Effects Of Imipramine Research Articles

Effect of imipramine on ether à-go-go potassium channel (Kv1.10) expression in DU145 prostate cancer cells.

In recent studies, it has been reported that ion channels play an important role in cancer formation. Therefore, it is possible that the use of pharmacological agents targeting ion channels will allow the development of new strategies for cancer treatment. In this study, we investigate the effect of imipramine on Eag1 channel expression in DU145 prostate cancer cells. Culture cellswere divided into 4 groups as the control, 10, 50 and 75µM imipramine. Eag1 channel currents and conductivity were determined by whole-cell patch-clamp technique and gene expression by real time-polymerase chain reaction (RT-PCR). Current records were taken before (at 0th minute, as control) and 10min after imipramine administration to the cells. It was observed that all three doses of imipramine significantly reduced Eag1 currents and conductivity compared with the control. However, the differences between dose groups were not significant. Similarly, Eag1 channel protein expression was found to be significantly reduced for all three doses of imipramine compared with the control group, but there was no significant difference in gene expression between dose groups. Obtained results suggested that imipramine has the potential to be used as a pharmacological agent targeting the Eag1 channel in the treatment of prostate cancer.

The effect of fluoxetine and imipramine on the improvement of depressive-like behaviors and HPA axis (hypothalamic-pituitary-adrenal cortex) activity – an animal model

Depression is one of the most common mental disorders and numerous medications are used to reduce the psychotic symptoms. The aim of this study was to evaluate the therapeutic effects of two commonly used antidepressant drugs, including Fluoxetine (Flx) and Imipramine (IMP) to improve depressive-like behaviors as well as the activity of hypothalamic pituitary-adrenal cortex (HPA). Methods: Initially, 40 adult male albino rats weighing 25±5g were selected for this experimental study. The animals were kept or housed in separate cages under standard temperature (25±1°C) and light-dark conditions (12 hours light/dark cycle). Rats were divided into four groups: each group containing 10 rats, control, immobility stress, Flx receiver, and IMP receiver. Polyethylene restrainer was used to induce immobility stress for 14 days. Finally, the parameters of IMT, ST, serum levels of corticosterone and glucose were evaluated in all four mentioned groups. Results: The results showed that the patient group's immobility time (IMT) increased compared to the control group, but the patient group's swimming time (ST) decreased compared to the control group. The effect of immobility stress on IMT, ST, corticosterone, and glucose factors in the patient group was increasing and decreasing, respectively, whereas the effect of Flx drug on these mentioned factors was decreasing, increasing and respectively, while the effect of IMP on all mentioned factors was decreasing and increasing, respectively. Conclusion: Based on the results, it can be concluded that the antidepressant Flx and IMP drugs have various effects on the HPA activity, and the application of immobility stress causes depressive-behavior. Moreover, Flx is more effective than IMP in the treatment of depressive behaviors

Upregulation of the mGlu5 receptor and COX-2 protein in the mouse brain after imipramine and NS398, searching for mechanisms of regulation

Imipramine belongs to a group of tricyclic antidepressants (TCAs). It has been also documented that its antidepressant activity connects with the modulation of cytosolic phospholipase A2 (cPLA2) and arachidonic acid (AA) turnover. Through this mechanism, imipramine can indirectly modify glutamate (Glu) transmission. Additionally, it has been shown that chronic treatment with imipramine results in the upregulation of the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) in the hippocampus of rats. Our previous study revealed that manipulation of the AA pathway via inhibition of cyclooxygenase-2 (COX-2) by selective COX-2 inhibitor (NS398) could effectively modulate the behavior of mice treated with imipramine. Here, we hypothesized that COX-2 inhibition could similarly to imipramine influence mGlu5 receptor, and thus NS398 can modulate the effect of imipramine on Glu. Moreover, such regulation changes should correspond with alterations in neurotransmission. Increased cPLA activity after imipramine administration may change the activity of the AA pathway and the endocannabinoid metabolism, e.g., 2-Arachidonyl-glycerol (2-AG). To verify the idea, mGlu5 receptor level was investigated in the hippocampus (HC) and prefrontal cortex (PFC) of mice treated for 7 or 14 days with imipramine and/or COX-2 inhibitor: NS398. Western blot and PCR analyses were conducted. Moreover, the excitatory (Glu) and inhibitory (gamma-aminobutyric acid; GABA) neurotransmitters were measured using HPLC and 2-AG using ELISA.A time-dependent change in mGlu5 receptor and COX-2 protein level, COX-2 expression, and 2-AG level in the PFC after imipramine administration was found. Up-regulation of mGlu5 receptor after NS398 was found in HC and PFC. A structure-dependent shift between excitatory vs. inhibitory transmission was detected when NS398 and imipramine were co-administered.

Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide

Patients with malignant glioma often suffered from depression, which leads to an increased risk of detrimental outcomes. Imipramine, an FDA‐approved tricyclic antidepressant, has been commonly used to relieve depressive symptoms in the clinic. Recently, imipramine has been reported to participate in the suppression of tumour progression in several human cancers, including prostate cancer, colon cancer and lymphomas. However, the effect of imipramine on malignant glioma is largely unclear. Here, we show that imipramine significantly retarded proliferation of immortalized and primary glioma cells. Mechanistically, imipramine suppressed tumour proliferation by inhibiting yes‐associated protein (YAP), a recognized oncogene in glioma, independent of Hippo pathway. In addition to inhibiting YAP transcription, imipramine also promoted the subcellular translocation of YAP from nucleus into cytoplasm. Consistently, imipramine administration significantly reduced orthotopic tumour progression and prolonged survival of tumour‐bearing mice. Moreover, exogenous overexpression of YAP partially restored the inhibitory effect of imipramine on glioma progression. Most importantly, compared with imipramine or temozolomide (TMZ) monotherapy, combination therapy with imipramine and TMZ exhibited enhanced inhibitory effect on glioma growth both in vitro and in vivo, suggesting the synergism of both agents. In conclusion, we found that tricyclic antidepressant imipramine impedes glioma progression by inhibiting YAP. In addition, combination therapy with imipramine and TMZ may potentially serve as promising anti‐glioma regimens, thus predicting a broad prospect of clinical application.

Inhibition of Neutrophil Secretion Upon Adhesion as a Basis for the Anti-Inflammatory Effect of the Tricyclic Antidepressant Imipramine.

Recent studies demonstrate the involvement of inflammatory processes in the development of depression and the anti-inflammatory effects of antidepressants. Infiltration and adhesion of neutrophils to nerve tissues and their aggressive secretion are considered as possible causes of inflammatory processes in depression. We studied the effect of the antidepressant imipramine on the adhesion and accompanied secretion of neutrophils under control conditions and in the presence of lipopolysaccharides (LPS). As a model of integrin-dependent neutrophil infiltration into tissues, we used integrin-dependent adhesion of neutrophils to the fibronectin-coated substrate. Imipramine inhibited neutrophil adhesion and concomitant secretion of proteins, including matrix metalloproteinase 9 (MMP-9) and neutrophil gelatinase-associated lipocalin (NGAL), which modify the extracellular matrix and basement membranes required for cell migration. Imipramine also significantly and selectively blocked the release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, an enzyme that affects the organization of the extracellular matrix by modifying collagen lysine residues. In contrast, imipramine enhanced the release of ROS by neutrophils during adhesion to fibronectin and stimulated apoptosis. The anti-inflammatory effect of imipramine may be associated with the suppression of neutrophil infiltration and their adhesion to nerve tissues by inhibiting the secretion of neutrophils, which provides these processes.

Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats.

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.

Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro.

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1‑adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D‑ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D‑AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.

Differential impact of imipramine on thapsigargin- and tunicamycin-induced endoplasmic reticulum stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells

The aim of our work was to study effect of antidepressant imipramine on both thapsigargin- and tunicamycin-induced ER stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells. ER stress in SH-SY5Y cells was induced by either tunicamycin or thapsigargin in the presence or absence of imipramine. Cell viability was tested by the MTT assay. Splicing of XBP1 mRNA was studied by RT-PCR. Finally, expression of Hrd1 and Hsp60 was determined by Western blot analysis.Our findings provide evidence that at high concentrations imipramine potentiates ER stress-induced death of SH-SY5Y cells. The effect of imipramine on ER stress-induced death of SH-SY5Y cells was stronger in combination of imipramine with thapsigargin. In addition, we have found that treatment of SH-SY5Y cells with imipramine in combination of either thapsigargin or tunicamycin is associated with the alteration of ER stress-induced IRE1α-XBP1 signalling. Despite potentiation of ER stress-induced XBP1 splicing, imipramine suppresses both thapsigargin- and tunicamycin-induced expression of Hrd1. Finally, imipramine in combination with thapsigargin, but not tunicamycin, aggravates ER stress-induced mitochondrial dysfunction without significant impact on intracellular mitochondrial content as indicated by the unaltered expression of Hsp60.Our results indicate the possibility that chronic treatment with imipramine might be associated with a higher risk of development and progression of neurodegenerative disorders, in particular those allied with ER stress and mitochondrial dysfunction like Parkinson's and Alzheimer's disease.

Imipramine alleviates memory impairment and hippocampal apoptosis in STZ-induced sporadic Alzheimer’s rat model: Possible contribution of MAPKs and insulin signaling

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, associated with several pathophysiological complaints. Impaired insulin signaling in the brain, is one of the important characteristic features of AD which is accompanied by cognitive deficits. According to the multifactorial and complicated pathology of AD, no modifying therapy has been approved yet. Imipramine is a kind of tricyclic antidepressant with reported anti-inflammatory and anti-oxidant effects in the brain. There are controversial studies about the effect of this drug on spatial memory. This study investigates the effect of imipramine on streptozotocin (STZ) induced memory impairment in rats. Pursuing this objective, rats were treated with imipramine 10 or 20 mg/kg i.p. once a day for 14 days. 24 h after the last injection, memory function was evaluated by the Morris water maze (MWM) test in 4 consecutive days. Then, hippocampi were removed and the activity of caspase-3, mitogen activated protein kinases (MAPKs) family and inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1ser307) were analyzed using Western blotting. Results showed that imipramine prevents memory impairment in STZ induced rats and this improvement was accompanied with an increase in ERK activity, reduction of caspase-3 and JNK activity, as well as partial restoration of P38 and IRS-1 activity. In conclusion, our study demonstrated that at least some members of the MAPK family are involved in the neuroprotective effect of imipramine.

Further characterization of the effect of the prototypical antidepressant imipramine on the microstructure of licking for sucrose.

We previously reported that treatment with the prototypical antidepressant imipramine induced a dose-dependent reduction of the ingestion of a 10% sucrose solution, due to reduction of the licking burst number, thus suggesting reduced motivation and/or increased satiation. Importantly, the experimental sessions were performed in an alternate order, either 1-h or 24-h after imipramine administration. The observation that imipramine effect was more pronounced in the "1-h after-treatment" sessions, i.e. at the time of the brain drug Cmax, led us to suggest that it was likely related to brain drug levels at testing time. However, such an experimental design does not allow to rule out the alternative possibility that the observed effect might be due to post-session administration, as previously observed with memantine. To determine whether imipramine-induced decrease of sucrose ingestion could be observed even in absence of post-session administration, we examined the effect of a daily 22 day treatment with imipramine (5, 10 and 20 mg/kg). In the first half of the treatment period all behavioural tests were performed 1-h after administration. In the second half of the treatment period, tests were performed alternatively either 1-h or 24-h after imipramine administration. The results confirm that imipramine reduces sucrose ingestion due to a reduction of the licking burst number. Most importantly, these results demonstrate that this effect does not require imipramine post-session administration, since it was present before the beginning of post-session administrations. This supports the interpretation of the reduction of sucrose ingestion as a consequence of reduced motivation and/or increased satiation. Thus, these findings, taken together with the results of our previous study, might be relevant in explaining the effects of imipramine in models of drug-seeking and in body weight gain reduction in rats, but not in accounting for the antidepressant therapeutic effect. At variance with the results of our previous study, an increase in burst size was present in the first half of the treatment period, which might be interpreted as a prohedonic effect and/or as a compensatory effect.

Intermittent repeated stress but not ketamine changes mice response to antidepressants

Discovery of the rapid antidepressant effect of ketamine has been considered one of the most important advances in major depressive disorder treatment. Several studies report a significant benefit to patients that lasts up to 19 days after treatment. However, concerns arise from the long-term use of ketamine, thus a safe and effective strategy for maintaining its antidepressant effect is still necessary. To this end, our work assessed the effects of imipramine and fluoxetine after repeated ketamine treatment in male mice. Ketamine (30 mg/kg/day for 14 days) induced an anti-immobility effect in the forced swimming (FS) paradigm, detected 1 and 3 days after treatment. Seven days after the last ketamine injection, mice received imipramine (20 mg/kg) or fluoxetine (30 mg/kg). Imipramine and fluoxetine did not change mice's immobility time, regardless of the pre-treatment (saline or ketamine). Since both drugs' anti-immobility effect was demonstrated in the classical FS test, we can assume that repeated exposure to intermittent stress inhibited the antidepressant drugs' anti-immobility effects. Moreover, pre-exposure to ketamine did not counteract stress-induced changes in mice response to antidepressants. Since exposure to forced swim and i.p. injections are stressful to rodents, each stressor's contribution to the blunted response to antidepressants was investigated. Our data demonstrated that both stressors (FS and i.p. injections) influenced the reported effect. In summary, our results showed that exposure to intermittent repeated stress inhibited the anti-immobility effect of imipramine and fluoxetine in mice and corroborated findings demonstrating that exposure to stress can blunt patients' response to antidepressants.

Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway.

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

Inhibition by Imipramine of the Voltage-Dependent K+ Channel in Rabbit Coronary Arterial Smooth Muscle Cells.

Imipramine, a tricyclic antidepressant, is used in the treatment of depressive disorders. However, the effect of imipramine on vascular ion channels is unclear. Therefore, using a patch-clamp technique we examined the effect of imipramine on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Kv channels were inhibited by imipramine in a concentration-dependent manner, with an IC50 value of 5.55 ± 1.24 µM and a Hill coefficient of 0.73 ± 0.1. Application of imipramine shifted the steady-state activation curve in the positive direction, indicating that imipramine-induced inhibition of Kv channels was mediated by influencing the voltage sensors of the channels. The recovery time constants from Kv-channel inactivation were increased in the presence of imipramine. Furthermore, the application of train pulses (of 1 or 2 Hz) progressively augmented the imipramine-induced inhibition of Kv channels, suggesting that the inhibitory effect of imipramine is use (state) dependent. The magnitude of Kv current inhibition by imipramine was similar during the first, second, and third depolarizing pulses. These results indicate that imipramine-induced inhibition of Kv channels mainly occurs in the closed state. The imipramine-mediated inhibition of Kv channels was associated with the Kv1.5 channel, not the Kv2.1 or Kv7 channel. Inhibition of Kv channels by imipramine caused vasoconstriction. From these results, we conclude that imipramine inhibits vascular Kv channels in a concentration- and use (closed-state)-dependent manner by changing their gating properties regardless of its own function.

Imipramine improves visceral sensation and gut barrier in rat models of irritable bowel syndrome

An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 μg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α2-adrenoceptors antagonist), sulpiride (a dopamine D2 receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α2-adrenoceptors, dopamine D2, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.

Proposing the sweet solution preference test as a screening assay for anti-manic effects of mood stabilizers

BackgroundThere is a desperate need for in-vivo behavioral screening tests for anti-manic effects. The frequently used psychostimulant-induced hyperactivity test appears to have lower validity than previously described, but other quick, simple and high throughput tests are currently unavailable. New methodIn the context of modeling the behavioral facets of mania, we previously suggested that the sweet solution preference test (SSP) in naive mice might have predictive validity for screening anti-manic effects. The current study further examined this proposal by testing the effects of lithium, valproate and imipramine on SSP in three strains of mice (male mice from the black Swiss, ICR and C57bl/6 strains) and an exploratory test in females (black Swiss strain). ResultsData demonstrate that lithium and valproate at appropriate dosing schedules significantly and reliably reduce SSP in all three strains (including in females) but that the antidepressant imipramine has no effects. Comparison with existing methodsThe results support the utilization of the SSP as mice screening model for anti-manic effects of drugs with stronger predictive validity compared with other methods. ConclusionsThe SSP is not a comprehensive model for bipolar disorder but it has good predictive validity and strong practical value that can be applied towards simple and fast screening of large numbers of animals, without the need for specialized equipment or complicated/prolonged procedures. We therefore propose that the SSP is an advantageous screening assay for testing novel mood stabilizing drugs for anti-manic properties.

Imipramine exerts antidepressant-like effects in chronic stress models of depression by promoting CRTC1 expression in the mPFC

Recent studies have suggested that CREB-regulated transcription coactivator 1 (CRTC1) plays a role in the pathophysiology of depression. Although imipramine is thought to prevent the reuptake of synaptic serotonin and norepinephrine, its antidepressant-like mechanisms remain elusive. In this study, the effects of imipramine on CRTC1 were studied in several models of depression, including the chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models. We examined whether repeated imipramine administration can reverse the effects of CRS, CUMS and CSDS on CRTC1 expression in both the hippocampus and medial prefrontal cortex (mPFC). Furthermore, genetic knockdown of CRTC1 by CRTC1-shRNA was used to determine whether CRTC1 is necessary for the antidepressant-like effects of imipramine in mice. Our results showed that imipramine reversed the down-regulating effects of CRS, CUMS and CSDS on CRTC1 expression in the mPFC but not the hippocampus, and that CRTC1-shRNA fully abolished the antidepressant-like actions of imipramine in mice. In conclusion, CRTC1 in the mPFC is involved in the antidepressant mechanism of imipramine.

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.

The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat

BackgroundThe aim of our research was to determine the effects of chronic treatment with the atypical antidepressant agomelatine on the expression and activity of liver cytochrome P450 (CYP) in the chronic mild stress (CMS) model of depression, and to compare the results with those obtained for the first-generation antidepressant imipramine.MethodsMale Wistar rats were subjected to CMS for 7 weeks. Imipramine (10 mg/kg ip/day) or agomelatine (40 mg/kg ip/day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3–7 of CMS). The levels of cytochrome P450 mRNA, protein and activity were measured in the liver.ResultsAgomelatine and imipramine produced different broad-spectrum effects on cytochrome P450. Like imipramine, agomelatine increased the expression/activity of CYP2B and CYP2C6, and decreased the CYP2D activity. Unlike imipramine, agomelatine raised the expression/activity of CYP1A, CYP2A and reduced that of CYP2C11 and CYP3A. CMS modified the effects of antidepressants at transcriptional/posttranscriptional level; however, the enzyme activity in stressed rats remained similar to that in nonstressed animals. CMS alone decreased the CYP2B1 mRNA level and increased that of CYP2C11.ConclusionWe conclude the following: (1) the effects of agomelatine and imipramine on cytochrome P450 are different and involve both central and peripheral regulatory mechanisms, which implicates the possibility of drug–drug interactions; (2) CMS influences the effects of antidepressants on cytochrome P450 expression, but does not change appreciably their effects on the enzyme activity. This suggests that the rate of antidepressant drug metabolism under CMS is similar to that under normal conditions.

Microstructure analysis of sucrose ingestion in the course of chronic treatment with imipramine

The analysis of licking microstructure provides measures which might be interpreted in terms of psychological constructs, such as pleasure and motivation, relevant for the interpretation of the effects of antidepressant drugs. The aim of this study was to characterise the effect of the prototypical antidepressant imipramine on the microstructure of licking for a 10% sucrose solution. In particular, ten 30-min sessions were performed in the course of a daily 21 day treatment with imipramine – 5, 10 and 20 mg/kg/die administered intraperitoneally. To interpret drug effects in relation to the presumed concentration of imipramine and its active metabolite desipramine, the experimental sessions were performed in an alternate order either 1-h or 24-h after imipramine administration. In the sessions performed 1-h after drug administration, the results showed a dose-dependent reduction of sucrose ingestion, accounted for by a reduction of the licking burst number. Moreover, reduced intra-burst lick rate and increased latency to lick were observed with the highest doses. Imipramine effect in the sessions performed 24-h after drug administration was similar but less pronounced. These results are consistent with the hypothesis that the reduction of sucrose ingestion might be due to reduced motivation and/or to a potentiation of satiety signals. These effects appear to be related, at least in part, to brain drug levels at testing time, and do not seem related to the mechanisms underlying the antidepressant therapeutic effect. However, these results might be relevant in explaining the effects of imipramine in models of drug-seeking and on body weight.

MGluR5 mediates ketamine antidepressant response in susceptible rats exposed to prenatal stress

BackgroundNew insights have recently been gained into ketamine's potential anti-depressive effects. However, the mechanisms that underlie ketamine's rapid antidepressant activity still remain a mystery. MethodsWe used a rat prenatal stress (PS) model of depression to explore the functional role of mGluR5 in ketamine's rapidly induced antidepressant activity. Effects of the antidepressants imipramine, escitalopram, ketamine, and fluoxetine were compared. AAV-mGluR5 and AAV-shRNA-mGluR5 were constructed to overexpress and knockdown hippocampal mGluR5 respectively. ResultsThis study shows that mGluR5, which is associated with depression-like behaviors, is increased in susceptible rats exposed to prenatal stress, and that ketamine could significantly alleviate these stress-induced effects. RU-38486 down-regulated expression of mGluR5 and up-regulated NR1. MPEP and CHPG also altered expression of both mGluR5 and NR1. Notably, hippocampal overexpression of mGluR5 in wild type rats changed NR1 and PSD-95 expression and induced depression-like behavior that could be blocked by ketamine activity. Further, knockdown of hippocampal mGluR5 in PS-S rats restored normal levels of mGluR5, NR1, and PSD-95, and alleviated depression-like behavior. LimitationsThe entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region. ConclusionThese results suggest that hippocampal mGluR5 may play a key role in mediating the rapid antidepressant effects of ketamine in a prenatal stress model of depression. This provides a novel therapeutic target in clinical treatment of depression.