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PubMed1999

Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X(L).

In order to investigate the molecular mechanism of the antineoplastic effects exerted by the antidepressive agents imipramine, clomipramine, and citalopram, we examined the effects of these compounds on cell viability, generation of reactive oxygen species (ROS), and mitochondrial membrane potential (DeltaPsi(m)) in human acute myeloid leukemia HL-60 cells. Our results indicate that exposure to these compounds causes a loss in cell viability by activating the apoptotic process, as identified by electron microscopy, DNA gel electrophoresis, and flow cytometry. The increased generation of ROS induced by these drugs was a relatively early event and preceded the loss of DeltaPsi(m). Overexpression of the antiapoptotic protein Bcl-2 or Bcl-X(L) prevents antidepressant-induced apoptosis, as well as loss of DeltaPsi(m), but does not affect the generation of ROS.

Antidepressive Agents↗

PubMed1999

Serotonin-induced platelet intracellular Ca2+ responses in untreated depressed patients and imipramine responders in remission.

BACKGROUND: Intracellular Ca2+ metabolism in platelets has been investigated as a peripheral marker of affective disorders. METHODS: We investigated the intracellular free Ca2+ concentration in platelets in both untreated depressed patients with no medications and patients in remission who were treated by imipramine (IMI) (IMI responders) using a Ca(2+)-sensitive fluorescent probe fura-2. RESULTS: The increases in intracellular free Ca2+ concentration in platelets induced by stimulation with serotonin (5-HT) ([Ca2+] delta) were significantly higher in both the untreated patients and the IMI responders compared with healthy controls; however, there were no significant differences in the basal Ca2+ levels in the platelets ([Ca2+]B) among the three groups. On the other hand, in the IMI responders, we observed positive correlations between the duration of the remission and [Ca2+]B, but not [Ca2+] delta. CONCLUSIONS: Our present data suggest that the enhancement of 5-HT2A-induced Ca2+ responses persisted after remission in depressed patients, and that the duration of the remission is a factor varying the intracellular basal Ca2+ levels.

Adult↗

PubMed1999

Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine: effect of alpha 2-adrenoceptor blockade.

BACKGROUND: Previous studies indicate a reduced feedback inhibition of brain noradrenaline (NA) neurons in the locus coeruleus (LC) during chronic administration of antidepressants which inhibit the NA reuptake mechanism due to functional downregulation of somatodendritic alpha 2-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness to administration of the alpha 2-adrenoceptor antagonist idazoxan (IDA) after both short-term and long-term imipramine (IMI) administration. METHODS: Rats were treated for different periods with systemic IMI. In these rats, basal activity of central noradrenergic function and the effect of IDA was assessed by means of extracellular single-cell recording from LC neurons and in vivo microdialysis of extracellular NA levels in the frontal cortex (FC). RESULTS: The average firing rate of LC neurons was significantly reduced in rats by short-term IMI treatment compared with long-term treatment. The output of NA in the FC of all IMI-treated animals was significantly increased compared with saline-treated rats. Moreover, the enhancing effect of IDA on both the firing rate of LC neurons and the cortical NA output was larger in rats after long-term treatment with IMI than after short-term administration. CONCLUSIONS: Our results clearly support the notion of development of functional downregulation of alpha 2-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the data suggest that addition of alpha 2-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression.

Adrenergic alpha-Antagonists↗

PubMed2002

Repeated imipramine and electroconvulsive shock increase alpha 1A-adrenoceptor mRNA level in rat prefrontal cortex.

alpha(1)-Adrenoceptors have been implicated in the mechanism of action of antidepressants, but their action on specific receptor subtypes was rarely reported. We compared now the action of two prototypic antidepressant treatments: repeated imipramine and electroconvulsive shock, on the expression of the alpha(1A)- and alpha(1B)-adrenoceptor mRNAs and on the receptor density in rats. The mRNA expression was assessed by Northern blot in the prefrontal cortex and the hippocampus, the receptor density was measured by [3H]prazosin binding in the total cerebral cortex and hippocampus. In the cortex, both treatments elevated the alpha(1A)-adrenoceptor mRNA and the expression of receptor protein. The expression of alpha(1B)-adrenoceptor mRNA remained unaffected. In contrast, in the hippocampus, the antidepressant treatments augmented the density of alpha(1A)-adrenoceptor protein without changing the level of its mRNA expression there. The results suggest that the alpha(1A)-adrenoceptor subtype is specifically involved in the mechanism of action of classical antidepressant treatments.

Animals↗

PubMed2002

Inhibition of SK3 channels in the TE671 human medulloblastoma cell line by desipramine and imipramine.

The TE671 human medulloblastoma cell line endogenously expresses SK3 channels. Using patch clamp, we tested the effects on this current of desipramine and imipramine. In both cases, we observed a complete, reversible and concentration-dependent block. The interaction of desipramine with the selective SK3 blocker, apamin, was studied in more detail. Co-application of desipramine and apamin at concentrations close to their IC(50) produced an additive effect that was significantly higher than that of each compound alone. This effect was also observed at IC(25) concentrations. Collectively, these data provide evidence against a common site of action for desipramine and apamin.

Desipramine↗

PubMed2002

Effects of triiodothyronine and imipramine on basal 5-HT levels and 5-HT(1) autoreceptor activity in rat cortex.

Clinical studies have shown that triiodothyronine (T3) both augments and accelerates the therapeutic response to antidepressant drugs, particularly tricyclics. There is evidence that this effect is mediated by the serotonergic system. We show here that T3 administered daily for 7 days over the range 0.02-0.5 mg/kg increases basal serotonin (5-hydroxytryptamine, 5-HT) levels, as measured by in vivo microdialysis in rat cortex, in a dose-dependent fashion. All the doses of T3 examined reduced 5-HT(1A) autoreceptor activity, as measured by the effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) to decrease 5-HT levels in frontal cortex. T3 administered daily for 14 days at 0.02 mg/kg also reduced 5-HT(1B) autoreceptor activity, as measured by the effect of locally administered 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129, 10 microM) to decrease 5-HT levels. In animals administered imipramine (10 mg/kg/day by osmotic minipump) concurrently with T3 injections, no further changes in either 5-HT(1A) or 5-HT(1B) autoreceptor activity were seen. We suggest that the effect of T3 to accelerate the therapeutic actions of antidepressant drugs may be due to a combination of the actions of T3 at autoreceptors and the actions of the drugs at postsynaptic 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1996

A genetic mouse model of helplessness sensitive to imipramine.

Lines of mice were selectively bred to diverge in their spontaneous helplessness in the tail suspension test. By the second generation of selection, only mice of the helpless line were sensitive to the antidepressant imipramine. Genetic factors substantially contribute to the susceptibility to helplessness in this mouse model. These selectively bred lines may represent potentially useful animal models to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗

PubMed2000

In vitro studies of the phototoxic potential of the antidepressant drugs amitriptyline and imipramine.

Amitriptyline and imipramine, two tricyclic antidepressant drugs, have been studied to evaluate their phototoxic potential using various models. Reactive oxygen species production was investigated. A negligible production of singlet oxygen was observed for both compounds whereas a significant production of superoxide anion was noted for amitriptyline in particular. Moderate red blood cell lysis under UVA light (365 nm) was induced in the presence of the two drugs at a concentration of 50 microM. Cellular phototoxicity was investigated on a murine fibroblast cell line (3T3). The two drugs were phototoxic causing cell death at a concentration of 100 microM and a UVA dose in the range of 3.3-6.6 J/cm2. Furthermore, the two drugs photosensitized the peroxidation of linoleic acid, as monitored by the formation of dienic hydroperoxides. The presence of BHA and GSH, two free radical scavengers, significantly reduced the lipid oxidation photoinduced by the drugs, suggesting a predominant involvement of radical species. Finally, the involvement of nucleic acids in the phototoxicity mechanism was also investigated using a pBR322 plasmid DNA as a model.

Amitriptyline↗

PubMed1981

Imipramine--a possible alternative to current therapy for urinary incontinence in the elderly.

Imipramine was given orally at night to 10 elderly patients with urinary incontinence associated with spontaneous unstable detrusor contractions. The dose was increased for each patient up to a maximum of 150 mg. at night, or until continence was achieved or side effects occurred. Of the 10 patients 6 became continent. In 3 of the 6 patients who underwent repeat cystometry bladder capacity had increased (mean 105 cc), bladder pressure at capacity decreased (mean 18 cm. water) and urethral pressure increased (mean 30 cm. water). There was no correlation between plasma desmethylimipramine and dose, or clinical or urodynamic effect.

Aged↗

PubMed2002

NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus.

Abrupt antidepressant withdrawal after chronic treatment is associated with a stress response that may negatively affect the long-term outcome of depression, the neurochemical correlates, of which, remain undetermined. Prolonged depression involves the stress-related release of glucocorticoids and glutamate, while response to antidepressants involves gamma-amino butyric acid (GABA) and the glutamate N-methyl-D-aspartate (NMDA) receptor. Here, imipramine (IMI) was administered to rats for three weeks followed by acute withdrawal for seven days. Levels of GABA in the hippocampus (HC), and effects on swim stress immobility (SSI), were determined. Furthermore, glutamate/NMDA receptor binding properties were determined using [(3)H]-CGP-39653. Finally, the ability of dizocilpine (MK801), a glutamate NMDA antagonist, to reverse IMI withdrawal was determined. Chronic IMI (15 mg/kg ip) significantly reduced SSI together with a slight but insignificant decrease in HC GABA levels. However, IMI significantly reduced specific binding (B(max)) of [(3)H]-CGP-39653. Withdrawal of IMI for 7 days resulted in a loss of efficacy on SSI, a slight increase in GABA and a significant reversal of IMI effects on [(3)H]-CGP-39653 binding. MK801 (0.2 mg/kg ip) alone for seven days caused a significant decrease in SSI, a significant suppression of HC GABA, and significantly decreased [(3)H]-CGP-39653 B(max). MK801 during IMI-withdrawal significantly decreased GABA, prompted recovery on SSI, though not significantly, but significantly reversed withdrawal effects on [(3)H]-CGP-39653 B(max). In conclusion, acute antidepressant discontinuation is associated with subtle changes on HC GABA, a resurgence of NMDA receptor density and a loss of its anti-immobility response. These responses are reversed by a NMDA antagonist suggesting that abrupt antidepressant discontinuation mobilises glutamate activity.

2-Amino-5-phosphonovalerate↗

PubMed1997

Chronic imipramine treatment downregulates IR1-imidazoline receptors in rat brainstem.

One subtype of imidazoline receptors (IR1) is similar to alpha 2-adrenoceptors (alpha 2 AR) based on their high affinity for clonidine and related imidazoline compounds. On the other hand, IR1 possess low affinity for norepinephrine (NE) and other catecholamines. Imidazoline receptors have also been found to be over-expressed in plasma membranes from platelets and brain tissues of depressed patients. Over-expression of IR1 in platelet membranes of depressed patients became normalized after various antidepressant treatment to the patients. Herein, the prototypic antidepressant, imipramine (IMI), has been studied in regard to its treatment effects on [125I]p-iodoclonidine binding to both alpha 2 AR and IR1 in rat brainstem membranes. No effects of chronic IMI treatment were found on brainstem alpha 2 AR binding sites (Bmax and/or KD parameters unchanged) after 25 days of daily injections (i.p. IMI 20 mg/kg/day). However, IMI induced a decrease in the density (Bmax measured under NE mask) of brainstem IR1 sites, with no change in KD. Downregulation of IR1 sites was dose-dependent (minimal effective dose of i.p. IMI was 10 mg/kg/day) and time-dependent (> 16 days of treatment). These results implicate brainstem IR1 in the chronic effects of antidepressants.

Affinity Labels↗

PubMed2000

Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in spontaneously hypertensive and Wistar-Kyoto rats.

Spontaneously Hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats differ in their emotional responses to stress and antidepressant administration. We have analysed different neurochemical and psychoneuroendocrine responses to repeated pretreatments with fluoxetine, imipramine or desipramine (10 mg/kg p.o. daily for 4 weeks) in SHRs and WKY rats exposed to a daily 2-h restraint episode for the last 5 days of antidepressant administration. Following a 24-h wash-out period, WKY rats displayed higher plasma antidepressant and antidepressant metabolite levels than SHRs. Fluoxetine pretreatment decreased [(3)H]citalopram binding at midbrain serotonin (5-HT) transporters, whereas tricyclic and/or fluoxetine decreased [(3)H]ketanserin binding at cortical 5-HT(2A) receptors, [(3)H]CGP-12177 binding at cortical ss-adrenoceptors, and [(3)H]nisoxetine binding at midbrain noradrenaline (NA) transporters in both strains. None of the antidepressants affected [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin binding at hippocampal 5-HT(1A) receptors. In WKY rats, repeated restraint triggered a desipramine-sensitive 140% increase in hypothalamus [(3)H]nisoxetine binding; moreover, plasma adrenocorticotropin-releasing hormone responses to a 5-min open field test were amplified by prior repeated restraint in both strains, but desipramine prevented such an amplification in WKY rats only. However, neither elevated plus-maze nor open field behaviors of SHRs and WKY rats were affected by desipramine pretreatment. Thus, the SHR and WKY rat strains may prove useful in understanding how genetic differences in noradrenergic responses to repeated stress and desipramine treatment impact on adaptive processes.

Adrenocorticotropic Hormone↗

PubMed1999

Alnespirone (S 20499), an agonist of 5-HT1A receptors, and imipramine have similar activity in a chronic mild stress model of depression.

A chronic mild stress (CMS) model of depression was used to study an antidepressant-like activity of alnespirone (S 20499), a selective agonist of 5-HT1A receptors. In this model, a substantial decrease in consumption of a palatable sucrose solution over time is observed in rats subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic (5 weeks) treatment with alnespirone, in a dose range between 1-5 mg/kg/day, gradually and dose dependently reversed the CMS-induced reductions in sucrose consumption without any significant effects in the non-stressed control animals. The onset of action of the most active doses (2.5 and 5 mg/kg/day) and the overall efficacy of alnespirone in the CMS model were comparable to those observed following similar administration of imipramine (10 mg/kg/ day). At the lower (0.5 mg/kg/day) and higher (10 and 20 mg/kg/day) doses, alnespirone was ineffective against the CMS-induced deficit in sucrose consumption. These data provide further support for previous suggestions, based on both the clinical observations and animal data, that agonism at 5-HT1A receptors may result in antidepressant action.

Adrenergic Uptake Inhibitors↗

PubMed1997

The efficacy of imipramine and psychotherapy in early-onset chronic depression: a reanalysis of the National Institute of Mental health Treatment of Depression Collaborative Research Program.

The authors compared the effectiveness of Cognitive Behavioral Therapy (CBT), Interpersonal Psychotherapy (IPT), Imipramine Clinical Management (ICM) to Placebo Clinical Management (PCM) for outpatients with early-onset chronic depression (N = 65) in the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDRP). The post-treatment depression scores of the CBT. IPT, and ICM groups were not significantly different from the PCM group. We did not find a relationship between the duration of Major Depression and response to a specific treatment. Studies are needed to determine if combining psychotherapy with medication improves social functioning and enhances the quality of life for patients with chronic depression.

Adult↗

PubMedDate not supplied

Antidepressant efficacy of Sudarshan Kriya Yoga (SKY) in melancholia: a randomized comparison with electroconvulsive therapy (ECT) and imipramine.

BACKGROUND: Sudarshan Kriya Yoga (SKY) is a procedure that involves essentially rhythmic hyperventilation at different rates of breathing. The antidepressant efficacy of SKY was demonstrated in dysthymia in a prospective, open clinical trial. This study compared the relative antidepressant efficacy of SKY in melancholia with two of the current standard treatments, electroconvulsive therapy (ECT) and imipramine (IMN). METHODS: Consenting, untreated melancholic depressives (n=45) were hospitalized and randomized equally into three treatment groups. They were assessed at recruitment and weekly thereafter for four weeks. RESULTS: Significant reductions in the total scores on Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HRSD) occurred on successive occasions in all three groups. The groups, however, did not differ. Significant interaction between the groups and occasion of assessment occurred. At week three, the SKY group had higher scores than the ECT group but was not different from the IMN group. Remission (total HRSD score of seven or less) rates at the end of the trial were 93, 73 and 67% in the ECT, IMN and SKY groups, respectively. No clinically significant side effects were observed. DISCUSSION: Within the limitations of the design (lack of double blind conditions), it can be concluded that, although inferior to ECT, SKY can be a potential alternative to drugs in melancholia as a first line treatment.

Adult↗

PubMed2002

Postnatally induced differences in adult pain sensitivity depend on genetics, gender and specific experiences: reversal of maternal deprivation effects by additional postnatal tactile stimulation or chronic imipramine treatment.

Postnatal endotoxin exposure, handling or maternal deprivation produce long-lasting individual differences in various neuroendocrine and behavioural responses. However, the impact of postnatal experiences on adult pain sensitivity and its reversibility by postnatal additional tactile stimulation or antidepressants in adulthood is not well understood. Therefore, postnatal endotoxin application as a model for infection, maternal deprivation as a model for depression, and postnatal handling as a model for stimulation were compared with respect to the effects on pain sensitivity in adult Fischer 344 (F344) and Lewis (LEW) rats. Handling increased hot plate latencies in adult F344 and LEW rats, while maternal deprivation shortened hot plate latencies only in LEW rats. Prophylactic treatment strategies, such as tactile stimulation of the dorsal neck region of pups directly after maternal deprivation, or chronic treatment of adult maternally deprived rats using imipramine, successfully provide protection against the maternal deprivation-induced shortening of hot plate latencies. Thus, there is considerable specificity of certain postnatal experiences in modulating adult pain sensitivity and the maternal deprivation-induced hyperalgesia is reversible by different interventional regimes. These findings may explain some of the individual differences in pain sensitivity of humans and the differential efficacy of antidepressants in pain syndromes.

Animals↗

PubMed2000

Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex--a possible mechanism of neuroprotection in major depression?

Antidepressant drugs have been used for decades, but the neurobiological substrate of their efficacy is not completely understood. Although these drugs have well-established effects on monoamines, evidence is emerging that they may also affect other neurotransmitter systems. It has been shown that treatment with a wide range of antidepressants changes the binding characteristics of the N-methyl-D-aspartate type of glutamate receptor. This change is delayed and occurs only in the cortex. The mechanism that triggers it is unknown. We hypothesized that N-methyl-D-aspartate receptor alterations may be due to changes in the dynamics of cortical excitatory amino acid release. Such changes are of particular interest in areas such as the prefrontal cortex, a region involved in stress responses and affected in major depression. We investigated the effects of two antidepressants with different modes of action, imipramine and phenelzine, on glutamate and aspartate outflow in rat prefrontal cortex and striatum. We showed that antidepressants significantly decreased stimulated glutamate outflow. The effect had a rapid onset, was sustained during chronic administration and was only seen in the prefrontal cortex. This change may initiate receptor alterations. Furthermore, if antidepressants can dampen states of hyperglutamatergic activity and the subsequent excitotoxicity, their chronic use may have a considerable neuroprotective potential in major depression.

Animals↗

PubMed2003

Effect of temperature on imipramine hydrochloride permeation: role of lipid bilayer arrangement and chemical composition of rat skin.

The aim of this investigation was to study the effect of temperature on the permeation of imipramine hydrochloride (IMH) across rat skin from two different vehicles. Differential scanning calorimetry (DSC) was used to characterize the phase transitions of rat epidermis and extracted rat SC lipids, and the transition temperatures were correlated with the permeability of IMH at different temperatures. Permeability of IMH from ethanol and propylene glycol (PG) was determined at five different temperatures and observed that a significant increase in IMH permeability occurred 45 degrees C from both the vehicles. Further, high energies of activation for rat skin permeation suggested that IMH diffuses across intercellular lipid matrix and therefore any change in the packing of SC lipids will have an effect on IMH permeation. Three endotherms T(1), T(2) and T(3) of rat epidermis were observed in DSC thermograms at 44, 53 and 64 degrees C and were assigned as transitions corresponding to orthorhombic to hexagonal, hexagonal to more disordered phase and melting of lipids with high cholesterol content, respectively. The high permeability values of IMH above 45 degrees C were therefore reasoned to be because of orthorhombic to hexagonal phase transition in rat skin from close to that temperature.

Animals↗