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Changes in developing behavior following prenatal administration of imipramine.

Female rats were given oral doses of Imipramine (5mg/kg) from 14-21 days prior to mating to conception or Day 19 or gestation and the physical maturation and behavioral development of their offspring was compared with that of controls. There were significant differences between the weights of the Imipramine and control animals at 21 days and the appearance of some reflexes was delayed. Behavior in an open field was observed when the rats were 9, 13, 17 and 21 days of age and it was found that exploratory responses were less frequent in the drug exposed offspring. In contrast there were no obvious physical anomalies and the adult behavior of the Imipramine animals on a spontaneous alternation task and a swimming maze did not differ from that of controls.

Aging↗

Effects of imipramine on separation-induced vocalizations in young rhesus monkeys.

Three Rhesus monkeys were removed from their mothers at birth and reared together in a group cage. When they were one year old they were subjected to repeated separations during which they were placed alone for 1 hour in another cage in an acoustically isolated adjacent room. The number of vocalizations and gross body movements were recorded automatically. Single injections of imipramine (3.75, 7.5 and 15 mg/kg IM) instead of decreasing tended to increase the number of vocalizations without affecting motor activity. A similar pattern was observed when imipramine (3.75 and 7.5 mg/kg IM) was administered repeatedly (2 injections/day/4 days). The failure of imipramine to decrease separation-induced vocalizations in our conditions suggests that the procedure would not be useful for testing potential antidepressants.

Animals↗

Effects of imipramine on responding reduced by methadone.

Interactions between methadone and acute and chronic imipramine were studied in pigeons key pecking under a multiple variable interval 15-sec variable interval 150-sec schedule of food presentation. Both drugs decreased response rates at the highest doses. The VI 15-sec schedule was slightly more sensitive to acute drug administration than was the variable interval 150-sec schedule. Acute combinations of the two drugs neither ameliorated nor exacerbated the effects of either drug alone. Chronic imipramine alone had no lasting effect on responding. Unlike acute combinations, chronic imipramine lessened the rate reducing effect of methadone.

Animals↗

Chronic imipramine effects on exploratory behavior in rats.

Approximately 100 days old hooded rats, socially isolated or group-housed since weaning, received 15 daily IP injections of isotonic saline, 10 mg/kg or 20 mg/kg of imipramine HCl. Following their last injection, the rats' active choices of a novel environment, frequencies of rearing and grooming, and cells entered in an exploration box were recorded. The drug treatment reduced rearing, ambulation and (for isolated rats only) grooming, but had no effect on novelty choices. There was a significant weight loss with the higher dose and (for males only) with social isolation during the drug treatment period. While imipramine reduced grooming in isolated but not group-housed rats, there were no other interactions between the two forms of treatment. It was concluded that, in spite of its sedative action on motor activity, chronic imipramine did not alter curiosity about a novel environment.

Animals↗

Alarm substance induces convulsions in imipramine-treated rats.

Male rats were injected with imipramine (0-30 mg/kg) and subsequently tested in the forced-swim test in either fresh water or water soiled by other rats, which presumably contains an alarm substance. Imipramine did not affect the behavior of rats in fresh water. More than half the animals given the combination of imipramine (30 mg/kg) and stress from alarm substance had clonic convulsions. Adrenalectomy did not affect this relationship. This is the first study demonstrating the potential of an alarm substance for inducing convulsions.

Adrenal Glands↗

Decreased platelet 3H-imipramine binding in primary major depression compared with depression secondary to medical illness in elderly outpatients.

Platelet 3H-imipramine binding and monoamine oxidase (MAO) activity were investigated in elderly outpatients with primary major depression, and in a group with depression secondary to medical illness (organic mood disorder, depressed by DSM-III-R criteria) in a multidisciplinary geriatric clinic. The density of the binding of 3H-imipramine (Bmax) was decreased significantly in subjects with major depression compared to subjects with secondary depression, and to controls. There was no difference in Bmax values between subjects with secondary depression and controls. MAO activity was increased in the group with secondary depression, but not in the group with primary major depression. These results provide preliminary evidence for the relative specificity of platelet 3H-imipramine binding as a marker for primary major depressive disorder compared to secondary depression in medically ill elderly people, supports the concept of biological heterogeneity in secondary depression, and extends the findings of decreased Bmax values in two previous studies in non-medically ill depressed elderly patients.

Aged↗

Platelet serotonin uptake dynamic changes in depression: effects of long-term imipramine treatment and clinical recovery.

The characteristics of the serotonin uptake mechanism were measured in blood platelets of depressed patients before treatment and after 3 weeks and 2 months of imipramine therapy. The results were then compared with data from normal volunteers. In the unmedicated, depressed patients, platelets showed two affinity components of serotonin uptake. Both affinity states differed, in opposite directions, from the platelet serotonin uptake in normal volunteers. In the latter, a two-state model was more difficult to establish. Successful imipramine treatment progressively normalized the platelet serotonin uptake changes seen in unmedicated patients. Those changes allowed the membrane to deal with a wider than normal range of extracellular serotonin concentration; they might reflect neuronal compensatory changes resulting from altered extraneuronal serotonin concentrations and leading, directly or via presynaptic receptors, to balancing them. Imipramine treatment assists the adaptive process and accelerates the clinical recovery.

Adult↗

Effects of fluoxetine treatment of platelet 3H-imipramine binding, 5-HT uptake and 5-HT content in major depressive disorder.

Platelet 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentrations were studied in 14 hospitalized patients with depressive disorder following 6 weeks of treatment with a selective 5-HT uptake blocker, fluoxetine. After 3 weeks of treatment there was a significant decrease in Bmax of 3H-imipramine binding and a significant increase in Kd. A highly significant decrease in Vmax of 5-HT uptake was seen after 3 weeks of treatment which was accompanied by a slight increase in Km. At the same time the platelet 5-HT content was significantly reduced by about 90% of its original level. The platelet 5-HT content continued to decrease with further treatment while there was a tendency for Vmax to return to pretreatment levels. The affinity of the 5-HT uptake carrier continued to decrease significantly. There was no further significant change in Bmax of 3H-imipramine binding during further treatment, although there was an increase in Bmax in the majority of patients. The changes in Bmax and Vmax were closely associated throughout the treatment. In some cases the changes in different platelet parameters correlated with the changes in depression rating scores during treatment, but this correlation did not reach statistical significance.

Adult↗

A study comparing paroxetine placebo and imipramine in depressed patients.

These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.

Adolescent↗

Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo.

This paper presents findings from a multisite study of 126 subjects meeting DSM-III-R criteria for Panic Disorder who also met criteria for a concurrent Major Depressive Episode, Dysthymia, or Depressive Disorder NOS. The study's primary aim was to discern the influence of varying degrees of depression on the comparative efficacy of alprazolam, imipramine and placebo on anxiety outcomes. A placebo-controlled, double-blind, parallel random assignment design was utilized over a total of 16 weeks. There was no medication effect on panic outcomes. At endpoint, percent of anticipatory anxiety (i.e., time spent worrying about having an anxiety attack) was significantly lower in the patients taking active medications vs. placebo. Phobic measures were significantly improved by alprazolam, vs. both imipramine and placebo early in the study; however, by week 8 both active medications were equally superior to placebo in the reduction of phobic symptoms. In addition, both active medications were significantly more effective than placebo in reducing depression. The same efficacy pattern (i.e., active medications superior to placebo) was observed on measures of general functioning. Importantly, there were no significant interactions observed between medication and presence of major depression on the depression measures, indicating that both alprazolam and imipramine were equally efficacious in treating the depression in patients with panic disorder and major depression. Since the patients enrolled in this study suffered from major depressive disorder in the mild to moderate severity range, these results may not be transferrable to patients with panic disorder and severe major depression.

Adult↗

Up-regulatory effect of triphasic oral contraceptive on platelet 3H-imipramine binding sites.

Triphasic oral contraceptive (Logynon) induced a significant increase (36%) in the maximal binding capacity of platelet membranes for [3H]imipramine. The increase was achieved in the second Logynon cycle as compared to pretreatment and first Logynon cycle binding values. The pill contains a combination of ethinyl estradiol and levonorgestrel, and it is as yet unclear which of the two hormones is responsible for the up-regulatory effect. The increase in the density of platelet imipramine binding sites may reflect a similar alteration in brain. The increase in imipramine binding did not correlate with alteration in mood as assessed by Beck Depression Inventory scores.

Adult↗

Platelet [3H]-imipramine binding is not modified in Alzheimer's disease.

Platelet [3H]-imipramine binding was studied in patients with Alzheimer's disease and control subjects matched to the patients for age and sex. There were no differences in the binding parameters of [3H]-imipramine on platelet membranes from patients with Alzheimer's disease, when compared with the control group. These results suggest that [3H]-imipramine binding could be a useful tool to discriminate between demented and depressive patients in elderly populations.

Aged↗

Platelet 3H-imipramine binding in euthymic bipolar patients.

Several recent studies have reported decreased maximal binding (beta max) of 3H-imipramine to platelets obtained from depressed patients. 3H-Imipramine binding was measured in 12 medication-free euthymic bipolar patients and 12 normal volunteers to determine whether the decreased beta max persisted in the euthymic state. No differences between these two groups were found in beta max or binding affinity (Kd). This suggests that 3H-imipramine binding to platelets is not a state-independent marker for affective illness.

Adult↗

Imipramine-induced increase in 5-HT2C receptor mRNA level in the rat brain.

Repeated oral administration of 20 mg/kg imipramine elevated the level of 5-HT2C mRNA in the rat brain. Hybridization signals in nearly all regions stained by digoxigenin-labeled antisense cRNA probe, such as the hippocampus, choroid plexus, habenular nucleus, and dorsomedial hypothalamic nucleus, were more intense following imipramine treatment. These results suggest that long-term treatment with imipramine stimulates 5-HT2C receptor gene expression.

Animals↗

Platelet 3H imipramine binding: a possible predictor of response to antidepressant treatment.

No significant difference in the density (Bmax) of platelet 3H imipramine recognition sites were found between the group of 20 unmedicated depressed patients and 10 healthy volunteers. The mean KD value was significantly higher in the population of depressives than in controls. Non-responders (after 2 weeks of treatment with antidepressants) had significantly lower initial Bmax values than responders or control subjects. Density of platelet 3H imipramine site may thus be a predictor of early response to antidepressant therapy. No significant sex differences were found in KD or Bmax values in the depressed group or in control subjects. There was, however, a seasonal variation in Bmax but not in KD values of platelet 3H imipramine binding.

Adult↗

Desensitization of the D1 dopamine receptors in rats reproduces a model of escape deficit reverted by imipramine, fluoxetine and clomipramine.

1. The present study investigated the effect of long-term D1 dopamine receptor stimulation on an animal model of depression derived from the learned helplessness paradigm. 2. The model used is based on the escape deficit produced by a series of unavoidable shocks administered to rats 24 h before the test session. SKF 38393 administered acutely, completely prevented the development of animal hyporeactivity, while given repeatedly produced tolerance to its own protective effect. Moreover it also reduced the spontaneous escape reactivity of rats not exposed to the inescapable shocks. Animals chronically receiving SKF 38393 and showing a clearcut escape deficit, were treated daily with either imipramine, fluoxetine, or clomipramine. After 21 days of combined treatment the 3 antidepressants appeared equally effective in reverting the behavioral deficit. Moreover, long term administration of both imipramine or SKF 38393 down regulated D1 dopamine receptor number in the prefrontal cortex, while the association of the two drugs resulted in a receptor density similar to that of control rats. 3. The present results further support the crucial role played by D1 dopamine receptors in the control of animal reactivity to stressful stimuli and in the mechanism of action of imipramine. Moreover they show that the D1 dopamine receptor related escape deficit is sensitive also to compounds selectively acting through the serotonergic neuronal system.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Imipramine prevents stress gastric glandular lesions in rats.

Intraperitoneal (i.p.) administration of imipramine dose-dependently inhibited gastric lesions induced by 3 h of cold restraint stress. The high dose of imipramine (5 mg/kg) almost completely abolished gastric lesion formation, and also suppressed acid secretion in rats with pyloric ligation. Intracisternal imipramine (1 microgram) was also protective. These findings suggest that tricyclic antidepressants may play an important role in preventing the deleterious effects of stress on the gut.

Analysis of Variance↗

Imipramine prevents gastric lesions induced by centrally administered thyrotropin-releasing hormone (TRH) in rats.

Increasing evidence indicates that thyrotropin-releasing hormone (TRH), and endogenous brain-gut peptide may play a role in experimental ulcerogenesis. Potential interactions between TRH and imipramine (a typical tricyclic antidepressant (TCA] on the development of TRH-induced gastric lesions have not been investigated. Imipramine (0.05, 0.5 and 5 mg/kg, i.p.) dose-dependently inhibited gastric lesion formation induced by intracisternal (i.c.) administration of TRH (1 micrograms). In addition, imipramine (5 mg/kg, i.p.) significantly decreased gastric acid secretion in response to i.c. TRH (1 microgram) in rats with pyloric ligation. These findings suggest the TCAs may be effective drug agents against centrally initiated gastric ulcerations. The mechanism of this response probably involves blockade of cholinergic (muscarinic) and H2 histamine receptors.

Animals↗