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PubMed2001

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test.

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Effect of imipramine on brain D-1 and 5-HT-2A receptors in a chronic unpredictable stress model in rats.

Chronic unpredictable stress (CUS) model of depression is one of the well validated animal models of depression. In this paper, we report the results of investigations into dopaminergic D-1 and serotonergic 5-HT-2A receptors in the brain of rats subjected to CUS procedure and treated chronically with imipramine. We have examined the dopaminergic D-1 ([3H-SCH 23390) in the limbic area and serotonergic 5-HT-2A ([3H-ketanserin) receptors in the cerebral cortex by a saturation radioligand binding method in rats subjected to CUS paradigm, imipramine, both CUS and imipramine and control animals. CUS procedure resulted in a significant 36% increase in the D-1 receptor density in the limbic system, which was attenuated by chronic imipramine treatment. Also a 21% increase in the density of 5-HT-2A receptors in the cerebral cortex induced by CUS was reduced by chronic imipramine treatment. The present data indicate that the increases in the density of brain D-1 and 5-HT-2A receptors of rats subjected to CUS, which are "normalized" by imipramine, might be involved in the pathophysiology of "animal depression" (and, thus, in pathophysiology of human depression) and in the mechanism of antidepressant therapy.

Animals↗

PubMed1975

Influence of some antidepressant drugs on the circulatory system. I. Imipramine.

Imipramine exerts various, dose-related, effects on arterial blood pressure. A distinct hypotensive effect occurs at dosses of at least 0-5 mg/kg body weight. At lower dosage, the action of the drug is biphasic. In experiments in situ with animals, imipramine diminished amplitude of the heart's contractions. Controlled respiration during experiments with imipramine reduced its toxicity. In decapitated animals the action of imipramine was the same as in animals with intact central nervous system. At all dosage levels its effect on blood pressure was biphasic. Blockade of the sympathetic, parasympathetic system and vegetative ganglia had no significant effect on the circulatory response to imipramine. Low doses of imipramine potentiated the hypertensive effect of noradrenaline, and high doses weakened it.

Animals↗

PubMed2005

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.

Animals↗

PubMed2006

[The effect of isoflurane anesthesia on dopamine release in rat striatum with pretreatment of imipramine].

BACKGROUND: Isoflurane anesthesia has been shown to have a possibility of inducing a biphasic effect on dopamine release in rat striatum. The current study investigated the effect of isoflurane on the extracellular concentration of dopamine in the rat striatum pretreated by a classical antidepressant, imipramine, using in vivo microdialysis techniques. METHODS: After intraperitoneal administration of 5 and 10 mg x kg(-10 of imipramine, the rats were anesthetized with 1 and 2.5% isoflurane inhalation. The control group was injected saline. Isoflurane anesthesia increased the extracellular concentration of dopamine metabolites without any change in dopamine concentration. RESULTS: Under pretreatment of 5 mg x kg(-1) of imipramine, the effect of isoflurane on the change in dopamine and its metabolites was preserved. Whereas, 10 mg x kg(-1) of imipramine pretreatment induced a marked increase in the extracellular concentration of dopamine when only 1% isoflurane was applied but not with 2.5% isoflurane. In the rat administered 10 mg x kg(-1) of imipramine, anesthesia-induced increase of 3-methoxytyramine was not found. CONCLUSIONS: Our previous investigation suggested that the isoflurane anesthesia has a biphasic effect on dopamine release in rat striatum under pargyline pretreatment. The same effect was shown in the rat administered imipramine. Isoflurane anesthesia might modify dopaminergic neural activity and release of neurotransmitters through different and complex ways.

Anesthesia, Inhalation↗

PubMed1991

[Inhibitory effects of imipramine on intracellular Ca2+ mobilization in rat fronto-cortical cultured neurons].

We examined the effects of imipramine on cytosolic Ca2+ concentration ([Ca2+]i) in rat fronto-cortical cultured neurons exposed to various treatments (high K+, acetylcholine; ACh or noradrenaline; NA) using the Ca(2+)-sensitive dye fura-2. Imipramine inhibited high K(+)-induced [Ca2+]i increases with IC50 value of 71 microM, after washing the cells free of the drug, these effects were abolished. ACh and NA increased [Ca2+]i in a dose-dependent manner. Imipramine also inhibited ACh- and NA-induced [Ca2+]i increases with IC50 values of 3.7 and 4.1 microM, respectively. These results indicated that imipramine inhibited the high K(+)-induced [Ca2+]i increase by the blockade of voltage-dependent Ca2+ channels, and the ACh- and NA-induced ]Ca2+i increases by the blockade of muscarinic receptors and alpha 1-adrenoceptors, respectively. Moreover, imipramine abolished the [Ca2+]i oscillations, periodic fluctuations in [Ca2+]i were observed in a few cells only. Because [Ca2+]i oscillations were mediated by not only voltage-dependent Ca2+ channels, but also various receptors, it was likely that the inhibition of [Ca2+]i oscillations by imipramine was due to the blockade of voltage-dependent Ca2+ channels, muscarinic receptors or alpha 1-adrenoceptors.

Acetylcholine↗

PubMedDate not supplied

The effect of imipramine on isolated skeletal muscle preparations.

Imipramine (2-10 microng/ml) noncompetitively inhibited acetylcholine responses of the frog rectus abdominis muscle, and markedly inhibited the contracture produced by carbachol and succinylcholine without affecting the contracture produced by KCl, caffeine, and chlorpromazine. The twitch responses to indirect and direct stimulation of the rat phrenic nerve-diaphragm and the frog sciatic nerve-gastrocnemius were first augmented and then depressed markedly and irreversibly by imipramine (5-20 microng/ml). The indirect stimulation was inhibited earlier and to a greater degree than the direct stimulation. The blockade in the nerve-sartorius developed and progressed quickly without prior augmented responses, and with a parallel time course for indirect and direct stimulation. On the frog rectus, physostigmine antagonised whereas d-tubocurarine and CaCl2 increased the imipramine-induced inhibition. In the nerve muscle preparations, physostigmine, CaCl2 and KCl did not affect the neuromuscular blockade produced by imipramine; tubocurarine (0.05 microng/ml) markedly increased the blocking effect of imipramine (20 microng/ml) on the rat phrenic nerve-diaphragm. The results have been discussed in relation to the memberane stabilizing and the calcium releasing actions of imipramine.

Acetylcholine↗

PubMed1990

Effects of histaminergic drugs on the contractile activity of smooth muscles from imipramine-treated rats.

The effects of histaminergic drugs and their interaction with adrenergic neurotransmission in smooth muscles from imipramine-treated animals were studied. The experiments were performed on isolated preparations (vasa deferentia and segments from terminal ileum and proximal colon) from male Wistar rats which were given imipramine, 10 mg/kg orally, twice daily for 2 weeks. The effects of histamine (HIST) and diphenhydramine (DPH) on the tone and phasic contractions of ileum and colon were investigated. The action of the histaminergic drugs on the vas deferens contractions evoked by low-frequency electrical stimulation (LFES) was also studied. In imipramine-treated animals LFES elicited much stronger contractions than in the controls. HIST modulatory action on the LFES-induced contractions was not markedly changed. The potentiation of the vas deferens contractions by DPH was strongly decreased. Imipramine reduced the potentiating action of both histaminergic agents on the ileum phasic contractions as well as the enhanced effects of HIST applied 10 min after DPH. Imipramine had opposite effects on the potentiating action of HIST and DPH on the colon phasic contractions: the HIST effects were slightly reduced and those of DPH were enhanced. After H1-blockade HIST exerted a stronger potentiation of the colon spontaneous contractions as compared to the controls. Present data show that imipramine could change the modifying action of histaminergic agents on adrenergic neurotransmission and also their interaction with histaminergic receptors in smooth muscles.

Animals↗

PubMed1989

[Changes in the circulation and blood catecholamines following electrical stimulation to the infraorbital nerve in rabbits which had received a long-term administration of imipramine].

The purpose of the present study was to observe how circulation would be affected with imipramine. An experimental model of rabbits which had received a long-term administration of imipramine was prepared, and electrical stimuli were applied to the infraorbital nerve to determine: i) the circulatory responses (the mean femoral arterial blood pressure, the regional cortical blood flow in the marginal gyrus measured by a hydrogen clearance method and the carotid blood flow measured by using an electromagnetic blood flow meter): and ii) the catecholamine levels in the femoral arterial blood and in the brain tissues, and the imipramine level in the left-ventricular blood measured by high performance liquid chromatography. After norepinephrine (4 micrograms/kg) was infused into the femoral vein, the electrical stimuli were applied to the infraorbital nerve to determine circulatory responses. The rabbits were initially anesthetized with a mixture of nitrous oxide, oxygen and halothane during the operation for the placement of the measuring device. During measurement the animal were lightly anesthetized with the same gas under spontaneous respiration through a tracheal cannula. The data obtained from the group of rabbits to which imipramine had been administered were compared with those obtained from the control group. The results of the present study are as follow: 1) The cerebral blood flow in both groups increased significantly (p less than 0.05, p less than 0.01) following the application of the electrical stimuli to the infraorbital nerve. When the same stimuli applied after norepinephrine had been infused into the femoral vein the cerebral blood flow was further increased (p less than 0.01). 2) The natural norepinephrine level in the femoral arterial blood increased significantly (p less than 0.001) in the imipramine group following the application of the electrical stimuli. 3) Although the natural norepinephrine level in the femoral arterial blood increased following the application of the electrical stimuli, the mean femoral arterial blood pressure and the carotid blood flow decreased significantly (p less than 0.05) in the imipramine group. It is considered that the decreases of the blood pressure and the cardiac blood flow were probably due to the reduction of the cardiac output.

Animals↗

PubMedDate not supplied

Circadian activity rhythms in hamsters and rats treated with imipramine in the drinking water.

Circadian rhythms of locomotor activity were recorded in 15 male golden hamsters and in 15 rats. The animals were exposed alternatingly to a variety of conditions with either light-dark cycles (LD) or continuous illumination (LL). The hamsters were split into two groups: 7 animals received plain water, and 8 animals water together with imipramine hydrochloride. The rats received plain water or water with imipramine in alternation. In all animals the addition of imipramine resulted in a reduction of water uptake and in a concomitant reduction of the daily amount of activity. Otherwise, no significant effects of imipramine could be observed: in LD, the phase-angle differences between rhythm and zeitgeber were not changed by imipramine, and, in the hamsters, the upper limits of entrainability and the rates of re-entrainment were identical in the two groups of animals; in LL, the period of the free-running rhythm was slightly lengthened by imipramine in the hamsters, but remained unchanged in the rats.

Administration, Oral↗

PubMed1985

[Autoradiographic study of the ontogeny of the imipramine receptors in the cerebral cortex of rats].

Localization of 3H-imipramine binding sites in the cerebral cortex of rats was studied on the 19th day of prenatal development and on the 3d and 14th days of postnatal ontogenesis. Imipramine was injected into rats on days 17, 18 and 19 of gestation. The maximal imipramine receptor density was found in cortex layers IV-V. The therapeutic doses of imipramine provoked marked stimulation of the formation of imipramine receptors on the 3d day of postnatal development. However, on the 14th day the 3H-imipramine binding level was stabilized.

Animals↗

PubMed1986

Single-site model of the neuronal 5-hydroxytryptamine uptake and imipramine-binding site.

Recently, a high affinity [3H]imipramine-binding site of protein nature that appeared to be related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated. This binding site was only part of desipramine-displaceable [3H]imipramine binding, which contained a significant amount of additional binding not related to 5-HT uptake. The present study further investigates the [3H]imipramine-binding site of protein nature in the rat brain. Displacement by 5-HT and 6-methoxytetrahydro-beta-carboline (6-MeO-TH beta C) revealed monophasic displacement patterns with 60% displaceable binding. This binding fraction was abolished by protease treatment of the brain tissue prior to binding assay. Saturation studies of [3H]imipramine binding (1-30 nM) in rat cortex showed that the binding displaced by 30 microM 5-HT [Bmax 322 +/- 16 fmol/mg of protein, Kd 4.17 +/- 1.07 nM (means +/- SE)] was not different from the binding displaced by 1.0 microM norzimeldine (Bmax 349 +/- 15 fmol/mg of protein, Kd 4.47 +/- 1.07 nM) or 30 microM 6-MeO-TH beta C (Bmax 439 +/- 28 fmol/mg of protein, Kd 5.49 +/- 1.09 nM). When 100 microM desipramine was used in saturation studies, the binding was different from that displaced by 5-HT with Bmax 608 +/- 42 fmol/mg of protein and Kd 6.68 +/- 1.09 nM. Both displacement and saturation studies in which two displacing agents were combined indicated that most of the binding competed by 5-HT (30 microM) and norzimeldine (1.0 microM) is identical. Similarly, the binding displaced by 5-HT or norzimeldine is subsumed within 6-MeO-TH beta C (30 microM)-displaceable binding. Lesion studies with parachloroamphetamine, a selective toxin for 5-HT terminals, which resulted in a 83% reduction of [3H] 5-HT uptake ( [3H]noradrenaline uptake unaffected), abolished cortical [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine. (greater than 80% reduction). However, with 100 microM desipramine as displacer, 40% of the binding remained in lesioned animals. The [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine was sodium dependent, and an increase in NaCl concentration from 0 to 120 mM resulted in a 10-fold increase in affinity without effect on Bmax, whereas no change in binding was observed with increasing concentrations of LiCl.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Cardiovascular effects of imipramine and bupropion in depressed patients with congestive heart failure.

There has been a long-standing concern over the cardiovascular effects of tricyclic antidepressants, particularly in patients with preexisiting cardiac disease. Recent studies have demonstrated that imipramine causes no deleterious effect on ejection fraction as determined by radionuclide angiography in patients with impaired left ventricular function (LVF). However, the high rate of severe orthostatic hypotension induced by imipramine makes use of the drug problematic in these patients. Bupropion is a new antidepressant of the aminoketone class which is structurally unrelated to the tricyclics and which is relatively free of cardiac side effects in healthy depressed patients. We compared imipramine and bupropion in 10 depressed patients with impaired LVF in a random, double-blind crossover study. Neither imipramine nor bupropion adversely affected ejection fraction or other indices of LVF. However, as previously reported, severe orthostatic hypotension requiring discontinuation of drug developed in 50% of patients on imipramine. This difficulty did not occur with bupropion. From a cardiac perspective, bupropion may offer a safe alternative to imipramine in depressed patients with congestive heart failure.

Aged↗

PubMed1988

The role of a transmembrane pH gradient in uptake and release of imipramine and haloperidol in synaptosomes.

By using the methylamine method, the influence of a transmembrane pH gradient on the distribution of the antidepressant imipramine and the neuroleptic haloperidol was assessed in synaptosomes. Resting synaptosomes concentrated methylamine 8- to 9-fold at pH 7.4, as compared with a 400- to 600-fold concentration of the lipophilic weak bases imipramine and haloperidol. Ignoring compartmentation, the methylamine ratio is consistent with an internal pH of 6.5. Weak acid partition yielded an internal pH of 7.1. In agreement with the pH partition hypothesis, elevation of the internal pH by NH4Cl reduced whereas internal acidification enhanced imipramine and haloperidol uptake. Release of both drugs could also be elicited with excess K+ or veratridine. The underlying mechanism is a depolarization-induced rise of the internal pH by 0.12 to 0.25 units. In polarized synaptosomes, about 70% of the uptake of imipramine and haloperidol depended on the transmembrane pH gradient. A predominant localization in synaptic vesicles in situ is derived from the proportional release of methylamine, imipramine, and endogenous dopamine by nigericin. It is concluded that the acidic internal pH plays an important role for the passive concentration of lipophilic bases like imipramine and haloperidol in the brain, thereby profoundly influencing the extra- and intracellular free concentrations. Binding to cellular constituents contributes to internal accumulation. Especially high concentrations are attained in acidic vesicles.

Animals↗

PubMed1987

Binding of imipramine to platelet membranes is lower in alcoholics than in controls.

The principal finding in this study was that imipramine binding to platelet membranes was lower in a group of ten alcoholics abstinent a mean of 11 days than in a group of ten age- and sex-matched controls (p less than 0.004). The mean (std dev, std error) for imipramine binding in the alcoholic subjects was 718 (110, 37) femtomol/mg platelet membrane protein and 931 (173, 58) femtomol/mg protein in the control subjects. Imipramine binding did not correlate significantly with age, severity of alcoholism, days of abstinence from alcohol, or severity of depression in the alcoholic subjects. Severity of depression did, however, correlate with severity of alcoholism (r = 0.678, p less than 0.03) in the alcoholic subjects in this study. The results of this preliminary experiment suggest that chronic ethanol exposure might affect either the synthesis of imipramine binding sites in megakaryocytes or the structural environment of imipramine binding sites in the platelet membrane. The significance of lower imipramine binding in alcoholics, all of whom expressed some depressive symptoms, remains to be established.

Adult↗

PubMed1985

A comparison of fluoxetine, imipramine, and placebo in patients with major depressive disorder.

The efficacy and safety of fluoxetine were compared with those of imipramine and of placebo in a 6-week randomized double-blind parallel study of patients with major depressive illness. Mean values for all efficacy measurements were improved over baseline with fluoxetine and imipramine treatment (p less than .001). More fluoxetine patients completed the study than did imipramine or placebo patients. Predominant adverse experiences reported by imipramine patients were dry mouth and dizziness/lightheadedness. Predominant adverse experiences reported by fluoxetine patients were drowsiness/sedation and excessive sweating. In a subsequent 48-week open-label study, the predominant adverse experience in the fluoxetine group was excessive sweating and in the imipramine group was still dry mouth. In this study, fluoxetine relieved the symptoms of major depressive illness effectively and significantly better than placebo and was better tolerated than imipramine.

Adult↗

PubMed1985

[Inhibitors of reverse serotonin uptake and of specific imipramine binding in human blood plasma].

Human blood plasma contains low-molecular substances that inhibit in a dose-dependent manner both high-affinity specific binding of imipramine and reverse serotonin uptake by platelets. Incubation of human blood plasma with alumina was made use of to extract and study these imipramine-like inhibitors. The extract obtained from human blood plasma inhibited imipramine binding and reverse uptake of serotonin with median inhibitory concentrations of 0.18 +/- 0.1 and 0.36 +/- 0.15 mg/ml, respectively. After gel chromatography on Biogel P-2 the elution profile of the extract showed 2 major peaks of reverse serotonin uptake and imipramine binding inhibition and 3 additional peaks of reverse serotonin uptake inhibition, which did not have any considerable effect on imipramine specific binding. It is assumed that endogenous inhibitors of imipramine binding and reverse serotonin uptake are involved in the development of affective disorders.

Adult↗

PubMed1979

The effects of imipramine treatment on the unconditioned alimentary behavior and classical conditioned salivary reactions in dogs.

In Experiment I the effect of imipramine treatment on the unconditioned food intake in dogs was tested. In Experiment II imipramine was injected in dogs in which classical conditioned salivary reflexes had been previously elaborated. Both conditioned and unconditioned salivation were decreased. The differentiation of conditioned salivation to CS+ and CS- was disturbed during the imipramine treatment, due to the prominent decrease of conditioned salivary reflexes to CS+ and also increase of reactions to CS-. Imipramine treatment produced only a slight decrease of food intake. In most dogs of both groups the increase of general arousal and improvement of social contact was observed. The variability of the imipramine effect on particular parameters of alimentary behavior depended on the individual characteristics of each dog. It is concluded that in the evaluation of the effect of imipramine one should take into consideration its differential influences on various motor, autonomic and emotional, central as well as peripheral components of alimentary behavior and characteristics of the individual subjects.

Animals↗