Chronic Administration Of Imipramine Research Articles

The sinking platform test: a novel paradigm to measure persistence in animal models.

Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to "failure trials," during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.

Pro-cognitive effect of acute imipramine administration correlates with direct interaction of BDNF with its receptor, Trkβ

Given the important role of brain-derived neurotrophic factor (BDNF)-mediated Trkβ signalling in the mechanism of action of antidepressants (ADs), we examined ligand–receptor interactions in the rat cingulate cortex using a proximity ligation assay (PLA) in response to acute and repeated administration of imipramine (IMI), followed by various drug-free periods. Both the acute and chronic administration of IMI increased the BDNF-Trkβ interaction observed 3 h after drug administration. Withdrawal of IMI for 72 h or 7 days did not alter BDNF-Trkβ interaction. A significant reduction in this interaction after chronic IMI administration followed by 21 drug-free days was observed, but it returned to the control value when a new dose of IMI was given after this time. The level of mRNA encoding BDNF or Trkβ did not change in the experimental groups of animals, so one can conclude that alterations in the BDNF-Trkβ interaction depend not on acute vs. repeated treatment with IMI but on the presence of the drug in the body. This effect correlates well with the strong pro-cognitive effect of acute IMI, assessed by the novel object recognition (NOR) test.

Disturbance of prefrontal cortical myelination in olfactory bulbectomized mice is associated with depressive-like behavior

Recent studies have reported that demyelination is associated with the development of depression. Olfactory bulbectomized (OBX) rodents are a useful experimental animal model for depressive disorder. However, little is known about the change in myelination in the brain of OBX mice. To address this question, we observed depressive-like behavior of OBX mice in the tail-suspension test, and determined the quantity of myelin proteins in the prefrontal cortex (PFC), striatum and hippocampus on day 14 or 21 after surgery. The number of nodes of Ranvier paired with the paranodal marker contactin-associated protein (Caspr), as well as the numbers of immature and mature oligodendrocytes in the PFC, were also measured on day 21 after surgery. We examined whether these behavioral and neurochemical changes observed in OBX mice were reversed by chronic administration of imipramine. OBX mice showed depressive-like behavior in the tail-suspension test together with a decrease in the levels of myelin proteins such as myelin basic protein, myelin-associated glycoprotein and cyclicnucleotide phosphodiesterase in the PFC on day 21 after surgery. The number of nodes of Ranvier and mature oligodendrocytes were also decreased in the PFC of OBX mice, while the number of immature oligodendrocytes was increased on day 21 after surgery. However, the number of immature oligodendrocytes in the PFC of OBX mice was decreased on day 35 after surgery. Administration of imipramine (20 mg/kg) for 2 weeks from day 21 after surgery improved OBX-induced depressive-like behavior and abnormal myelination in the PFC. The present findings suggest that the disturbance of myelin function in the PFC may contribute to the pathophysiology of depression, and further support the notion that it plays an important role in the psychological state.

Role of 5-HT1A and 5-HT2C receptors of the dorsal periaqueductal gray in the anxiety- and panic-modulating effects of antidepressants in rats

Antidepressant drugs are first-line treatment for panic disorder. Facilitation of 5-HT1A receptor-mediated neurotransmission in the dorsal periaqueductal gray (dPAG), a key panic-associated area, has been implicated in the panicolytic effect of the selective serotonin reuptake inhibitor fluoxetine. However, it is still unknown whether this mechanism accounts for the antipanic effect of other classes of antidepressants drugs (ADs) and whether the 5-HT interaction with 5-HT2C receptors in this midbrain area (which increases anxiety) is implicated in the anxiogenic effect caused by short-term treatment with ADs. The results showed that previous injection of the 5-HT1A receptor antagonist WAY-100635 in the dPAG blocked the panicolytic-like effect caused by chronic systemic administration of the tricyclic AD imipramine in male Wistar rats tested in the elevated T-maze. Neither chronic treatment with imipramine nor fluoxetine changed the expression of 5-HT1A receptors in the dPAG. Treatment with these ADs also failed to significantly change ERK1/2 (extracellular-signal regulated kinase) phosphorylation level in this midbrain area. Blockade of 5-HT2C receptors in the dPAG with the 5-HT2C receptor antagonist SB-242084 did not change the anxiogenic effect caused by a single acute injection of fluoxetine or imipramine in the Vogel conflict test. These results reinforce the view that the facilitation of 5-HT1A receptor-mediated neurotransmission in the dPAG is a common mechanism involved in the panicolytic effect caused by chronic administration of ADs. On the other hand, the anxiogenic effect observed after short-term treatment with these drugs does not depend on 5-HT2C receptors located in the dPAG.

NS398, a cyclooxygenase-2 inhibitor, reverses memory performance disrupted by imipramine in C57Bl/6J mice

Imipramine has been widely used as an antidepressant in the clinic over the years. Unfortunately, it produces a detrimental effect on memory. At the same time, COX-2 inhibitors engagement in the mechanisms of memory formation, and synapse plastic changes has been well documented. Our previous studies have demonstrated the contribution of cyclooxygenase-2 (COX-2) inhibition to the parameters of the mGluR5 pathway in memory formation. Because chronic administration of imipramine has been shown to affect mGluR5, the purpose of this study was to verify the hypothesis of COX-2 pathway engagement in disrupting effects of imipramine. Imipramine is currently used as a reference compound, and therefore it seems important to decipher and understand mood-related pathways, as well as cognitive changes activated during its use. This study covers the examination of spatial, and motor parameters.To this end, C57Bl/6J mice received imipramine, and NS398 (a COX-2 inhibitor) alone, or in combination for 7 or 14 days. We performed the modified Barnes maze (MBM), modified rotarod (MR) tests, and electrophysiological studies. The harmful effect of imipramine on MBM learning was improved by NS398 use. The same modulatory role of the COX-2 inhibitor in procedural learning in the MR test was found. In conclusion, our data show the involvement of the COX-2 pathway in changes in the long-term memory, and procedural memory of C57Bl/6J mice after chronic imipramine treatment.

Gevo & Praj Industries enter agreement to commercialize renewable isobutanol

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder.The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin.Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597.In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Bimetallic catalytic complexes for the polymerisation of carbon dioxide and an epoxide

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder.The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin.Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597.In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors.

There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder. The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin. Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597. In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.

Pentoxifylline ameliorates chronic stress/high-fat diet-induced vascular wall disease: the role of circulating endothelial progenitor cells.

Depression and cardiovascular disease (CVD) are two faces of one coin. A pro-inflammatory state was previously suggested in the pathology of both diseases. We investigated the effect of chronic administration (2weeks) of imipramine (20mg/kg/day) and pentoxifylline (50mg/kg/day) on behavioral, aortic histological abnormalities, and level of circulating endothelial progenitor cells (CEPCs) in peripheral blood of male Wistar rats exposed to chronic mild stress (CMS) and high-fat diet. Exposure to CMS and high-fat diet induced a depressive-like behavior alongside aortic immunohistochemical changes associated with an increase in aortic TNF-α level. Markers of CEPCs, VEGFR-2 and CD133, were significantly disturbed in aortic sections, as compared to control animals and those exposed to CMS while fed high-fat diet, although flowcytometric analysis did not show any significant changes in the level of CEPCs in peripheral blood. Chronic pentoxifylline treatment was more effective in ameliorating the histological changes and endothelial damage compared to imipramine. Pro-inflammatory cytokines-induced disturbances in CEPCs could constitute a plausible link between depression and atherosclerotic cardiovascular disease. Current antidepressants reduce symptoms of depression without tackling the underlying link between it and cardiovascular disease. Targeting pro-inflammatory cytokines might open a new therapeutic approach to alleviate depression and reduce the risk of mortality from cardiovascular disease.

Role of 5-HT2C receptors of the dorsal hippocampus in the modulation of anxiety- and panic-related defensive responses in rats

The role of 5-HT2C receptors (5-HT2CRs) in the regulation of anxiety has been widely acknowledged. However, conflicting results have been reported on whether stimulation of these receptors increases or decreases anxiety. We here investigated the role of 5-HT2CRs of the dorsal hippocampus (DH) in the mediation of anxiety- or panic-associated defensive behaviors and in the anxiolytic effect of the tricyclic antidepressant imipramine. In the Vogel conflict test, administration of the mixed 5-HT2CR agonist mCPP into the DH of male Wistar rats was anxiogenic, whereas infusions of the more selective agonists MK-212 and RO-600175 were anxiolytic. The 5-HT2CR antagonist SB-242084, on the other hand, was anxiogenic. A sub-effective dose of this antagonist blocked the anxiolytic effect of RO-600175, but not the increase in anxiety observed with mCPP, indicating that the latter effect was not due to 5-HT2CR activation. In full agreement with these findings, MK-212 and RO-600175 in the DH also inhibited inhibitory avoidance acquisition in the elevated T-maze, whereas SB-242084 caused the opposite effect. None of these drugs interfered with escape expression in this test, which has been associated with panic. Chronic administration of imipramine (15 mg/kg, ip, 21 days) caused an anxiolytic effect in the elevated T-maze and light-dark transition tests, which was not blocked by previous infusion of SB-242084 into the DH. Therefore, facilitation of 5-HT2CR-mediated neurotransmission in the DH decreases the expression of anxiety-, but not panic-related defensive behaviors. This mechanism, however, is not involved in the anxiolytic effect caused by imipramine.

BIOCHEMICAL STUDIES OF HIPPOCAMPAL GENE EXPRESSION OF BRAIN-DERIVED NEUROTROPIC FACTOR AND TOLL-LIKE RECEPTOR-4 IN DIABETIC RATS EXPOSED TO CHRONIC STRESS: EFFECTS OF ANTIDEPRESSANT DRUGS

Objective: Depression and diabetes are closely associated in a reciprocal manner, leading to significant morbidity and mortality with an evidence of a pro-inflammatory state underlying pathophysiology of both diseases. Unfortunately, little information is available about the effects of antidepressant drugs on hippocampal brain-derived neurotrophic factor (BDNF) and toll-like receptor-4 (TLR-4) expression in diabetes.Methods: We investigated the effect of chronic administration of fluoxetine (FLU) and imipramine (IMIP) on behavioral, metabolic, and inflammatory abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP. Diabetic and non-diabetic rats exposed to CRS showed a significant increase in hippocampal expression of TLR-4 and pro-inflammatory cytokines alongside a decrease in BDNF expression. FLU and IMIP ameliorated these inflammatory abnormalities.Conclusion: Diabetes mellitus (DM) and chronic stress induced a depressive-like behavior associated with an increase in hippocampal expression of TLR-4, tumor necrosis factor-α, and interleukin-1ß with a significant correlation to decreased BDNF expression. FLU and IMIP showed comparable effects regards the improvement of depressive and inflammatory abnormalities associated with DM.

BIOCHEMICAL STUDIES OF HIPPOCAMPAL GENE EXPRESSION OF BRAIN-DERIVED NEUROTROPIC FACTOR AND TOLL-LIKE RECEPTOR-4 IN DIABETIC RATS EXPOSED TO CHRONIC STRESS: EFFECTS OF ANTIDEPRESSANT DRUGS

Objective: Depression and diabetes are closely associated in a reciprocal manner, leading to significant morbidity and mortality with an evidence of a pro-inflammatory state underlying pathophysiology of both diseases. Unfortunately, little information is available about the effects of antidepressant drugs on hippocampal brain-derived neurotrophic factor (BDNF) and toll-like receptor-4 (TLR-4) expression in diabetes.Methods: We investigated the effect of chronic administration of fluoxetine (FLU) and imipramine (IMIP) on behavioral, metabolic, and inflammatory abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP. Diabetic and non-diabetic rats exposed to CRS showed a significant increase in hippocampal expression of TLR-4 and pro-inflammatory cytokines alongside a decrease in BDNF expression. FLU and IMIP ameliorated these inflammatory abnormalities.Conclusion: Diabetes mellitus (DM) and chronic stress induced a depressive-like behavior associated with an increase in hippocampal expression of TLR-4, tumor necrosis factor-α, and interleukin-1ß with a significant correlation to decreased BDNF expression. FLU and IMIP showed comparable effects regards the improvement of depressive and inflammatory abnormalities associated with DM.

Comparative Analysis of Responses to Administration of Imipramine to Catatonic GC and Wistar Rats

Chronic administration of imipramine (7.5 mg/kg) led to stable reactions consisting of decreases in excitability in response to sound stimuli in Wistar rats and a phasic behavioral response in rats of the catatonic strain GC. Wistar rats showed increases in frontal cortex and striatum noradrenaline levels in Wistar rats, while there were no differences in noradrenaline levels in any of the brain structures studied in GC rats. Increases in plasma corticosterone levels in GC rats decreased in response to the antidepressant. In intact GC rats, triglyceride levels and body weight were lower and relative adrenal weight was higher than in Wistar rats. It is suggested that there are different pathways mediating the effects of imipramine: in Wistar rats via influences on the noradrenergic system of the brain, which is involved in regulating psychoemotional states, and in GC rats via influences on the functional state of the adrenal cortex.

Alterations in behavioral responses to dopamine agonists in olfactory bulbectomized mice: relationship to changes in the striatal dopaminergic system.

Olfactory bulbectomy (OBX) in rodents is considered a putative animal model of depression. It has been reported that some abnormal behaviors observed in this animal model of depression involve dopaminergic neurons of the mesolimbic pathway. Therefore, we examined changes in the dopaminergic system in the caudate putamen (CPu), nucleus accumbens core (NAcC), and shell (NAcSh) of OBX mice and whether or not these alterations were reversed by chronic administration of imipramine. We observed climbing behavior, which is a dopamine (DA) receptor-associated behavior, to demonstrate changes in the dopaminergic system of the mesolimbic pathway, when mice were administrated either the nonselective DA agonist apomorphine only or were pre-treated with the selective D1 antagonist SCH23390, with the selective D2 antagonist sulpiride, or with the D2/D3 partial agonist aripiprazole (ARI). Moreover, we examined tyrosine hydroxylase (TH) and D1- and D2-like receptor levels in the CPu, NAcC, and NAcSh using immunohistochemistry and autoradiography. The OBX group exhibited significantly enhanced apomorphine-induced climbing behavior, and this enhanced behavior was reversed by administration of sulpiride, ARI, and imipramine but not SCH23390. Moreover, we found a reduction in TH levels in the CPu, NAcC, and NAcSh of OBX mice and an increase in D2 receptor densities in the NAcC of OBX mice. The increased D2 receptor density observed in OBX mice was reversed by imipramine administration. These findings reveal that OBX mice display enhanced DA receptor responsiveness, which may relate to some of the behavioral abnormalities reported in this animal model.

IL-4/10 prevents stress vulnerability following imipramine discontinuation.

BackgroundIdentifying stress vulnerability after antidepressant discontinuation may be useful in treating relapses in depression. Previous studies have suggested significant effects of the immune system as well as the central nervous system (CNS) on progression and induction of major depression. In the present study, we hypothesized that the factors that are not rescued by a tricyclic antidepressant imipramine may be associated with stress vulnerability and relapses in depression.MethodsTo address this issue, mice were exposed to 2 h of restraint stress for 21 consecutive days (chronic restraint stress (CRS)) with or without co-treatment of imipramine. These groups were exposed to an electronic foot shock (FS) as additional stress after imipramine washout. Main targets of stress and antidepressants were analyzed in the hippocampus, lymph node, and serum after a series of depression-like behavior analysis.ResultsIn this study, we found for the first time that mice exposed to CRS with a tricyclic antidepressant imipramine co-treatment, which did not show depressive-like behaviors, were vulnerable to subsequent stressful stimuli compared to the non-stressed mice after imipramine washout. CRS mice with imipramine co-treatment did not show any difference in BDNF, serotonin receptors, pro-inflammatory cytokines, or kynurenine pathway in the hippocampus compared to the controls. However, peripheral IL-4, IL-10, and alternatively activated microglial phenotypes in the hippocampus were not restored with sustained reduction in CRS mice despite chronic imipramine administration. Supplementing recombinant IL-4 and IL-10 in co-Imi+CRS mice prevented the stress vulnerability on additional stress and restored factors related to alternatively activated microglia (M2) in the hippocampus.ConclusionThus, our results suggest that the reduced IL-4 and IL-10 levels in serum with hippocampal M2 markers may be involved in the stress vulnerability after imipramine discontinuation, and the restoration and modulation of these factors may be useful to some forms of depression-associated conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0416-3) contains supplementary material, which is available to authorized users.

Chronic imipramine treatment differentially alters the brain and plasma amino acid metabolism in Wistar and Wistar Kyoto rats

In the present study, the amino acids which have the possibility for the therapeutic efficacy of imipramine were explored and compared between Wistar Kyoto rats, an animal model of depression, and Wistar rats as a normal model. The antidepressant-like effect caused by chronic imipramine treatment was confirmed by decreased immobility in the forced swimming test. Chronic imipramine administration altered the amino acid dynamics in the brain. In the striatum, the concentrations of asparagine, glutamine and methionine were significantly increased by chronic imipramine administration. In the thalamus and hypothalamus, chronic imipramine administration significantly decreased the valine concentration. On the other hand, no amino acid was altered by chronic imipramine administration in the hippocampus, brain stem and cerebellum. In addition, lower concentration of asparagine in the prefrontal cortex of WKY rats was improved by chronic imipramine administration. This amelioration only in WKY rats may be a specific effect of chronic imipramine administration under the depressive state. In conclusion, chronic imipramine administration altered the several amino acid dynamics in the brain. Modification of the amino acid metabolism in the brain may provide a new strategy in the development of therapeutic treatment of major depression.

Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline

ObjectivesThe present study examined the effect of combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together. This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of the tricyclic antidepressant imipramine and the anti-TNF-α pentoxyphylline were investigated. MethodsWistar rats were exposed to either repeated LPS (50μg/kg i.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks of CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes. ResultsAnimals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression showed significant increase in the LPS/CMS model compared to those in saline, LPS or CMS groups. The immunohistochemical findings scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-α gene expression changes induced by the LPS/CMS protocol. ConclusionThis study gave a clue to the neurobiological processes underlying, at least, the subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.

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.

Mechanisms of Neuroprotective Action of Imipramine against Dexamethasone Neurotoxicity

Imbalances in the corticosteroid millieu have been implicated in several neuropsychiatric disorders and neuronal damage. Administration of the high therapeutic doses of the glucocorticoids also induces neuronal damage. We investigated the early electrophysiological manifestations of neurotoxic action of the glucocorticoids. Administration of the toxic doses of dexamethasone (7 and 20 mg/kg) per 24 hours before the electrophysiological studies of rats hippocampal slices induced a dose-dependent decrease of reactivity of the glutamatergic synapses in CA1 pyramidal and granular neurons of dentate gyrus. This neurotoxic action of dexamethasone (at the dose of 7 mg/kg) was reinforced by a co-agonist of NMDA receptors glycine (50 mg/kg) and a administration of single dose of antidepressant imipramine (25 mg/kg). The neurotoxic effect of studied glucocorticoid was decreased by a noncompetitive blocker of the NMDA receptors ketamine (30 mg/kg), an inhibitor of tyrosine phosphoprotein phosphatases sodium ortovanadate (15 mg/kg) and chronic over two weeks administration of imipramine (25 mg/kg). It can be supposed that dexamethasone neurotoxicity is a result of the glutamate accumulation in brain extracellular spaces and intensive activation of NMDA receptors as well as of the inhibiton of providing survival of the neurons tyrosine phosphorilation of the neuronal protein substrates, which produced by the different activators of tyrosine protein kinases. Chronic administration of imipramine probably decreases the both components of dexamethasone neurotoxicity.

Chronic administration of imipramine but not agomelatine and moclobemide affects the nitrergic relaxation of rabbit corpus cavernosum smooth muscle

Sexual dysfunction is a common and underestimated effect of antidepressants. However, the mechanism by which these drugs cause erectile dysfunction is unclear. We investigated the reactivity of the corpus cavernosum of rabbits that were treated with either chronic imipramine, which is a tricyclic agent; agomelatine, which is a melatonergic agonist and serotonin 5HT2c antagonist; or moclobemide, which is a reversible inhibitor of monoamine-oxidase A. Twenty rabbits were randomly divided into four groups: the control group (n=5), the imipramine-treated group (n=5), which received i.p. injections of 10mg/kg/day of imipramine, the moclobemide-treated group (n=5), which received i.p. injections of 20mg/kg/day of moclobemide, and the agomelatine-treated group (n=5), which was orally administered 10mg/kg/day of agomelatine. The reactivities of corpus cavernosum tissue obtained from the antidepressant-treated and the control groups were studied in organ chambers after the animals were subjected to 21 days of drug administration. The acetylcholine-induced endothelium-dependent and the electrical field stimulation (EFS)-induced neurogenic relaxation of the corpus cavernosum of the imipramine-treated group was significantly decreased compared with the control group. However, neither the acetylcholine- nor EFS-induced relaxation was changed in the moclobemide- or agomelatine-treated groups. There were no change in the relaxant response to the nitric oxide (NO) donor sodium nitroprusside and contractile response to KCl between the groups. This study suggests that chronic imipramine treatment but not agomelatine and moclobemide treatments causes significant functional changes in the penile erectile tissue of rabbits and that these changes may contribute to the development of impotence.