Imipramine Response Research Articles

Disrupted MEK/ERK signaling in the medial orbital cortex and dorsal endopiriform nuclei of the prefrontal cortex in a chronic restraint stress mouse model of depression

Depression is one of the most prevalent mental illnesses, and causes a constant feeling of sadness and lose of interest, which often leads to suicide. Evidence suggests that depression is associated with aberrant MEK/ERK signaling. However, studies on MEK/ERK signaling in depression have only been done in a few brain regions, such as the hippocampus and mesolimbic reward pathways. Recent studies also implicate the involvement of the prefrontal cortex in depression. Thus, we examined the changes in MEK/ERK signaling in subregions of the prefrontal cortex of C57BL/6 mice by immunohistochemistry using phospho-MEK1/2 (Ser 217/221) and ERK1/2 (Thr202/Tyr204) antibodies. Mice were subjected to 21 consecutive days of restraint stress (for 2h daily), and depression-like behavior was evaluated using a sociability test and tail suspension test. The antidepressant, imipramine (20mg/kg) was injected intraperitoneally 30min before restraint stress exposure. Chronic/repeated restraint stress produced depressive-like behavior, such as increased social avoidance in the social interaction test, and enhanced immobility time in the tail suspension test. This depressive behavior was ameliorated by imipramine. The behavioral changes well corresponded to a decrease in MEK/ERK immunoreactivity in the medial orbital (MO) cortex and dorsal endopiriform nuclei (DEn), which was averted by imipramine, but not in cingulate, prelimbic, infralimbic, and motor cortex. These results suggest that MEK/ERK signaling is disrupted in the DEn and MO subregions of the prefrontal cortex in the depressive phenotype, and that blocking a decrease in activated MEK/ERK is inherent to the antidepressant imipramine response.

Effects of sex and rearing environment on imipramine response in mice

Antidepressant treatments are commonly prescribed, but few studies have been published, even in animal models, on differences in reactivity to antidepressants with respect to rearing environment and sex. Using a mouse model, we investigated the hypothesis that rearing environment (weaning time) and sex could impact responses to imipramine treatment. ICR mice were assigned to four groups for each sex: early weaned saline or imipramine treated, normally weaned saline or imipramine treated. Early weaning was conducted on postnatal day 14. All groups were injected intraperitoneally with drug or vehicle for 2 weeks from the age of 6 weeks and tested in the elevated plus maze to estimate anxiety levels. Hippocampal neurogenesis was also assessed with immunostaining for calretinin and calbindin because it has suggested that neurogenesis is required for the behavioral effects of antidepressants. Imipramine treatment decreased anxiety levels in females, but not in males, in the normal weaning condition. By contrast, the same treatment decreased anxiety levels in males, but not females, in the early weaning condition. Hippocampal changes, which correlated these behavioral responses to imipramine, were seen in the extragranule cell layer: the number of calretinin-positive cells was increased by imipramine in females, but not in males, in the normal weaning condition. In the early weaning condition, however, the treatment was associated with similar changes in males but not in females. The results suggest that rearing environment and sex differences are implicated in responses to imipramine treatment with respect to anxiety behavior and neurogenesis in the hippocampus.

Ozone modulates the effects of imipramine on immobility in the forced swim test, and nonspecific parameters of hippocampal oxidative stress in the rat

Depression has been associated with oxidative stress. There is increased awareness of the role of environmental toxins in the development of mood disorders. Ozone, a pro-oxidant and environmental pollutant, has been noted to have central nervous system effects. We investigated the effects of acute and chronic ozone inhalation on the response of imipramine in the forced-swim test (FST) and on biomarkers of oxidative stress in rat hippocampus. Sprague Dawley rats were exposed to 0, 0.25 or 0.7 ppm ozone per inhalation 4 h daily for either 30 days (chronic) or once (acute). Animals were then injected intraperitoneally with imipramine (10 mg/kg) or saline 24, 5 and 1 h before the forced-swim test. Hippocampal superoxide accumulation and lipid peroxidation were measured. Imipramine evoked an antidepressant-like effect independent of acute or chronic ozone exposure. However, 0.7 ppm acute ozone and 0.25 ppm chronic ozone attenuated the antidepressant-like effects of imipramine. The ozone exposures also elevated hippocampal superoxide accumulation and lipid peroxidation. Importantly, imipramine reversed the lipid peroxidation induced by chronic ozone, thereby preventing cellular damage induced by oxidative stress. Ozone exposure presents a feasible model with etiological validity to investigate oxidative stress in depression and antidepressant action.

Genetic Dissection of the Tail Suspension Test: A Mouse Model of Stress Vulnerability and Antidepressant Response

The tail suspension test (TST) is a mouse screening test for antidepressants. An F2 intercross was derived from NMRI and 129S6 inbred strains (n = 747). Mice underwent standardized TST with 2 sessions: (1) baseline and (2) imipramine (30 mg/kg, intraperitoneally) TST. A whole genome scan of this intercross mapped significant basal TST quantitative trait loci (QTL) on chromosomes (chr) 5 (peak 61 cM, Lod 5.7), 12 (peak 43 cM, Lod 5.2), and 18 (peak 51 cM, Lod 3.0). A suggestive QTL on chr 4 (peak 62 cM; Lod 3.1) overlapped regions containing previously mapped QTLs. For TST imipramine response, QTL were mapped on chr 1, 4, and 5. The chromosome 5 locus affected basal TST, antidepressant immobility response, and tail suspension-induced hyperthermia (TSIH) behaviors. An outbred NMRI F2 population provided further evidence for a chr 5 QTL. This chr 5 region harbors a cluster of gamma aminobutyric acid (GABA)-A receptor subunits and the human syntenic region includes chr 4p, 1p11, 12q24, and 22q11.24. A significant TSIH QTL (Tsih1) mapped on chr 4 near the Leptin receptor (Lepr). These QTL provide potential regions of interest for human genetic studies in stress-diathesis models of psychiatric illness and antidepressant responsiveness.

Effects of imipramine on the expression and development of morphine dependence in mice

In the present study, the effects of imipramine and/or α-adrenoceptor agents on naloxone-induced jumping in morphine-dependent mice were examined. In the first set of experiments, the drugs were used before naloxone injection, to test their effects on the expression of jumping. Administration of imipramine (10–60 mg/kg) 15 min before naloxone increased the number of jumping in mice. Injection of the α 2-adrenoceptor agonist, clonidine (0.1 mg/kg), or α 1-adrenoceptor agonist, phenylephrine (4 mg/kg), themselves neither altered naloxone-induced jumping nor influenced the imipramine response. The α 2-adrenoceptor antagonist, yohimbine (4 mg/kg), itself but not the α 1-adrenoceptor antagonist, prazosin (1 mg/kg), increased jumping and decreased the imipramine effect. In the second set of experiments, imipramine and/or the α-adrenoceptor drugs were injected during the development of morphine dependence. Imipramine (10–40 mg/kg) increased the development of dependence and increased jumping was seen. Clonidine did not influence the imipramine effect. Phenylephrine was lethal in combination with imipramine. Both yohimbine and prazosin decreased the effect of imipramine. Imipramine and phenylephrine but not clonidine, yohimbine or prazosin decreased locomotion. It is concluded an α 2-adrenoceptor mechanism may be involved in the influence of imipramine on the expression and development of naloxone-induced withdrawal signs in mice.

Imipramine-Induced Antinociception in the Formalin Test

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10–40 mg/kg) and 0.5–3 min of swim stress (17°C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through α₂-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.

An exploratory factor analysis of the Tail Suspension Test in 12 inbred strains of mice and an F2 intercross

To explore the genetic dimensions of the stress response in rodents, we tested 12 inbred strains of mice and an F2 intercross ( n=745) on the Tail Suspension Test (TST) and the Tail Suspension-Induced Hyperthermia (TSIH) paradigm. These selected 12 strains provide a representative sampling of the genetic heterogeneity of mousedom. An F2 intercross was derived from NMRI and 129S6 strains, which differ in their responses on the TST. Both inbred strains and F2 mice underwent a standardized protocol of automated TST with two sessions: (1) baseline and (2) imipramine TST. The duration of immobility and the body temperature after TST were recorded. The inbred strains were also tested in the Light–Dark Transition (LDT) test and in the Open Field Test (OFT), measuring the distance traveled, vertical movements, and center time as independent variables. The F2 mice were measured for core temperature after TST (TSIH). High intercorrelations among strain means were found for the LDT and OFT measures. Principal components analysis extracted four factors: “exploratory fear,” body weight, imipramine response on immobility, and “stress reactivity.” These dimensions were largely confirmed in the F2 population with one additional factor: imipramine response on TSIH. The results support a distinction between “stress reactivity” as measured by the TST and “exploratory fear” behavior as measured by the LDT and OFT.

Effect of Alpha-Adrenoceptor Agonists and Antagonists on Imipramine-Induced Antinociception in the Rat Formalin Test

In this study, the effect of central administration of the α-adrenoceptor agents on the antinociception induced by imipramine in the formalin test has been investigated. Intraperitoneal (IP) administration of different doses of imipramine (10–80 mg/kg) and intracerebroventricular (ICV) administration of the α₂-adrenoceptor agonist clonidine (0.05–0.8 µg/rat) elicited a dose-dependent antinociception in the both phases of the test. Furthermore, different doses of clonidine (0.05–0.2 µg/rat) increased the antinociception induced by imipramine (10 and 20 mg/kg). The α₂-adrenoceptor antagonist yohimbine (2 µg/rat, ICV) reduced the response of a low dose imipramine (10 mg/kg, IP) plus different doses of clonidine (0.05, 0.1 and 0.2 µg/rat, ICV), but did not alter the response induced by higher doses of imipramine (20 and 40 mg/kg) alone or in combination with clonidine. Yohimbine by itself elicited no effect. The α₁-adrenoceptor agonist phenylephrine (0.07–1.5 µg/rat) induced antinociception in both phases of the formalin test, but did not alter the imipramine-induced antinociception. The α₁-adrenoceptor antagonist prazosin neither elicited antinociception nor altered the imipramine response. Yohimbine (2 µg/ rat, ICV) in combination with prazosin (0.5 µg/rat, ICV) caused more inhibition of the response of imipramine or imipramine plus clonidine. Therefore, it is concluded that α₂-adrenoceptor mechanism may be involved in the imipramine-induced antinociception.

Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice

Background: The tail suspension test (TST) is a simple screening test for the behavioral effects of antidepressants in rodents. This experiment investigated the interindividual differences in responses to stressful situations measured by duration of immobility in the TST and the effects of imipramine (30 mg/kg intraperitoneally) in reducing immobility among 11 inbred strains of mice. The 11 inbred strains were 129S6/SvEvTac, A/J, AKR/J, Balb/cJ, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ, NMRI, SencarA/PtJ, and SWR/J. Methods: All mice underwent two trials of TST: 1) spontaneous, basal TST and 2) imipramine or saline TST. The duration of immobility was the trait measured during a 6-min test. Results: In the four strains tested, female mice had longer duration of immobility than male mice in basal TST duration of immobility. For male mice ( n = 11 strains), significant strain differences in immobility duration were found for both basal TST and imipramine response TST, with heritability estimates of .31 and .60, respectively. Immobility duration for the DBA/2J, FVB/NJ, and NMRI strains were significantly reduced by imipramine, relative to saline. Surprisingly, this reduction of immobility by imipramine was independent of the basal immobility. Conclusions: These results suggest that the responses on basal TST and the imipramine-mediated responses on TST are mediated by separate genetic pathways.

Effect of α-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice

In this study, the effects of adrenoceptor agonists and antagonists on antinociception induced by imipramine in sciatic-nerve-ligated mice were investigated. The response of different doses of morphine, imipramine and adrenoceptor agonists and antagonists was examined 14 days after unilateral nerve-ligation in the hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), imipramine (10, 20 and 40 mg/kg), the α 2-adrenoceptor agonist, clonidine (0.05, 0.1 and 0.2 mg/kg) or the α 1-adrenoceptor agonist, phenylephrine (2, 4 and 8 mg/kg) induced dose-related antinociception in both intact and nerve-ligated mice. The antinociception induced by morphine but not that of imipramine, clonidine or phenylephrine, in nerve-ligated mice was significantly less than that induced in intact animals. Imipramine in combination with clonidine tends to induce a higher response, but the combination of imipramine with phenylephrine did not lead to significant potentiation. The α 2-adrenoceptor antagonist, yohimbine, reduced the response induced by imipramine or imipramine plus clonidine in intact and nerve-ligated animals. However, the α 1-adrenoceptor antagonist, prazosin, did not alter imipramine response. It may be concluded that imipramine induced antinociception in both intact and nerve-ligated mice through an α 2-adrenoceptor mechanism(s).

GABA B receptor mechanism and imipramine-induced antinociception in ligated and non-ligated mice

This study concerned the effects of GABA B receptor agents on imipramine-induced antinociception in ligated and non-ligated mice in hot-plate test. The data showed that different doses of morphine (3, 6 and 9 mg/kg) induced a dose-dependent antinociception in non-ligated or ligated mice. However, the opioid response was decreased in the ligated animals. Intracerebroventricular (i.c.v.) administration of imipramine (5, 10, 20 and 40 μg/mouse) did not induce antinociception in either non-ligated or ligated mice. However, the response induced in the ligated mice was less than that induced in the non-ligated animals. Intraperitoneal (i.p.) administration of imipramine (10, 20, 30 and 40 mg/kg) induced antinociception in both ligated and non-ligated animals. The responses to the drug were not significantly different in the two groups. Administration of baclofen either i.c.v. (0.125, 0.25 and 0.5 μg/mouse) or i.p. (0.5, 1, 2 and 4 mg/kg) induced antinociception. The response to the drug was not significantly different in ligated and non-ligated mice. I.c.v. administration of a lower dose of baclofen (0.125 μg/mouse) with different doses of imipramine (2.5, 5 and 10 mg/kg) potentiates the response of imipramine. This effect was reduced by i.c.v. injection of GABA B receptor antagonist, CGP35348 [ P-(3-aminopropyl)- p-diethoxymethyl-phosphinic acid] (20 μg/mouse). The higher dose of antagonist (20 μg/mouse) also decreased the response induced by baclofen or imipramine. CGP35348 itself (2.5, 5, 10 and 20 μg/mouse) induced dose-dependent antinociception with no significant difference in the ligated and non-ligated mice. It is concluded that a GABA receptor mechanism(s) may modulate the antidepressant-induced antinociception.

Identification of amino acid residues associated with modulation of flavin-containing monooxygenase (FMO) activity by imipramine: structure/function studies with FMO1 from pig and rabbit.

The activity of the flavin-containing monooxygenase (FMO) can be modulated by a number of nitrogen-containing compounds in a manner that is both isoform and modulator-dependent. We now show that the direction (activation or inhibition) and extent of modulation can also be dependent on substrate concentration. Imipramine activates methimazole metabolism catalyzed by rabbit FMO1 or FMO2 at methimazole concentrations greater than 50 or 100 microM, respectively, and inhibits at lower methimazole concentrations. The extent of the activation increases as the substrate concentration increases, and the extent of inhibition increases as the substrate concentration decreases. With either inhibition or activation, the magnitude of the effect shows a similar, direct dependency on imipramine concentration. In contrast, imipramine inhibits the metabolism of methimazole catalyzed by pig FMO1 at all substrate concentrations. The structural basis for this unique ortholog difference between the responses of rabbit and pig FMO1 to imipramine was studied by random chimeragenesis and site-directed mutagenesis. Results with chimeras indicated that modulation of FMO1 activity by imipramine is controlled to a great extent by two areas of the FMO primary structure (residues 381-432 and 433-465). Four amino acids in these regions (positions 381, 400, 420 and 433) and one additional residue (position 186) were identified by site-directed mutagenesis as primary determinants of the imipramine response. When the residues at these positions in rabbit FMO1 are exchanged for the corresponding residues of pig FMO1, a mutant with the functional properties of pig FMO1 is produced. Our results suggest that the response of FMO1 to imipramine involves a distribution between two sites that is regulated by structural features that do not alter the overall binding. The inhibition observed, although it appears to be competitive, likely does not involve competition for a binding site since alteration of imipramine metabolism has no effect on the parameters of methimazole metabolism.

Investigation into electrochemical pretreatment of carbon fiber electrodes for the analysis of bamipine and imipramine

AbstractThe influence of the parameters of electrochemical pretreatment of carbon fiber electrodes on the differential pulse voltammetric response of bamipine and imipramine is described. Upon increasing the pretreatment potential a slight activation is followed by a deep suppression of peak current in the analysis of both substances. After a turning point the currents rise again and exceed the initial values many times over. The peak potential is affected as well. A slight deactivation is followed by a greater activation. The surfaces were characterized by chronoamperometry, chronopotentiometry and inverse voltammetry of the electrode material. At the carbon fiber epoxy matrix electrode it is possible to distinguish three different stages, which are interpreted as a phase of slightly activating functional groups in a submonolayer, a phase of passivating multilayer oxidation and finally a strongly activating phase of burn‐off and consumption of the electrode surface with change in its structure. These are thought to be responsible for the effects at the surface. It was shown that the effects within the third phase are diametrically opposed for aromatic and aliphatic amines.

Imipramine plasma concentrations and response in panic disorder

Imipramine plasma concentrations and response in panic disorder

Predictive Value of Symptoms of Atypical Depression

Data for 401 depressed outpatients with mood reactivity who participated in a randomized trial comparing placebo, imipramine, and phenelzine were analyzed for predictors of differential response by stepwise multiple regression techniques. Features of the Columbia criteria for atypical depression including oversleeping, overeating, severe anergy, and pathologic rejection sensitivity were each predictive of a poorer response to imipramine than to phenelzine only when compared to those patients with none of the features. These features were not additive in their contribution to differential outcome. Lack of endogenous features was not predictive of a differential drug treatment response. Compared with patients who have no symptoms of atypical depression, patients with any of the four features had an inferior imipramine response rather than a superior phenelzine response. These analyses indicate that the clear differential responsivity to medication treatment in atypical depression is not simply related to any one defining symptom and that further correlates of this apparent biological heterogeneity need to be explored.

Acid Alpha-1 Glycoprotein, Tritiated Imipramine Binding and Response To Treatment in Depression

Acid Alpha-1 Glycoprotein, Tritiated Imipramine Binding and Response To Treatment in Depression

Does 24-h urinary MHPG predict treatment response to antidepressants? II. Association between imipramine response and low MHPG

Thirty depressed patients collected 24-h urine samples for a 3-methoxy-4-hydroxyphenylglycol (MHPG) determination prior to imipramine treatment. Patients responding to treatment had lower levels of MHPG than did non-responders.

Naloxone enhances myocardial responses to isoproterenol in dog isolated heart-lung.

Intracoronary injection of naloxone produces rapid local increases in myocardial performance. The role of beta-adrenergic activation in this response was investigated. Naloxone was injected into the left anterior descending artery (LAD) of anesthetized dogs with the adjacent circumflex territory serving as control. Naloxone increased the contractile state locally in the LAD region. Pretreatment with propranolol eliminated the regional inotropic response. An isolated heart-lung model was set up, and isoproterenol dose responses were determined. When repeated after naloxone, contractile (dP/dt) responses to isoproterenol were both augmented and prolonged. In a third study imipramine was used to determine whether naloxone might act by reducing neuronal uptake of the isoproterenol. Imipramine extended the effect of isoproterenol temporally but did not alter the peak response. Adding naloxone increased the peak response to isoproterenol and maintained it above the extended imipramine response. The data support the concept that the blockade of opiate receptors facilitates adrenergic activity mediated by myocardial beta 1-receptors 1) directly through postsynaptic mechanisms, 2) indirectly through beta 2-mediated release of norepinephrine, or 3) via interference with nonneuronal disposal mechanisms.

A statistical model for the classification of imipramine response in depressed inpatients.

We present a statistical model, recently developed for application in mathematical economics, that yields empirical evidence for the existence of two distinct subtypes of depression. We reanalyze previously reported data on 65 depressed patients treated with imipramine and repeatedly rated on the Hamilton Rating Scale (HRS). The estimated model parameters suggest two underlying response processes. Patients in the first subgroup were initially more severely depressed (as measured by the total HRS score), but exhibited a rapid rate of symptomatic response over time. In contrast, patients in the second subgroup were initially less severely depressed, yet showed a much slower rate of improvement. These findings recommend a refinement of the clinical definitions of endogenous depression. While this model suggests that there are two underlying response processes, it does not classify individual patients. Subject classification was made possible by fitting an item-response model to the data. This model relates the 17 individual symptom ratings, at baseline, to the total post-treatment HRS scores. The results of this analysis suggest that the previously described relationship between high initial severity of depression and more rapid improvement over time is characteristic of subjects who exhibit initial motor retardation and decreased sexual interest. Graphical analysis clearly indicates that subjects who exhibit both motor retardation and decreased sexual interest at baseline have higher total HRS scores at baseline and show more pronounced improvement in total HRS scores in response to treatment with imipramine. Patients not exhibiting motor retardation and decreased sexual interest were less severely depressed initially and show virtually no clinical response over time.

MMPI prediction of imipramine response: a replication study.

18 hospitalized male depressives were treated with imipramine hydrochloride for 28 days. Prior to initiating treatment, each patient completed the Minnesota Multiphasic Personality Inventory (MMPI). At the end of the treatment period, the patients were divided into groups of responders and nonresponders based on the change in their Hamilton Depression Rating Scale scores. The Imipramine Response Scale - Male (IRS-M) was scored for each patient and the ability of the scale to predict response or nonresponse in our sample of patients was examined. There was no evidence that the IRS-M was better than chance in its ability to predict response.