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PubMed1999

Neutrophil beta(2)-adrenoceptor function in major depression: G(s) coupling, effects of imipramine and relationship to treatment outcome.

Abnormal beta(2)-adrenoceptor density and beta(2)-adrenoceptor-mediated cyclic adenosine monophosphate (cAMP) responses were inconsistently reported in major depressive disorder. Tricyclic antidepressants downregulate beta-adrenoceptor density and decrease coupling to G(s) protein. Abnormal beta-adrenoceptor coupling may exist in major depressive disorder and may relate to treatment response. We investigated beta(2)-adrenoceptor coupling to G(s) protein in 25 controls, 23 major depressive disorder drug-free patients and 16 major depressive disorder patients after chronic imipramine treatment using agonist displacement experiments. Pretreatment beta(2)-adrenoceptor coupling and density were normal in patients as a whole. Chronic imipramine induced beta(2)-adrenoceptor uncoupling. This effect was observed in treatment responders who had increased beta(2)-adrenoceptor density in the high-conformational state and supercoupling prior to treatment. Beta(2)-adrenoceptor density decreased after imipramine treatment. Treatment non-responders had seemingly normal pretreatment beta(2)-adrenoceptor function, which was not changed by imipramine. Differences in beta(2)-adrenoceptor regulation in major depressive disorder may underlie treatment response. The results indirectly implicate abnormal agonist-mediated beta(2)-adrenoceptor gene expression, protein kinase A, and protein kinase C in major depressive disorder.

Adrenergic Uptake Inhibitors↗
PubMed1981

Determination of clomipramine or imipramine and their mono-demethylated metabolites in human blood or plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the quantitative assay of clomipramine or imipramine and their mono-demethylated metabolites in human blood or plasma is described. After addition of the internal standards, imipramine for clomipramine, desipramine for desmethylclomipramine and conversely, the compounds are extracted from blood or plasma at pH 10 into heptane containing 1% isoamyl alcohol; they are then back-extracted into an acidic aqueous phase and re-extracted at a basic pH into heptane. After evaporation, the residue is dissolved in 300 microliters of mobile phase and 150 microliters is injected. Both drugs and their mono-demethylated metabolites are well separated from the blood or plasma components and the other metabolites on a silica gel column using ethanol--hexane-dichloromethane-diethylamine (30:62:8:5 . 10(-3)) as the mobile phase at a flow-rate of 1.5 ml/min. The limit of sensitivity is 5 ng/ml for clomipramine and imipramine and 10 ng/ml for the corresponding mono-demethylated metabolites. This method has been used to analyse plasma from subjects given therapeutic doses of clomipramine or imipramine.

Chromatography, High Pressure Liquid↗
PubMed1982

Simultaneous analysis of imipramine and its metabolite desipramine in biological fluids.

A method for the simultaneous quantitation of imipramine and its N-demethylated metabolite desipramine at the nanogram level in a single gas chromatograph peak is presented, utilizing gas chromatography-mass spectrometry with selected ion recording. The assay is specific and quantitation is achieved using [2H4]imipramine as the internal standard. The method involves the in situ methylation of desipramine with [2H2]formaldehyde and sodium borohydride to give [2H2]imipramine. Quantitation is then achieved by selected ion recording at m/z 280, 282 and 284, whence the ratio of the ion currents at 280/284 and at 282/284 gives the quantities of imipramine and desipramine respectively.

Desipramine↗
PubMed2003

Associative and nonassociative learning after chronic imipramine in rats.

We investigated effects of 15 daily injections of imipramine (20 mg/kg; in one experiment also 10 and 30 mg/kg). The associative learning types (place learning and object recognition) as well as nonassociative learning (habituation of exploration in an open field and within the object recognition test) were studied. Tests were performed immediately after the final injection (early test) and 24 h after the final injection (late test). The 5-HT(1A), 5-HT(1B/D), 5-HT(2A), beta-adrenergic, D(2) receptors were assayed 24 h after the final injection and the 5-HT(2A) and beta-adrenergic receptors were also measured 60 and 96 h after the final injection. While associative types of learning were impaired in early tests, they remained unaffected in late tests and, while the nonassociative learning (habituation of exploration) remained unaffected in early tests, it was changed in late tests. Measured 24 h after the final injection, imipramine (20 and 30 mg/kg per day) down-regulated the concentration of beta-adrenergic and 5-HT(2A) receptors, while leaving all other measured receptors unaffected. However, only the down-regulation of the 5-HT(2A) receptor outlasted the initial 24-h period after the final injection. On the basis of present and previous results, we interpret the impairment of associative types of learning in early tests as a reflection of anticholinergic effects of imipramine, while the modifications of habituation of exploration in late tests are likely primarily to be mediated by imipramine-provoked regulations of serotonergic receptors.

Animals↗
PubMed2000

Behavioral effects of acute and chronic imipramine in the elevated T-maze model of anxiety.

The elevated T-maze is an animal model of anxiety, consisting of three elevated arms: one enclosed and two open. Inhibitory avoidance of the open arms-representing learned fear-has been related to generalized anxiety and the unconditioned escape from one of the open arms to panic. In the present study, we investigated the effects of acute and chronic (21 days) administration of imipramine (5, 10, and 15 mg/kg; IP) in male Wistar rats that have been previously exposed for 30 min to one of the open arms of the T-maze, 24 h before the test. The results show that this preexposure shortens the first escape latency, without changing open-arm avoidance. Under these experimental conditions, chronic imipramine exerted anxiolytic-like effects in the two elevated T-maze tasks; impaired the acquisition of inhibitory avoidance and prolonged escape latency from the open arms. Acute imipramine enhanced both avoidance and escape latencies. Both acute and chronic imipramine decreased locomotor activity measured in a square arena. The obtained results are compatible with the view that inhibitory avoidance and one-way escape in the elevated T-maze reflect different types of fear/anxiety, that may be related to generalized anxiety and panic disorder, respectively.

Animals↗
PubMed1998

Ethopharmacology of imipramine in the forced-swimming test: gender differences.

Most of the pre-clinical tests used to assay the efficacy of prospective new agents are done with male experimental animals. In this case, a large part of the population is disregarded as is the interaction of the new agent's effects with female hormonal fluctuations. The present study reviews the technical procedures characteristic for the forced-swimming test and the behavioral outcome induced by the testing procedure in males. It also compares the anti-immobility effects of the classic antidepressant imipramine (IMI) in male and female rats using a detailed behavioral scoring. Female rats had vaginal smears done before the beginning of the behavioral testing and were administered with three doses 24 h, 5 h and 1 h before the retest, as were male rats. Tests were videotape-recorded for analysis of the frequency and duration of the behaviors during forced-swimming. Male rats spend around 50% of the time immobile during the retest. There was a significant, dose-dependent decrease in immobility duration and a decrease in head-shakes of male rats treated with IMI. Both active behaviors of climbing and swimming were equally enhanced by the tricyclic antidepressant, climbing behavior comprising 75% of the mobile behaviors. Females showed much lower immobility duration and head-shake frequency during the forced-swimming than males and spent longer periods in mobile behaviors. Imipramine only decreases immobility frequency and head-shakes of females, and increases the escape-type behavior of climbing, decreasing swimming in the middle of the tank. This effect is more noticeable during estrus and proestrus. These results demonstrate the main behavioral differences between males and females in the forced-swimming test. It also elucidates that the effects of imipramine are measurable in males using the duration of the behaviors, while the frequencies of behaviors are modified in females treated with imipramine.

Animals↗
PubMed2001

Oral imipramine and intravenous xylazine for pharmacologically-induced ex copula ejaculation in stallions.

This study is part of ongoing work toward developing pharmacological methods for enhancing and inducing ejaculation in stallions with ejaculatory dysfunction or disabilities that interfere with normal breeding behavior. The objective was to evaluate a treatment regimen involving oral imipramine followed by intravenous xylazine that, in uncontrolled field clinical trials, had shown promise for a higher rate of ejaculation and fewer side effects using a more easily obtained and administered form of imipramine. Eight stallions each underwent eight trials in which treatment consisted of imipramine hydrochloride (3mg/kg, orally in a small portion sweet feed) followed 2h later by xylazine hydrochloride (0.66 mg/kg, intravenously). Trials were conducted with the stallion in a stall. Semen was collected using a collection bag secured over the prepuce with a girth band. Overall, 44 of the 64 attempts (68%) resulted in ejaculation. Within-stallion ejaculation rate ranged from 3 of 8 to 7 of 8 attempts. Interval from xylazine treatment to ejaculation ranged from 1.2 to 14 min. As is typical for induced ejaculations in which imipramine is included in the treatment regimen, ejaculates were of low volume, high sperm concentration, and with a higher total number of sperm than for in copula ejaculates of these stallions. These results represent a modest improvement in rate of ejaculation over previous treatment regimens.

Administration, Oral↗
PubMed1988

Simultaneous determination of imipramine, desipramine and their deuterium-labelled analogues in biological fluids by capillary gas chromatography-mass spectrometry.

A specific, sensitive and accurate method for the determination of imipramine, desipramine and their d4 analogues in biological fluids using d8 analogues as internal standards using capillary gas chromatography-chemical ionization mass spectrometry was developed. Drug concentrations were measured by selected-ion monitoring of the quasi-molecular ions of imipramine and the trifluoro-acetyl derivative of desipramine. The coefficient of variation and relative error at a concentration of about 2 ng/ml in plasma were found less than 10% and 7%, respectively, for both drugs. No isotope effect was observed following the oral administration of an equimolar mixture of imipramine and [2H4]imipramine to a rat.

Animals↗
PubMed1983

Thin-layer chromatographic determination of imipramine and desipramine in human plasma and urine at single-dose levels.

Thin-layer chromatographic methods were up-dated for pharmacokinetic studies of imipramine in plasma and urine. The free parent compound and its free desmethyl metabolite desipramine are determined in plasma. Conjugates of both compounds in urine are cleaved on treatment with glucuronidase/arylsulfatase. Following chromatography, intense yellow derivatives are obtained overnight on standing or by exposure to nitrous gases. Detection is performed in the visible range at 405 nm (plasma) or 460 nm (urine). The methods are selective, accurate and sensitive, with detection limits for plasma of 2 ng/ml imipramine--HCl and 2 ng/ml desipramine--HCl, and 0.06 micrograms/ml total imipramine--HCl and 0.126 micrograms/ml total desipramine--HCl for urine. Pharmacokinetic data from plasma and urine results following single oral doses of 50 mg imipramine--HCl to eight volunteers were computed using one-compartment open models.

Adult↗
PubMed1999

Effect of imipramine on enkephalin-degrading peptidases.

In recent years, there has been increasing evidence of the involvement of the endogenous opioid system in mental depression and its treatment. In this work, we have measured the effect of imipramine on enkephalin-degrading peptidases in several rat brain areas. Aminopeptidase activities have been assayed using Tyr-beta-naphthylamide as substrate and puromycin as selective inhibitor. Dansyl-D-Ala-Gly-Phe(pNO2)-Gly has been the substrate for neutral endopeptidase 24.11. Imipramine in vitro inhibits puromycin-sensitive activities in all brain areas studied, without affecting the rest of the enzymes assayed. However, subacute imipramine treatment increases neutral endopeptidase activity in the hypothalamus and chronic treatment increases this activity in the hypothalamus and the striatum. These results suggest to us that enkephalin-degrading peptidases are involved in the acute and chronic action mechanism of imipramine and reinforce the idea that the central enkephalinergic activity is dynamically changed during the treatment of depressive illness.

Animals↗
PubMed1998

Variations in [3H]imipramine and 5-HT2A but not [3H]paroxetine binding sites in suicide brains.

Both the [3H]imipramine and [3H]paroxetine binding sites and the 5-HT2A receptor were simultaneously determined in frontal cortex, cingulate cortex, hippocampus and amygdala from 17 control subjects and 17 depressed suicide victims. A significant decrease in the maximum binding (Bmax) of [3H]imipramine was observed in the hippocampus of suicide victims as compared to control subjects (160 +/- 25 vs. 328 +/- 52 fmol/mg protein; P = 0.007) without changes in the apparent affinity constant (Kd). Furthermore, a significant decrease in the number of 5-HT2A binding sites, together with a significantly lower Kd, was also observed in the hippocampus of suicides as compared to control subjects (129 +/- 18 vs. 225 +/- 32 fmol/mg protein; P = 0.02 and 0.91 +/- 0.07 vs. 1.38 +/- 0.08 nM, respectively; P = 0.006). [3H]Paroxetine binding did not display modifications between the two groups in either Bmax or Kd from any of the brain regions studied. When all four brain regions were taken together, a down-regulation was noted between presynaptic [3H]imipramine binding and the postsynaptic 5-HT2A receptor (r = -0.40; P = 0.0013) in the control group. This correlation did not appear in the suicide group. No correlation was observed between [3H]paroxetine binding and the 5-HT2A receptor in either control subjects or suicides. Taken together, these results suggest that the 5-HT uptake site measured with [3H]imipramine and the 5-HT2A receptors are reliable markers of serotonergic dysfunction.

Adult↗
PubMed1996

A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat.

The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans.

Animals↗
PubMed2004

Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells.

myo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPgammaS binding to G alpha(q) protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.

Adrenergic Uptake Inhibitors↗
PubMed1988

First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype.

Four rapid extensive metabolizers (EM), four slow EM, and three poor metabolizers (PM) of sparteine were given single intravenous doses of 50 mg imipramine and desipramine. All subjects had previously taken single oral doses (100 mg) of imipramine and desipramine. The first-pass metabolism of imipramine and desipramine ranged from 23% to 73% and 0% to 48%, respectively, and was more pronounced for both drugs in EM than in poor metabolizers. The study suggested saturable 2-hydroxylation of imipramine and desipramine during the first-pass through the liver, especially in EM.

Adult↗
PubMed1991

Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine.

The formation of three oxidative metabolites of imipramine, N-desmethylimipramine (desipramine), 2-hydroxyimipramine, and 10-hydroxyimipramine was studied in microsomes of an extensive metabolizer liver (KDL 26) and of a poor metabolizer liver (KDL 31) and in a homogenate of COS-1 cells in which the P450IID6 complementary deoxyribonucleic acid had been expressed. The following data support the role of P450IID6 in the 2-hydroxylation of imipramine: (1) The formation of 2-hydroxyimipramine was reduced to less than 20% of the control value when microsomes were incubated with serum containing inhibitory antibodies against P450IID6 (anti-LKM1), whereas no effect was seen with regard to formation of desipramine and 10-hydroxyimipramine, (2) quinidine and levomepromazine were potent competitive inhibitors of 2-hydroxylation of imipramine (ki approximately 70 nmol/L, and ki approximately 1 mumol/L, respectively) but had no effect on N-demethylation and 10-hydroxylation, and (3) in the COS-1 cell, homogenate, 10-hydroxyimipramine, 2-hydroxyimipramine, and desipramine were formed at rates of 48, 164, and 256 pmol per hour per milligram of homogenate protein, respectively. The P450 isozymes that are responsible for N-demethylation and 10-hydroxylation of imipramine have not yet been identified.

Antibodies↗
PubMed1997

Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates.

1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes. 2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy. 3. The Bmax value of [3H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls. 4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats. 5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections. 6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.

Adrenergic Uptake Inhibitors↗
PubMed1998

The effect of prolonged treatment with imipramine on the biosynthesis and functional characteristics of D2 dopamine receptors in the rat caudate putamen.

1. The present study shows the effects of imipramine in a single dose (10 mg kg(-1), p.o.) or following repeated (14 days, twice a day) treatment on the level of mRNA coding for D2 dopamine receptors in the rat caudate putamen (CP). Repeated administration of imipramine resulted in the increase of the level of mRNA coding for D2 dopamine receptors. 2. Radioligand binding studies with the D2 receptor agonist, [3H]-N-0437, indicated, that following imipramine administration, the affinity of the agonist for the D2 dopamine receptor significantly increased, though without any alterations in the Bmax. 3. Pharmacological manipulations (by use of forskolin, GppNHp and quinpirole) of the cyclic AMP generating system, ex vivo following administration of imipramine indicated that an up-regulation of factors inhibiting cyclic GMP formation takes place. 4. Most probably it is the D2 dopamine receptor which undergoes functional up-regulation, resulting from the enhancement of its biosynthesis.

Animals↗
PubMed2005

Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine.

Immobilization stress upregulates c-Fos expression in several CNS areas. Repeated stress or the use of drugs can modulate stress-induced c-Fos expression. Here, we investigated in 40 different areas of the rat brain the effects of dexamethasone (SDX, a synthetic glucocorticoid), diazepam (SBDZ, a benzodiazepine), and imipramine (IMI, an antidepressant) on the c-Fos expression induced by restraint stress. Wistar rats were divided into four groups and submitted to 20 days of daily injection of saline (three first groups) or imipramine, 15 mg/kg, i.p. On day 21, animals were submitted to injections of saline (somatosensory, SS), SDX (1 mg/kg, i.p.), SBDZ (5 mg/kg, i.p.), or IMI (15 mg/kg, i.p.) before being submitted to restraint. Immediately after stress, the animals were perfused and their brains processed with immunohistochemistry for c-Fos (Ab-5 Oncogene Science). Dexamethasone reduced stress-induced c-Fos expression in SS cortex, hippocampus, paraventricular nucleus of the hypothalamus (PVH), and locus coeruleus (LC), whereas diazepam reduced c-Fos staining in the SS cortex, hippocampus, bed nucleus of stria terminalis, septal area, and hypothalamus (preoptic area and supramammillary nucleus). Chronic administration of imipramine decreased staining in the hippocampus, PVH, and LC, while increasing it in the nucleus raphe pallidus. We conclude that dexamethasone, diazepam and imipramine differentially modulate stress-induced Fos expression. The present study provides an important comparative background that may help in the further understanding of the effects of these compounds and on the brain activation as well as on the behavioral, neuroendocrine, and autonomic responses to stress.

Analysis of Variance↗