Comparison of the effects of desmethylimipramine on behavior in the forced swim test in peripubertal and adult rats

Although there are similarities in the clinical presentation of adolescent and adult depression, there are differences in the biological correlates and the responses to pharmacologic treatment. Selective serotonin reuptake inhibitor-type antidepressants are efficacious, but tricyclic antidepressants have no or limited efficacy in treating adolescent patients. The forced swim test (FST) is a widely accepted animal model used to screen drugs for antidepressant activity. It is not known whether tricyclic antidepressants produce differential effects in peripubertal and adult rats, as is found in adolescent and adult humans. The objective of the study was to test the hypothesis that the tricyclic antidepressant desmethylimipramine (DMI) would show efficacy in the FST in adult, but not in peripubertal, rats. Thirty-day-old (peripubertal) and 112-day-old (young adult) rats were pretreated with saline or DMI and subjected to the FST. DMI reduced the amount of floating behavior and increased the amount of climbing behavior in both peripubertal and adult rats. Thus, the tricyclic antidepressant DMI has antidepressant-like activity in peripubertal rats in the FST. Owing to the discrepancy between the preclinical and clinical data, the predictive validity of the FST might need to be reevaluated across different age groups.     

Effects of acute and chronic treatment with magnesium in the forced swim test in rats

The antidepressant-like activity of magnesium, the non-specific N-methyl-D-aspartate glutamate receptor antagonist, in the mice forced swim test was demonstrated previously. In the present study, the effects of this biometal were studied in the rat forced swim test. Magnesium (MgCl2) at doses ranging from 15 to 50 mg Mg/kg reduced the immobility time in the forced swim test, thus exerting antidepressant-like activity. To evaluate tolerance to this effect, we also performed experiments with the following acute/chronic magnesium treatment schedule: chronic saline and saline challenge at 0.5 h before behavioral experiments (S + S), chronic saline and magnesium challenge (S + Mg), chronic magnesium and saline challenge (Mg + S), chronic magnesium and magnesium challenge (Mg + Mg). The antidepressant-like effect of magnesium was demonstrated in the group treated acutely with magnesium (S + Mg) but not in the chronically treated group (Mg + S) and (Mg + Mg). It is interesting to note that in Mg + Mg group serum concentration of magnesium was quite similar to the S + Mg group (6.44 vs. 6.08 mg/100 ml, respectively), which displayed antidepressant-like effect. The results confirmed that magnesium administered acutely induced the antidepressant-like effects also in rats. However, contrary to mice, chronic treatment with magnesium induced tolerance to this effect in rats.     

Influence of sildenafil on the antidepressant activity of bupropion and venlafaxine in the forced swim test in mice

Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s-citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20 mg/kg, but not 5 and 10 mg/kg, significantly increased the anti-immobility action of bupropion (20 mg/kg). The antidepressant activity of venlafaxine (2 mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20 mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant-like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies.     

Influence of acute or chronic administration of ovarian hormones on the effects of desipramine in the forced swim test in female rats

Rationale

Gender may influence antidepressant (AD) treatment outcome. In order to address this preclinically, the potential effects of ovarian hormones on AD treatment in ovariectomized female rats were investigated.

Objectives

In the first study, the effect of acute administration of estrogen and progesterone on the antidepressant-like effects of desipramine (DMI), a selective norepinephrine reuptake inhibitor (SNRI), was investigated in the forced swimming test (FST). In the second study, the effect of chronic administration of these hormones on the effects of chronically administered DMI was investigated.

Results

In the acute study, the hormones blocked the effects of DMI in the FST as demonstrated by the absence of either a reduction in immobility or an increase in climbing behavior in animals treated with DMI in combination with the hormones. Concentration-response experiments on hippocampal synaptosomes revealed no changes in the Km or Bmax for uptake of ³H-NE in hormone-treated rats. In the chronic study, the antidepressant-like effects of DMI in the FST were not blocked by chronic administration of hormones. Interestingly, the hormones affected the serum concentrations of DMI. These levels were significantly higher in animals receiving 10 or 15 mg/kg/day in hormone-treated rats as compared to those with placebo.

Conclusions

Acute administration of hormones blocked the effects of DMI (given three times over 24 h) in the FST. However, chronic administration of these hormones failed to block the effects of chronically administered DMI (at a dose that produces clinically relevant serum concentrations).     

Effect of citalopram in the modified forced swim test in rats

The present study examined the effect of citalopram (7.5 and 15 mg/kg) in the modified forced swim test (FST) in Wistar rats, in comparison to the effect of desipramine at the same doses. The citalopram at both doses increased swimming behavior, at the cost of climbing and immobility. The administration of desipramine increased climbing behavior while immobility counts were decreased. The modified FST is indeed more sensitive than the conventional FST in describing precisely the behavioral effects of antidepressant drugs, allowing to roughly estimate the contribution of individual neurotransmitter system to the mechanism of action of the studied drug.     

Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in rats

The effects of neuropeptide-Y were examined in the forced swim model of depression in rats. Following a 15-min preswim, four groups of rats were given three intracerebroventricular (i.c.v.) injections of neuropeptide-Y (0.5, 5, or 10 microg) or saline over a 24-h period. Several behaviors were subsequently measured during a 5-min forced swim. Neuropeptide-Y treatment dose dependently increased swimming and decreased immobility. The pattern of results is consistent with that produced by serotonergic antidepressant drugs in this model.     

Inhibition of catecholamine synthesis depresses behavior of rats in the holeboard and forced swim tests: influence of previous chronic stress.

Catecholaminergic pathways in the brain are activated during stress and are presumably involved in the control of physiological and behavioral changes triggered by stress. When repeatedly stressed, adaptive changes have been observed in catecholaminergic activity in the brain. In the present experiment, it was assessed whether or not chronic exposure to immobilization (IMO) altered the influence of catecholamines on behavior in the holeboard and forced swim test by administering alpha-methyl-p-tyrosine (an inhibitor of catecholamine synthesis). Adult Sprague-Dawley rats were used. Chronic stress amortiguated the inhibitory effect of acute IMO on some but not all behaviors in the two tests. Whereas previous chronic IMO exacerbated the effects of the drug on struggling and immobility in the forced swim test, no change in response to the drug as a consequence of chronic IMO was observed in the holeboard test. The present data suggest that chronic IMO-induced changes in the catecholaminergic control of some behaviors might be related to depression-like states in rats. The actual physiological meaning of these changes and the specific receptors involved remain to be elucidated.     

Stressors affect the response of male and female rats to clomipramine in a model of behavioral despair (forced swim test)

Aim of the present study was to evaluate the effects of physical stressors (electric foot-shocks) on effect of the antidepressant drug, clomipramine and plasma corticosterone levels in male and female rats tested in a model of behavioral despair (forced swim test,). Male and female rats of the Wistar strain were injected with clomipramine (50 mg/kg, i.p.) or saline. A group of animals also received electric shocks of different intensity and duration of 24, 5 and 1 h before being subjected to forced swim test. At the end of behavioral procedures, vaginal smears were assessed in all female animals and data on immobility time were plotted according to the ovarian cycle phase. After decapitation, corticosterone plasma levels were measured by radioimmunoassay in both male and female rats. Application of mild shocks (5 ms, 0.1 mA) significantly reduced immobility time in forced swim test of untreated male rats and augmented clomipramine effect on this parameter. Moderate shocks of higher intensity or duration (5 ms, 1.0 mA) also resulted in decreased immobility time of untreated male rats, but in reduced effect of clomipramine treatment. Furthermore, application of severe shocks (10 ms, 1.0 mA) increased the immobility time in untreated animals and totally abolished clomipramine effect in forced swim test. Untreated non-shocked female rats in proestrous and estrous phases exhibited a longer immobility time as compared to diestrous animals. Immobility time appeared to be generally higher when mild, moderate or severe shocks were applied prior to behavioral testing in proestrous and estrous animals, while the behavioral response of diestrous and metestrous animals did not differ from that of controls. Clomipramine effect on immobility time was generally reduced by application of shocks of every strengths. Stress-induced plasma corticosterone levels surge correlated with intensity and duration of shocks in both male and female rats, but clomipramine treatment generally blunted the hormonal response. However, severe shocks were followed by a surge of plasma corticosterone levels in both male and female clomipramine-treated rats.

These results demonstrate that duration and intensity of stressful stimuli may deeply affect the behavioral response of rats in forced swim test and influence clomipramine effect in this behavioral model depending on gender-based variables, probably of the hormonal type. Plasma corticosterone levels correlate with the behavioral response to clomipramine treatment suggesting that reactivity of hypothalamus–pituitary–adrenal axis to stress may be involved in the antidepressant effect of this drug.     

Sex-dependent effects of fluoxetine and triiodothyronine in the forced swim test in rats.

The effects of triiodothyronine (T3) and fluoxetine, administered separately and combined, on behavior of male and female rats in the forced swim test, a procedure for screening antidepressant-like activity, were determined. There were no consistent effects of low doses of fluoxetine (5 mg/kg) or T3 (20 microg/kg), administered daily for 2 weeks. Fluoxetine administered daily at 10 mg/kg for 7 days reduced immobility and increased active behaviors in male rats, but had no effects in female rats. The effects of fluoxetine in male rats were not potentiated by T3. In female rats, T3 at 100 microg/kg given daily for 7 days decreased immobility and increased swimming when these were measured 72 h after the last injection, but not when measurements were performed at an earlier time point. These results provide some support from an animal model for the efficacy of T3 as antidepressant therapy in female patients, but do not provide support for the augmentation and acceleration effects seen clinically when T3 is used in conjunction with established antidepressants such as fluoxetine.     

Antidepressant-like effect of nicotinamide adenine dinucleotide in the forced swim test in rats

Nicotinamide adenine dinucleotide (NADH), a cosubstrate for energy transfer in the oxidative phosphorylation, has supposedly beneficial effects on central nervous system (CNS)-related diseases, e.g., shown in an open study with depressive patients. To our knowledge there are no data concerning the efficacy of NADH in animal tests. Acute effects of NADH and the precursor nicotinamide, compared to controls and the antidepressants desipramine and fluoxetine, were examined in the forced swim test (FST) in Wistar rats. NADH, but not nicotinamide, reduced immobility and increased swimming behaviour in the FST, with a minimum effective dose of 5 mg/kg. NADH-induced behavioural profile was similar to fluoxetine, but different from desipramine. Since NADH did not induce hyperlocomotion but even decreased motor activity in the open field test, the antidepressant-like effect cannot be attributed to an increase in motor activity. These data support an antidepressant potential of NADH.     

Antidepressant-like effects of baclofen and LY367385 in the forced swim test in rats

Baclofen, an agonist of GABA(B) receptors and LY367385, an antagonist of mGluR(1a) receptors, given alone or jointly, reduced the immobility time in the forced swim test but only their separate administration enhanced motility in group of rats without hypoxia. Short-term hypoxia (2% O2, 98% N2, 4 min) did not change the activity of the rats in the forced swim test and it did robustly decrease the motility of these animals. LY367385 reduced the immobility time in the forced swim test but induced locomotion in rats subjected to hypoxia. The obtained results indicated that baclofen and LY367385 given alone or jointly induce an antidepressant-like effect in the forced swim test but only LY367385 possesses such activity in rats that had undergone hypoxia. Both tested ligands are involved in the motility of rats, however, LY367385 influences hypolocomotion hypoxia-induced.     

Inhibition of the CRF1 receptor influences the activity of antidepressant drugs in the forced swim test in rats

Naunyn-Schmiedeberg's Archives of Pharmacology - Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are...     

Selegilin exerts antidepressant-like effects during the forced swim test in adrenocorticotropic hormone-treated rats

In the present study, we investigated the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after the administration of selegiline, a selective and irreversible monoamine oxidase (MAO)-B inhibitor. Single and repeated administration of selegiline significantly decreased the duration of immobility in normal rats. When selegiline was administered for 15 days, we observed a significant decrease in immobility in rats treated with ACTH for 14 days. The immobility-decreasing effect of selegiline was blocked by nafadotride, a selective dopamine D(3)-receptor antagonist in normal and ACTH-treated rats. Selegiline may be useful in an animal model of depressive conditions resistant to tricyclic antidepressant treatment via the dopamine D(3) receptor.     

Paradoxical effects of chronic corticosterone on forced swim behaviours in aged male and female rats.

The effects of chronically administered corticosterone on forced swim test and open field test behaviours were explored in aged male and female rats. Though corticosterone has typically been associated with depressive behaviours, recent data have suggested a putative antidepressive effect of corticosterone. The current study used the forced swim test as a model of antidepressant efficacy in order to explore this. Aged male and female rats received either corticosterone (20 mg/kg) or the vehicle for 10 days before testing in the forced swim test, then for an additional 3 days before testing in the open field test. On day 11, each animal was individually tested on the duration of swimming, immobile, and struggling behaviours, and on day 14, for the display of rearing and line crossing behaviours. Results revealed that corticosterone significantly increased swimming and decreased immobility behaviour in females, but failed to do so in males. Additionally, there was a main effect of corticosterone on struggling behaviour such that it decreased it in males. There were no effects of corticosterone or sex on open field test behaviours, suggesting that the present findings are not accounted for by a general effect of corticosterone on motor behaviour. Overall, the data suggest that chronically administered corticosterone possesses effects that are sex-specific, and that it may exert mildly antidepressive effects in females, but the opposite effects in males. These data are consistent with emerging evidence that corticosterone may play a paradoxical antidepressive effect.     

Antidepressant-like activity of anthocyanidins from Hibiscus rosa-sinensis flowers in tail suspension test and forced swim test

Aim:

Flowers of Hibiscus rosa-sinensis Linn (Malvaceae) popularly known as “China-rose flowers” contain flavonoids. Flavonoids have been found to have antidepressant activity. The aim of the present study is to evaluate the antidepressant activity of flavonoids in H. rosa-sinensis flowers with possible involvement of monoamines.

Materials and Methods:

Anti-depressant activity of methanol extract containing anthocyanins (MHR) (30 and 100 mg/kg) and anthocyanidins (AHR) (30 and 100 mg/ kg) of H. rosa-sinensis flowers were evaluated in mice using behavioral tests such as tail suspension test (TST) and forced swim test (FST). The mechanism of action involved in antidepressant activity was investigated by observing the effect of extract after pre-treatment with low dose haloperidol, prazosin and para-chlorophenylalanine (p-CPA).

Results:

Present study exhibited significant decrease in immobility time in TST and FST, similar to that of imipramine (10 mg/kg, i.p.) which served as a positive control. The extract significantly attenuated the duration of immobility induced by Haloperidol (50 μg/ kg, i.p., a classical D₂-like dopamine receptor antagonist), Prazosin (62.5 μg/kg, i.p., an α₁-adrenoceptor antagonist) and p-chlorophenylalanine (100 mg/kg, i.p., × 3 days; an inhibitor of serotonin synthesis) in both TST and FST.

Conclusion:

It can be concluded that MHR and AHR possess potential antidepressant activity (through dopaminergic, noradrenergic and serotonergic mechanisms) and has therapeutic potential in the treatment of CNS disorders and provides evidence at least at preclinical levels.KEY WORDS: Anthocyanidins, dopamine, flavonoids, quercetin, serotonin     

The effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice

BackgroundAccording to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2–4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10 mg/kg) on the activity of antidepressant agents from diverse pharmacological groups.MethodsThe antidepressant-like effect was assessed by the forced swim test in mice.ResultsIfenprodil potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (5 mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5 mg/kg) or tianeptine (15 mg/kg).ConclusionThe concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.     

Influence of the phosphodiesterase type 5 inhibitor, sildenafil, on antidepressant-like activity of magnesium in the forced swim test in mice

Magnesium, which acts as an antagonist of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, exerts antidepressant-like activity in animal models of depression. The present study was undertaken to elucidate the influence of sildenafil, a phosphodiesterase type 5 inhibitor, on the anti-immobility action of magnesium in the forced swim test in mice. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. Serum and brain magnesium levels were assayed spectrophotometrically. Magnesium at a dose of 30 mg/kg, i.p. significantly decreased the immobility time while sildenafil (5, 10 and 20 mg/kg, i.p.) in a dose-dependent manner reduced the antidepressant-like activity of magnesium. The co-administration of magnesium with sildenafil at the highest dose entirely abolished the antidepressant-like effect of magnesium and caused a statistically significant increase in immobility duration as compared to the control group. Combination of magnesium with sildenafil resulted in a potent reduction (80%) of locomotor activity and pharmacokinetic studies showed a significant increase of magnesium concentration in serum (as compared to magnesium treatment alone) without changes within brain tissue in mice treated with magnesium and sildenafil. When given alone, sildenafil caused a significant increase in magnesium levels in both serum and brain. Our results indicate that a simultaneous treatment with magnesium and sildenafil results in hypermagnesemia in laboratory animals. However, the mechanism underlying this effect remains elusive.     

Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats

The dopamine D2/D3 receptor agonist pramipexole has clinically been proven to improve depression or treatment-resistant depression. However, the involvement of the dopamine receptor system on the effect of pramipexole on depression remains unclear. We examined the influence of pramipexole on the duration of immobility during the forced swim test in normal and adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which pramipexole acts in this model was explored specifically in relation to the site of action through the use of microinjections into the intramedial prefrontal cortex and nucleus accumbens. Pramipexole (0.3–1 mg/kg) significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by L-741,626, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, in normal rats. Furthermore, infusions of pramipexole into the intranucleus accumbens, but not the medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Taken together, the results of these experiments suggested that pramipexole, administered into the intranucleus accumbens rather than the medial prefrontal cortex, exerted an antidepressant-like effect on ACTH-treated rats via the dopaminergic system. The immobility-decreasing effect of pramipexole may be mediated by dopamine D2 and D3 receptors.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.