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PubMed1983

Temperature-sensitive reversible loss of [3H]imipramine binding sites: evidence suggesting different conformational states.

Previous studies have indicated that the tertiary tricyclic antidepressant imipramine binds with high affinity to a site related to the serotonin uptake mechanism. We have further characterized this site with regards to the effects of temperature, pH and calcium ions on both rat cerebral cortex homogenates and outdated human platelets. The binding of [3H]imipramine to these sites is maximal at 4 degrees C. When the assay temperature is increased to 23 degrees C, there is approximately a 50% decrease in the maximal number of binding sites (Bmax) with no apparent change in the affinity for the ligand. On further raising the temperature to 37 degrees C there is no further decrease in Bmax but there is an increase in the dissociation constant (KD). These temperature related changes are reversed when the assay temperature is again lowered to 4 degrees C. Decreasing the pH of the incubation mixture from 7.5 to 7 (which is the pH change also observed upon changing the temperature of the incubation mixture from 4 to 37 degrees C) decreased [3H]imipramine binding by 10-20%, an amount which does not account for the changes observed. Similarly, neither calcium nor EDTA altered these reversible changes. Irreversible loss of binding sites was observed on prolonged incubation at 23 or 37 degrees C. After 20 h preincubation at 23 or 37 degrees C, 15 or 30% of the binding respectively could not be restored by lowering the temperature to 4 degrees C. This permanent loss was enhanced by calcium and inhibited by EDTA. These results suggest that reversible conformational changes in the [3H]imipramine binding site can be observed.

Animals↗
PubMed1983

Solubilization and assay of [3H]imipramine binding sites from human platelets.

[3H]Imipramine binding sites were characterized on outdated (72-96 h) human platelets. The binding site profile was very similar to that previously described for fresh platelets and for CNS membrane preparations. [3H]Imipramine binding sites are believed to represent the recognition site for the 5-hydroxytryptamine uptake system. In order to further investigate this molecular relationship, we solubilized [3H]imipramine binding sites using 1% digitonin and characterised them using a polyethylene glycol precipitation assay. Solubilization did not alter the pharmacological specificity or affinity of the [3H]imipramine binding site and recovery of sites was very high. It was concluded that the solubilization procedure left the binding site remarkably intact. The ready availability of platelets and the convenience of the binding assay makes this system amenable for further purification steps.

Binding Sites↗
PubMed1983

High affinity binding of [3H]paroxetine and [3H]imipramine to human platelet membranes.

Paroxetine, one of the most potent and specific serotonin uptake inhibitors, was tritiated and used for binding studies with human platelet membranes. Specific, high affinity binding was demonstrated. The binding was compared with [3H]imipramine binding; it was found that the maximal binding (Bmax) was the same for [3H]paroxetine and [3H]imipramine, whereas the affinity was much higher for [3H]paroxetine (KD 0.08 nM and 0.56 nM for paroxetine and imipramine binding, respectively). IC50 was calculated for the inhibition of [3H]paroxetine and [3H]imipramine binding by a number of antidepressants; the corresponding Hill coefficients were also calculated.

Antidepressive Agents, Tricyclic↗
PubMed1984

Differentiation of two components of specific [3H]imipramine binding in rat brain.

Specific binding of [3H]imipramine to membrane preparation from rat cerebral cortex can be resolved in two distinct components: the high-affinity binding with a KD in nanomolar range (6.9 +/- 0.4 nM) and a maximum number of binding sites (Bmax) 285 +/- 19 fmol/mg protein and the low-affinity component with a KD of 292 +/- 45 nM and Bmax of 2459 +/- 428 fmol/mg protein. Tricyclic antidepressants, a non-tricyclic serotonin uptake inhibitor fluoxetine and a tetracyclic antidepressant maprotiline show a markedly different pattern in displacing [3H]imipramine binding at the high- and the low-affinity site. When the high-affinity sites were protected, the differences in potency of tested drugs in displacing specific [3H]imipramine binding, and the correlation with their ability to inhibit serotonin reuptake, were not observed. The Hill coefficients of competing drugs at low-affinity sites were markedly lower (0.45-0.69) and the shape of displacement curves indicated that more than one site may be involved in low affinity binding of [3H]imipramine.

Animals↗
PubMed1986

Enhancement of central and peripheral alpha 1-adrenoceptor sensitivity and reduction of alpha 2-adrenoceptor sensitivity following chronic imipramine treatment in rats.

After chronic imipramine treatment (20 mg/kg i.p., once daily for 14 days) the dose-response curve of the isolated rat anococcygeal muscle to phenylephrine shifted to the left, and furthermore, the -log KA value (affinity) for phenylephrine was significantly increased without affecting the affinity for guanfacine. On the other hand, such treatment caused a shift to the right of the dose-response curve to guanfacine on aortic strips and the affinity of the alpha-adrenoceptor for guanfacine was lowered without any accompanying changes in the affinity value for phenylephrine. However the relative efficacies of phenylephrine or guanfacine were not influenced by imipramine in either preparation. The ability of phenylephrine to displace [3H]prazosin from its specific binding sites was significantly enhanced after chronic imipramine treatment. These results may indicate that following chronic imipramine treatment the alpha 1-adrenoceptors of both central and peripheral tissues responded with supersensitivity to an alpha 1-preferential agonist, and the alpha 2-adrenoceptors with reduced sensitivity to an alpha 2-preferential agonist.

Adrenergic alpha-Agonists↗
PubMed1990

Non-specific inhibition of imipramine binding argues against an endogenous ligand.

We have attempted to characterize the product(s) inhibiting [3H]imipramine binding from rat cortical membranes. Fractions inhibiting [3H]imipramine binding were analysed by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography-mass spectrometry (HPLC-MS). Tissue extracts showed marked inhibitory activity (two different peaks); however, extracts containing no brain tissue (blanks) also exhibited inhibitory activity (one peak after HPLC pre-purification). The chemical composition of the compound that inhibited [3H]imipramine binding was identical in both cases (tissue and blank extracts) and consisted of zinc chelates, probably formed by the use of zinc sulfate during the extraction procedure. The second inhibitory peak in the tissue extracts was 5-hydroxytryptamine (serotonin, 5-HT). These results suggest that the inhibitory activity on [3H]imipramine binding attributed to a low-molecular weight putative endacoid is non-specific and due to ions introduced in the sample during purification.

Animals↗
PubMed1993

p-chlorophenylalanine-reversible reduction of sigma binding sites by chronic imipramine treatment in rat brain.

Repeated treatment with imipramine (10 mg/kg intraperitoneally (i.p.), once daily for 14 days) caused a decrease in the Bmax, without affecting the Kd, of [3H]DTG (1,3-di-o-tolylguanidine) binding to the haloperidol-sensitive sigma sites in the striatum, hippocampus and cerebral cortex of the rat. A similar reduction was observed after chronic administration of a selective serotonin uptake inhibitor, fluoxetine (10 mg/kg i.p., twice daily for 14 days), but not of a selective norepinephrine uptake inhibitor, desipramine (10 mg/kg i.p., once daily for 14 days). Neither a single injection of imipramine (10 mg/kg i.p.) nor addition of imipramine or fluoxetine into the binding assay medium mimicked the changes in the maximal binding of brain sigma sites induced by chronic treatment with these drugs. Finally, depletion of brain serotonin by means of repeated administration of p-chlorophenylalanine, which produces inhibition of the amine synthesis, blocked the ability of repeated imipramine treatment to reduce the maximal number of [3H]DTG binding sites in the striatum and hippocampus. The present results suggest that cerebral serotonergic transmission may play a role in the regulation of cerebral sigma binding sites in the rat.

Animals↗
PubMed1993

Alpha-methyl-para-tyrosine antagonizes the effect of chronic imipramine on learned helplessness in rats.

alpha-Methyl-para-tyrosine, co-administered with imipramine to rats at a dose that only partially inhibits tyrosine hydroxylase, has been found to prevent completely the decrease of dopamine D1 receptor function. The present report shows that, in the same experimental conditions, alpha-methyl-para-tyrosine significantly antagonized the capacity of imipramine to prevent the development of learned helplessness behavior in rats. This suggests that a catecholaminergic mechanism is crucial in determining the effect of imipramine on the development of learned helplessness behavior. alpha-Methyl-para-tyrosine co-administration also prevented imipramine-induced down-regulation of beta-adrenoceptor function.

Adenylyl Cyclases↗
PubMed1989

Serotonin uptake in cerebral cortex cultures: imipramine-like inhibition by N-isopropyl-p-iodoamphetamine.

In cultured rat neocortex, uptake of [3H]serotonin (5-HT) and the SPECT radiopharmaceutical N-isopropyl-p-[123I]iodoamphetamine (IMP) was demonstrated after 4 and 14 days in vitro. Both imipramine and cold IMP inhibited [3H]5-HT uptake. Uptake of [123I]IMP was inhibited by imipramine but not by cold 5-HT. The similarity in the behaviors of IMP and imipramine indicates that uptake of IMP might be related to a serotonergic uptake system in a way that is similar to that in which imipramine is related to such a system.

Amphetamines↗
PubMedDate not supplied

Imipramine treatment of panic disorder with agoraphobia: the second time around.

The purpose of the present study was to assess and compare the therapeutic effects of imipramine during the initial treatment and retreatment of panic disorder with agoraphobia patients. Seven women with panic disorder with agoraphobia who had shown a marked and stable response to imipramine (121.4 +/- 41.8 mg/day) during their initial treatment of 24 weeks were retreated with the same dose (125 +/- 40.8 mg/day) of imipramine when they relapsed, on average 3 months following discontinuation of the drug. Assessments included operationalized criteria for response and relapse and plasma drug concentrations to verify treatment compliance. Data on phobic, panic, anxiety and depression measures were analyzed for 6 assessment times common to all patients; pretreatment, week 8 and 24 weeks follow-up of initial treatment, relapse which was also the beginning of retreatment, week 8 and 16-24 weeks follow-up of retreatment. At the end of retreatment all patients were marked responders and there was no significant difference on any outcome measure between the end of initial and retreatment assessment periods. However, overall therapeutic response to retreatment was slower than during initial treatment, in particular on phobic and patient rated panic measures. Although the full restoration of remission is clinically reassuring, the results caution that relapse may have sensitizing effects which delay, and if repeated could impede the response of panic disorder with agoraphobia patients to imipramine.

Adult↗
PubMedDate not supplied

Loading dose imipramine--new approach to pharmacotherapy of melancholic depression.

This study investigated the therapeutic efficacy of loading doses of imipramine hydrochloride and compared it with that of conventional gradually escalating dose regimen of the same drug in 16 melancholic depressives (DSM III-R), done in a comparative, randomized, double-blind research design. There were four males and four females in each group who were comparable on socio-demographic and clinical variables. The study group received the bolus doses of imipramine on two consecutive days and was free of any antidepressant treatment between day 3 and day 7 of the treatment period, whereas the control group received the conventional regime of gradual escalation of imipramine dose over a period of 7 days. The results indicate that imipramine hydrochloride can relieve depression almost completely within 72 h, if given in high bolus doses, thus challenging the theory of lag period for antidepressant action as an inherent property of this drug. The study shows that the pulse loading dose was superior to a conventional dose regime with regard to both antidepressant efficacy and rapidity of onset of action. The various mechanisms possibly involved in such a dramatic improvement and its implications have been discussed.

Adolescent↗
PubMed1982

Effect of methiothepin on imipramine- or mianserin- induced subsensitivity of serotonergic receptors.

Effect of methiothepin on imipramine- or mianserin- induced subsensitivity of serotonergic receptors was examined in rat brain. Treatment with either imipramine plus methiothepin or mianserin plus methiothepin for 4 days resulted in a significant decrease in [3H]5-hydroxytryptamine ([3H]5-HT) binding in synaptic membranes. The binding was not significantly decreased after treatment for this period of time with either methiothepin, imipramine or mianserin alone. It is suggested that the elevated intrasynaptic 5-HT levels could contribute to potentiation effect of methiothepin on imipramine- or mianserin-induced down regulation of serotonergic receptors.

Animals↗
PubMed1982

Sex differences in the uptake and retention of imipramine and desmethylimipramine in the rat lung.

14C-Imipramine was administered to male and female Sprague-Dawley rats and animals were sacrificed at 4, 8, 12, and 20 hours later. At all time points, total radioactivity in female lung was several-fold higher than in males. In addition, female lungs had a higher concentration of desmethylimipramine (DMI) as compared to imipramine than did male rat lungs. This was reflected by a higher conversion of imipramine to DMI by hepatic and pulmonary microsomes from female rats. Finally male rats cleared both imipramine and DMI from their lungs at a slower rate than did female rats.

Animals↗
PubMed1983

[3H]2-Nitroimipramine: a selective "slowly-dissociating" probe of the imipramine binding site ("serotonin transporter") in platelets and brain.

Previous studies have demonstrated a close functional and structural relationship between the "high affinity" binding site for [3H]imipramine and the presynaptic and platelet uptake site(s) for serotonin. Recently we have synthesized several nitro derivatives of imipramine which have a very high affinity for the imipramine binding site and which dissociate very slowly when incubations are performed at 0-4 degrees C. In this report, we describe the characteristics of [3H]2-nitroimipramine binding to platelet and brain membranes. Our results support the relative utility of this ligand for studying the impramine binding site (serotonin transporter) since this analogue has both a higher affinity and specific activity than [3H]imipramine. [3H]2-Nitroimipramine by virtue of its extremely slow dissociation rate should be a valuable tool in subsequent characterization and purification of the serotonin uptake or transport site.

Animals↗
PubMed1983

Distribution of chlorpromazine and imipramine in adipose and other tissues of rats.

Adipose tissue kinetics of chlorpromazine and imipramine, two drugs which are more lipophilic than thiopental, were studied in the rat. After single i.v. doses, the time-course of drug distribution was followed in adipose and various other tissues, until their concentrations in adipose tissues declined. Under these conditions the two drugs behaved almost identically. Among the tissues analyzed, the lowest concentrations were found in adipose tissue, with the exception of plasma. At its maximum concentration after about 30 minutes, total adipose tissue contained only 3% of the dose of administered drugs. Adipose/plasma and adipose/lung concentration ratios were 2-5 and 0.05, respectively. After maximum tolerated oral doses of imipramine for 3 weeks, similar steady state concentration ratios (plasma:adipose:brain:lung 1:3:12:96) were observed. In adipose tissue the imipramine/desmethylimipramine ratio was about 1, and the desmethylimipramine steady state levels did not increase with time. Literature data indicate that many basic lipophilic drugs are not stored in adipose tissue. This is now clearly shown for chlorpromazine and imipramine, even under extreme, subchronic conditions in the case of imipramine.

Adipose Tissue↗
PubMed1983

Serotonin uptake and imipramine binding in blood platelets and brain of Fawn-hooded and Sprague Dawley rats.

The kinetic parameters of serotonin (5-HT) uptake and imipramine binding of the synaptosomes and blood platelets of male Fawn-hooded rats, which have a 5-HT storage abnormality, and normal Sprague-Dawley rats were compared. The Vmax for 5-HT uptake of synaptosomes from Fawn-hooded rats was significantly greater than that of Sprague-Dawley rats whereas that of the platelets did not differ. The Km values of both the synaptosomes and platelets of the two rat strains were not significantly different. The Bmax values for 3H-imipramine binding in both platelets and brain of Fawn-hooded rats were significantly lower than those of the Sprague-Dawley rats. The Kd of imipramine binding to platelet membranes from Fawn-hooded rats was significantly less than that of the Sprague-Dawley rats but the Kd of the synaptosomes was not significantly different. These results indicate that 5-HT uptake and imipramine binding sites may be independently regulated and that platelets do not always manifest abnormalities present in brain 5-HT neurons and vice versa.

Animals↗
PubMed1985

Demonstration of endogenous "imipramine like" material in rat brain.

The extraction and partial purification of an endogenous "imipramine- like" material from rat brain is described. The endogenous factor obtained after gel filtration and silica chromatography inhibits [3H] imipramine specific binding and mimics the inhibitory effect of imipramine on [3H] serotonin uptake in both brain and platelet preparations. The effects of the endogenous material are dose-dependent and it inhibits [3H] imipramine binding in a competitive fashion. The factor is unevenly distributed in the brain with high concentration in the hypothalamus and low concentration in the cerebellum.

Animals↗
PubMed1985

Serotonin uptake inhibitors differentially modulate high affinity imipramine dissociation in human platelet membranes.

The influence of selective serotonin uptake inhibitors on the dissociation rate of 3H-imipramine from its high affinity binding site in human platelet membranes was studied. Of the uptake inhibitors tested, one group of compounds attenuated dissociation, another group accelerated it, while a third group had little effect on the dissociation process. Drugs unrelated to the serotonin uptake system were ineffective. Removal of sodium ions markedly increased imipramine dissociation. Dose response curves of the active compounds indicated that micromolar concentrations were required to exert an effect on imipramine dissociation. These results can be adequately explained by an allosteric model which includes effector binding sites and distinct conformational states of the high affinity imipramine binding site.

Blood Platelets↗