Co-administration Of Imipramine Research Articles

Co-administration of imipramine and doxorubicin reduces the survival rate and body weight of mice.

Doxorubicin (DOX) is a chemotherapeutic agent widely used to treat cancers, particularly breast cancer. DOX has side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity. Imipramine is an antidepressant that increases the release of neurotransmitters. This study aimed to investigate the effect of co-administration of imipramine and DOX on DOX-induced toxicity. Forty female mice (10-12-weeks-old, 30-38 g) were divided into four groups (n = 10 per group). The animals in the control group received a single-dose saline injection. The animals in the DOX group received a single dose of DOX (20 mg/kg) by intraperitoneal (i.p.) injection. The animals in the imipramine group received the drug daily in their drinking water (0.13 mg/mL) for 9 days, starting 1 day before the DOX injection received by the DOX group. The animals in the combination group (DOX+imipramine) received a single dose of DOX (20 mg/kg, i.p. injection), and a daily dose of imipramine in their drinking water (0.13 mg/mL) for 9 days starting 1 day before the DOX injection. The animals were observed daily to record mortality, and their body weights were recorded every alternate day. DOX treatment increased the rate of mortality compared with that for control animals. Imipramine co-administration with DOX increased the rate of mortality significantly (p < 0.05) compared with DOX treatment alone. The mortality rate in both the control and imipramine-treatment groups was zero. DOX co-administered with imipramine resulted in significantly reduced body weight compared with control animals. The combination of DOX and imipramine reduced the survival rate of female mice, suggesting that imipramine increases the toxic effects of DOX.

Imipramine Influences Body Distribution of Supplemental Zinc Which May Enhance Antidepressant Action.

Zinc (Zn) was found to enhance the antidepressant efficacy of imipramine (IMI) in human depression and animal tests/models of depression. However, the underlying mechanism for this effect remains unknown. We measured the effect of intragastric (p.o.) combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice. The effect of Zn + IMI on serum, brain, and intestinal Zn concentrations; Zn transporter (ZnT, ZIP) protein levels in the intestine and ZnT in the brain; including BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) protein levels in the brain were evaluated. Finally, the effect of IMI on Zn permeability was measured in vitro in colon epithelial Caco-2 cells. The co-administration of IMI and Zn induced antidepressant-like activity in the FST in mice compared to controls and Zn or IMI given alone. This effect correlated with increased BDNF and the ratio of pCREB/CREB protein levels in the prefrontal cortex (PFC) compared to the control group. Zn + IMI co-treatment increased Zn concentrations in the serum and brain compared to the control group. However, in serum, co-administration of IMI and Zn decreased Zn concentration compared to Zn alone treatment. Also, there was a reduction in the Zn-induced enhancement of ZnT1 protein level in the small intestine. Zn + IMI also induced an increase in the ZnT4 protein level in the PFC compared to the control group and normalized the Zn-induced decrease in the ZnT1 protein level in the hippocampus (Hp). The in vitro studies revealed enhanced Zn permeability (observed as the increased transfer of Zn through the intestinal cell membrane) after IMI treatment. Our data indicate that IMI enhances Zn transfer through the intestinal tract and influences the redistribution of Zn between the blood and brain. These mechanisms might explain the enhanced antidepressant efficacy of combined IMI/Zn treatment observed in the FST in mice.

Investigation of anti-depressant effect of aqueous and ethanolic extract of Cydonia oblonga in rats

BackgroundDepression is a mood disorder characterized by feeling of sadness, change in sleep and appetite and loss of interest. PurposeThe current study enumerates the intrinsic role of Cydonia oblonga Mill fruit extract in methyl isobutyl ketone induced depression in Rats. MethodsDepression was prompted through injection of methyl isobutyl ketone (MIBK) (100 mg/kg i.p) twice daily for one month. 54 rodents were used in the study. Total 9 groups was included in the present study. After treatment, for 15 days all groups were evaluated for behavioral testing namely Forced Swim Test (FST) and Tail Suspension Test (TST). ResultsThe results presented that of Cydonia oblonga Mill fruit exhibit antidepressant effect. Consequently, a gradual decrease was observed in immobility time (P < 0.05) in contrast to normal group and depressed group. On treatment with aqueous extract of Cydonia oblonga (AECO) and ethanolic extract of Cydonia oblonga (EECO) 200 mg/kg and imipramine 15 mg/kg immobility period gradually fall. Co-administration of imipramine and of Cydonia oblonga Mill extract indicate alteration in biochemical parameters. ConclusionIt was observed in the study that co-administration of aqueous extract of Cydonia oblonga (AECO) and ethanolic extract of Cydonia oblonga (EECO) with small dose of imipramine appears to have therapeutic effect in the treatment of depression.

Behavioral and metabolic effects of S-adenosylmethionine and imipramine in the Flinders Sensitive Line rat model of depression.

Depression is associated with dysregulation of methyl group metabolism such as low S-adenosylmethionine (SAM). We previously reported that Flinders Sensitive Line (FSL) rats, an animal model of depression, had lower concentrations of liver SAM than the control rats, Flinders Resistant Line (FRL) rats. The present study investigated if SAM supplementation may correct liver SAM and behavioral abnormalities in this model. Moreover, we compared one-carbon (C1) metabolites, neurotransmitters, and gastrointestinal (GI) transit in SAM-treated versus imipramine (IMI)-treated animals. FSL rats received vehicle, IMI, SAM, or IMI + SAM (n = 9-10 per group) once daily through oral gavage for 4 weeks; FRL rats received vehicle. Behavior was assessed using standard tests for locomotion, cognition, and depressive-like behavior. Monoamine neurotransmitters and C1 metabolites were measured using UHPLC-ECD and UPLC-MS/MS, respectively. Compared to FRL rats, FSLs had lower liver SAM, higher plasma serotonin, lower hippocampal dopamine and serotonin turnover, and faster GI transit. Behaviorally, FSL rats showed impaired cognitive performance as well as increased depressive-like behavior compared to FRLs. Coadministration of IMI and SAM seemed to have adverse effects on spatial memory. SAM or IMI administration did not reverse C1 metabolites, neurotransmitters, or GI transit in FSLs. Despite low liver SAM in FSL rats, orally administered SAM did not show antidepressant effects in this specific animal model of depression.

Effects of Imipramine and Lithium on the Expression of Hippocampal Wnt 3a and Cyclin D1 in ACTH-Treated Rats

We have shown previously that chronic administration of adrenocorticotropic hormone (ACTH) causes a significant decrease in hippocampal cell proliferation and neurogenesis. This effect in rats treated chronically with ACTH was not influenced by the chronic administration of imipramine, but was reversed by coadministration of imipramine and lithium. The present study was undertaken to further characterize the mechanism underlying the effect of imipramine and lithium on hippocampal cell proliferation and neurogenesis, by investigating the effects of treatment on the expression of brain-derived neurotrophic factor (BDNF), total cyclic adenosine monophosphate response element-binding protein (CREB), and phosphorylated CREB (pCREB) of the CREB signaling system, as well as Wnt 3a and cyclin D1 of the Wnt signaling pathway in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1. Treatment with imipramine and lithium increased the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF, CREB, pCREB, and Wnt 3a did not change in either saline-treated or ACTH-treated rats. These findings suggest that the antidepressant effect of imipramine and lithium in ACTH-treatment-resistant rats may be attributed, at least in part, to an enhancement of cyclin D1 expression.

English

The objective of the study was to determine the effect of nifedipine, imipramine and sertraline on the acute and long-term antidepressant-like responses of furosemide in the forced swim (FST) and tail suspension (TST) tests in mice. Groups of mice of six in each group were treated for 30 days with Tween 80, furosemide (10 mg/kg) + nifedipine (5 mg/kg), furosemide (10 mg/kg) + imipramine (10 mg/kg) and furosemide (10 mg/kg) + sertraline (5 mg/kg), respectively. Experiments were done on day 1, 15 and 31 in the FST and TST. In the FST and TST, results showed that in the test groups, sertraline, imipramine and nifedipine enhanced the reduction of immobility of furosemide significantly when 15-days values were compared with acute values (F(3, 20) = 14.21, P &lt; 0.05, &lt; 0.01) and when 30-days values were compared with 15-days values (F(3, 20) = 24.26, P &lt; 0.05, &lt; 0.01).&nbsp;Duncan multiple range (DMR)&nbsp;post-hoc test showed that the furosemide + sertraline combination gave the most significant response. In conclusion, results show that the antidepressant-like action of furosemide is enhanced in the FST and TST models of depression in mice by co-administration of imipramine, sertraline and nifedipine. &nbsp; Key words: Furosemide, nifedipine, imipramine, sertraline, forced swim test (FST), tail suspension test (TST), antidepressant.

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14 d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14 d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

Effects of imipramine and lithium on the suppression of cell proliferation in the dentate gyrus of the hippocampus in adrenocorticotropic hormone-treated rats.

We examined the influence of chronic adrenocorticotropic hormone (ACTH) treatment on the number of Ki-67-positive cells in the dentate gyrus of the hippocampus in rats. ACTH treatment for 14 days decreased the number of such cells. The administration of imipramine or lithium alone for 14 days had no effect in saline-treated rats. The effect of ACTH was blocked by the administration of imipramine. Furthermore, the coadministration of imipramine and lithium for 14 days significantly increased the number of Ki-67-positive cells in both the saline and ACTH-treated rats. The coadministration of imipramine and lithium normalized the cell proliferation in the dentate gyrus of the hippocampus in rats treated with ACTH.

Combination therapy of imipramine and melatonin: Additive antidepressant effect in mouse forced swimming test

Although there are tools to treat depressive patients, a considerable amount of the cases remains to be untreated. These drug-resistant patients need new drugs or drug combinations to overcome this problem. Thus, the potential synergistic effect of melatonin on a classical drug, imipramine was evaluated in the present study. To test this hypothesis, porsolt swim test, a test predictive of antidepressant-like action, was conducted in mice. Imipramine at doses of 20 and 40 mg/kg caused no alteration and statistically significant reduction in the duration of immobility in forced swim test, respectively. While 5 mg/kg melatonin had no effect, 10 mg/kg melatonin slightly reduced the duration of immobility. When sub-effective doses of imipramine and melatonin (20 and 5 mg/kg, respectively) were co-administered, there was no alteration in responses compared with those of each drug alone. Likewise, the effective dose of melatonin (10 mg/kg) did not cause any increase in responses to 20 mg/kg imipramine. Although combination of imipramine (40 mg/kg) and melatonin (5 mg/kg) did not exert an antidepressant effect above that of imipramine alone, co-administration of the effective doses (10 and 40 mg/kg for melatonin and imipramine, respectively) displayed an additive effect. There were no significant differences between groups in relation with locomotor activity test. The results show that co-administration of imipramine and melatonin exhibits an additive effect and that there seems to be no interaction between the drugs.

Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice

A dysregulated hypothalamic-pituitary-adrenal axis (HPA) has been implicated in major depressive disorder and most commonly used animal models of depression have been shown to elevate circulating levels of plasma corticosterone. We have compared the effects of chronic and acute corticosterone administration on hippocampal cell proliferation (as measured by BrdU immunohistochemistry), hippocampal volume and the appearance of anxiety (light dark box) and depression (forced swim test) like behaviours in CD1 mice. We have also examined the effects of chronic administration of fluoxetine and imipramine on these parameters. Chronic (14 days) but not acute treatment with corticosterone resulted in reduced hippocampal cell proliferation and granule cell layer volume, these changes were prevented by co-administration of imipramine and fluoxetine. In contrast, acute and 7 day but not 14 or 21 day treatment with corticosterone gave rise to a “depressed” phenotype in the forced swim test. Mice treated for 14 days with corticosterone also developed an anxious phenotype in the light dark box but only upon repeated testing. The results presented here demonstrate that moderately elevated corticosterone for a prolonged period is sufficient to induce cellular changes in the hippocampus that are prevented by chronic administration of antidepressants.

Effects of co-administration of antidepressants and monoamine oxidase inhibitors on 5-HT-related behavior in rats

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur during co-administration of a monoamine oxidase (MAO) inhibitor and an antidepressant. We investigated the effects of acute administration of MAO inhibitors and subchronic administration of tricyclic and heterocyclic antidepressants, and a serotonin-noradrenaline reuptake inhibitor (SNRI) on 5-HT syndrome in rats treated with 5-hydroxytryptophan (5-HTP). The irreversible and non-selective MAO inhibitor pargyline, and the reversible and selective MAO-A inhibitor clorgyline, produced increases in 5-HT syndrome in the 5-HTP-treated rats, while subchronic co-administration of imipramine partly intensified and partly attenuated the syndrome, whereas milnacipran only attenuated the syndrome. Co-administration of mianserin partly intensified and partly attenuated the syndrome but the attenuating effect was dominant. Administration of the irreversible and selective MAO-B inhibitor selegiline did not produce any increase in 5-HT syndrome in the 5-HTP-treated rats, compared with the saline control. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with antidepressants. Furthermore, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor selegiline.

Long-term imipramine effects are prevented by NMDA receptor blockade

Long-term exposure to different antidepressant treatments induces increased motor response to central stimulants, due to a selective supersensitivity of dopamine D 2 receptors in the limbic areas. Such an effect is accompanied by down-regulation of dopamine D 1 receptor number, and by a decreased response of adenylyl cyclase to dopamine stimulation in the limbic system. Moreover, the number of β-adrenergic receptors and the response of adenylyl cyclase to β-adrenergic stimulation in the cortex result to be reduced. The present data confirms that imipramine (10 mg/kg twice a day for 3 weeks) produces such effects, and shows that the co-administration of imipramine with MK-801 (administered by a subcutaneously implanted minipump delivering 0.05 mg/kg/day of the compound) prevented the occurence of both the behavioral supersensitivity to quinpirole, and the decrease of dopamine D 1 and β-adrenergic receptor function.

Acceleration of rat brain beta-adrenoceptor subsensitivity following the coadministration of histamine receptor antagonists with imipramine

Systemic administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively blocked by propranolol. This dipsogenic effect was significantly inhibited by the subacute (4 days) administration of imipramine (18.1 mg/kg/day) together with either the H1-histamine receptor antagonist, chlorpheniramine (0.1 or 1.32 mg/kg/day), or the H2-histamine antagonist, cimetidine (1.91 mg/kg/day) or ranitidine (0.60 or 1.51 mg/kg/day). The oral subacute administration of imipramine alone had no significant effect on this behavior. However, chronic ingestion of imipramine alone (21 days) caused a significant reduction in the isoprenaline-induced behavior. It is concluded that the desensitization of central beta-adrenoceptors, as evidenced by inhibition of isoprenaline-induced drinking, can be accelerated following the oral subacute co-administration of imipramine with either H1- or H2-histamine receptor antagonists. It is also seems the central histamine receptors may partially contribute towards the mechanism of antidepressant effect of imipramine.

Down‐Regulation in Peripheral α2‐Receptor Function by the Administration of Imipramine and the Coadministration of Imipramine and Yohimbine

<b>Down‐Regulation in Peripheral α₂‐Receptor Function by the Administration of Imipramine and the Coadministration of Imipramine and Yohimbine</b>

Behavioral evidence for beta-adrenoceptor subsensitivity after subacute antidepressant/alpha 2-adrenoceptor antagonist treatment.

The behavioral consequences of beta-adrenoceptor subsensitivity were investigated by determining whether a physiological response that is mediated by beta-receptors, isoproterenol-induced drinking (IID), would be reduced by subacute antidepressant/alpha 2-antagonist treatment. The coadministration of typical (e.g., imipramine) or atypical (e.g., mianserin) antidepressants with yohimbine or piperoxan twice daily for four consecutive days reduced IID. Both the time course as well as the magnitude of beta-adrenoceptor subsensitivity could be behaviorally demonstrated. In addition, the reduction in IID observed after coadministration of imipramine with yohimbine was a centrally mediated effect since it was observed after systemic (subcutaneous) and central (intraventricular) administration of isoproterenol. These results provide evidence that IID is an appropriate behavioral model to demonstrate beta-adrenoceptor subsensitivity following subacute antidepressant/alpha 2-antagonist treatment.