The anti-depressant action of melatonin was sensitive to reversal by peripheral BZ receptor antagonist, PK11195. Whereas, flumazenil failed to reverse the anti-depressant action of melatonin, thereby suggesting that central BZ receptor were not involved in its action. In conclusion the study showed that at pharmacological doses melatonin has anti-depressant action in chronic forced swimming-induced despair behavior by an action involving peripheral BZ receptors.     

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test

Rationale: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. Objectives: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Methods: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Results: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Conclusions: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems. Received: 4 February 1999 / Final version: 2 June 1999