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PubMed1987

Uptake of imipramine in neurons cultured from rat cerebellum.

Imipramine was taken up by rat cerebellar neurons in primary culture. The process was dependent on time, temperature and pH and was reduced in the presence of the adenosine triphosphatase (ATPase) inhibitor dicyclohexylcarbodiimide or in the absence of glucose. Uptake approached saturation at 100 microM imipramine where approximately 42 nmol of the drug accumulated intracellularly per mg cell protein. Propranolol, but not serotonin, competed for imipramine uptake and uptake was inhibited by the 'lysosomotropic' amine chloroquine and by the Na+/H+ ionophore monensin, both of which dissipate proton gradients. Neurons were fractionated on Percoll gradients and the fractions exposed to [3H]imipramine. MgATP-dependent accumulation of [3H]imipramine was found mainly in fractions enriched for dense lysosomes. We conclude that imipramine was taken up by cerebellar neurons in primary culture and accumulated at high concentrations in intracellular compartments.

Animals↗
PubMed1989

Imipramine alters beta-adrenergic, but not serotonergic, mediated responses in rat hippocampal pyramidal cells.

Imipramine, a tricyclic antidepressant, acts acutely to block the reuptake of serotonin (5-HT) and norepinephrine (NE). However, imipramine's action as an antidepressant takes several weeks to develop. This study investigated acute and chronic effects of imipramine on intracellularly-recorded responses mediated by 5-HT and beta-adrenergic receptors on pyramidal cells from area CA1 of rat hippocampal slices maintained in vitro. Addition of 10 microM imipramine in the perfusion medium sinistrally shifted the 5-HT1A concentration-response curve for membrane hyperpolarization and the 5-HT concentration-response curve for the reduction in the amplitude of the slow afterhyperpolarization (AHP) elicited by a train of action potentials. After two weeks of treatment with imipramine (10 mg/kg daily i.p. injections or s.c. osmotic mini-pumps) the responses to 5-HT were not altered. In contrast the concentration-response curve for the beta-adrenergic mediated reduction in AHP amplitude was significantly altered; there was a reduction in Emax and a log unit dextral shift in EC50. There was no change in the concentration-response curve for the beta-adrenergic mediated depolarization. These data are in agreement with previous biochemical results reporting a decrease in beta-adrenergic receptor mediated stimulation in adenylyl cyclase and down-regulation of beta-receptor in cortex and hippocampus. These findings suggest that a consequence of long-term imipramine treatment is a decrease in the augmentation of cell excitation normally produced by beta-adrenergic receptor stimulation.

Action Potentials↗
PubMed1983

[3H]imipramine binding in subcellular fractions of rat cerebral cortex after chemical lesion of serotonergic neurons.

The specific high affinity binding of [3H]imipramine was investigated in subcellular fractions of rat cerebral cortex before and after chemical denervation of serotonergic neurons. In control animals the proportion of the total number of [3H]imipramine binding sites in the nuclear (N), heavy mitochondrial (M), light mitochondrial (L) and microsomal (P) fractions corresponded respectively to 3, 45, 16 and 36% of the total number of binding sites. After chemical lesion of serotonergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) the density of [3H]imipramine binding sites in fractions M and L was decreased by 42 and 52% respectively. In these experiments the uptake of [3H]5-HT in fractions M and L decreased by approximately 80%. The Bmax of [3H]imipramine binding in fraction P was decreased by 80% after chemical denervation with 5,7-DHT. In the control group there was no detectable [3H]5-HT uptake while the endogenous serotonin levels in fraction P were rather low. Our results support the view that the high affinity binding of [3H]imipramine is partly located on serotonergic nerve terminals. The significance of the [3H]imipramine binding sites present in the microsomal (P) fraction remains to be clarified.

5,7-Dihydroxytryptamine↗
PubMed1983

Imipramine associations with plasma components and its uptake by cultured human cells.

It has been proposed that in vivo variability in response to certain hydrophobic chemicals or drugs, such as imipramine, may be due in part to the varying plasma lipid levels in patients. The distribution of [3H]imipramine into the lipoproteins of human plasma was therefore studied. Differential density centrifugation of plasma containing [3H]imipramine resulted in flotation of very low density, low density and high density lipoproteins (VLDL, LDL, HDL) and approximately one-third of the total 3H radioactivity. Twelve percent of the radioactivity was present in the sedimented fraction which included most of the plasma proteins. There appeared to be little specific binding of [3H]imipramine to VLDL or LDL, as shown by ultracentrifugation, dialysis and column chromatography. [3H]Imipramine was readily incorporated into cultured human fibroblasts;o no differences were observed in cellular uptake whether it was added to the medium in plasma, LDL or HDL. Also, no differences in uptake of [3H]imipramine by LDL-receptor positive and receptor negative cells were noted. These experiments indicate that LDL is not a major vehicle for the transport of this drug and that both the bound and free fractions are available for cellular uptake.

Cells, Cultured↗
PubMed1986

Pharmacokinetics of imipramine are affected by age and sex in rats.

Chronic treatment with the antidepressant imipramine (IMI) leads to accumulation of imipramine's major metabolite desmethylimipramine (DMI) in the brain. Juvenile, young and middle-aged female rats, as well as juvenile and young male rats were treated chronically with imipramine (14 days) and analyzed 24 hours later for levels of IMI and DMI in the hypothalamus-preoptic area (HPA) and serum. Older animals of both sexes showed higher levels of DMI than juvenile animals, in both the HPA and serum. Females also had higher DMI levels than males at comparable ages. Analysis of IMI and DMI levels at intervals after a single imipramine injection suggested that the initial metabolism of imipramine is slower in older animals and in females (compared to males). The results indicate that age and gender alter the initial metabolism of imipramine, leading to enhanced accumulation of metabolites during chronic treatment in older animals and in female rats, compared to younger rats and males, respectively.

Aging↗
PubMed1983

On the mode of action of imipramine: relationship between serotonergic axon terminal function and down-regulation of beta-adrenergic receptors.

Recognition sites for [3H]imipramine and [3H]mianserin are located in different structures and regulate different neuronal functions. Recognition sites for [3H]imipramine are located on serotonergic terminals, are part of the supramolecular organization of the uptake mechanisms and can be down-regulated by prolonged administration of the drug. When the number of recognition sites for imipramine is down-regulated, uptake of 5-hydroxytryptamine (5HT) in rat brain hippocampal slices is increased. The presence of the binding sites for imipramine in 5HT terminals is essential to mediate the down-regulation of recognition sites for norepinephrine (NE) and NE-mediated stimulation of adenylate cyclase. Mianserin binds on a site that is modulated by 5HT, the number of its binding sites is not down-regulated by repeated treatment and, like imipramine, decreases the NE-dependent cyclase but not the number of beta-adrenergic receptor recognition sites. Repeated treatment with imipramine and mianserin down-regulated the number of 5HT2 recognition sites. Several lines of evidence indicate that binding site for mianserin is related but not identical to the 5HT2 receptor binding site.

Animals↗
PubMed1985

The effects of imipramine and iprindole on the metabolism of octopamine in the rat.

Acute injections of imipramine and iprindole in rats produced significant decreases in the concentration of p-hydroxyphenylglycol (pHPG), a neutral metabolite of octopamine in brain at 6 and 24 hr after the administration of drugs. The 24-hr urinary levels of both free and total pHPG were reduced to 25-29% of control with acute administration of imipramine, while iprindole produced a 30% decrease in free pHPG. With chronic administration of imipramine, concentrations of pHPG in brain returned to normal, while the 24-hr urinary levels were still decreased (to 24%). Octopamine in brain was unaltered after both single and repeated injections of imipramine. Thus, these data suggest that the turnover of octopamine in brain is reduced after acute administration of imipramine and iprindole, while after chronic treatment with imipramine, turnover of octopamine in brain has returned to control levels.

Animals↗
PubMed1988

Norepinephrine and (Na+, K+)-ATPase: evidence for stabilization by lithium or imipramine.

These experiments examined the effects of lithium and imipramine on the regulation by norepinephrine in vivo of (Na+, K+)-ATPase in brain and heart. The binding of ouabain and the activity of K+-phosphatase were used as indices of (Na+, K+)-ATPase. In the cerebral cortex, imipramine prevented, and lithium reduced, the increase in (Na+, K+)-ATPase associated with repeated injections of yohimbine. Imipramine and yohimbine had synergistic effects on the increased release of norepinephrine and on decreased binding to beta-receptors. Effects on the binding of beta-noradrenergic receptors suggested that imipramine partially reduced stimulation of ATPase by reducing the maximum effect of beta-receptors, while the effect of lithium may have involved a reduction in the exposure of receptors to norepinephrine. Imipramine also increased (Na+, K+)-ATPase in the cerebral cortex of reserpine-treated rats. These results suggest that lithium and imipramine, by different mechanisms, can stabilize fluctuations in the physiological consequences of binding to noradrenergic receptors.

Animals↗
PubMed1981

Human platelet imipramine recognition sites: biochemical and pharmacological characterization.

The influence of the membrane environment on the integrity of the human platelet [3H]-imipramine recognition site was examined. When platelet membranes were isolated in a buffer containing enzyme inhibitors (EDTA, EGTA and antiprotease) a significantly greater number of high affinity [3H]-imipramine binding sites was observed. A calcium-stimulated degradation of imipramine sites was also demonstrated. This degradation occurred in vitro over physiologically relevant time periods. Furthermore, inactivation of imipramine binding was achieved by very low concentrations (IC50 = 5 microgram/ml) of phospholipase A2. Specific serotonin reuptake inhibitors were potent displacers of [3H]-imipramine binding; histamine (H1), alpha-adrenergic (alpha 1), and muscarinic agents were much less active. The receptor was shown to be proteinaceous in nature due to its sensitivity to protease, heat denaturation and chemical modification with N-ethylmaleimide. From these results it is proposed that membrane lipid perturbations, catalyzed by calcium, may control expression of platelet [3H]-imipramine sites. The relation of this recognition site to aminergic systems and the possible relevancy to the action of antidepressants are addressed.

Blood Platelets↗
PubMed1991

Involvement of 5-HT1A activity in the discriminative stimulus effects of imipramine.

Pigeons were trained to discriminate the tricyclic antidepressant imipramine (3.0 or 5.6 mg/kg) from saline. The selective 5-HT1A agonist 8-OH-DPAT (0.03-1.0 mg/kg) resulted in dose-dependent increases in responding on the key correlated with imipramine administration. Doses of 8-OH-DPAT from 0.3 to 1.0 mg/kg substituted completely for imipramine. NAN-190 (0.3-3.0 mg/kg), a putative 5-HT1A antagonist with affinity for both 5-HT1A and alpha 1 receptors, blocked the discriminative stimulus effects of imipramine and resulted in saline-key responding. The discriminative stimulus effects of imipramine were also blocked by administration of the alpha 1-adrenoceptor antagonist prazosin, suggesting a dual mediation of imipramine through both 5-HT1A and alpha 1-adrenoreceptor systems. Although antidepressants have not been used frequently as stimuli in drug discrimination studies, it may be possible to arrive at a more complete understanding of their neurochemical and behavioral effects using this procedure.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Disappearance of memory deficits in outpatient depressives responding to imipramine.

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

Adult↗
PubMed1985

Decreased high affinity 3H-imipramine binding in platelets of enuretic children and adolescents.

High affinity 3H-imipramine binding sites have been demonstrated in human brain and platelet membranes. It has been suggested that these binding sites selectively label serotonin transporter or uptake sites. Since imipramine has a beneficial effect in the treatment of nocturnal enuresis, the present study was carried out to investigate a possible association between alteration in 3H-imipramine binding parameters in enuretics in comparison to nonenuretic control subjects. 3H-Imipramine binding to platelets was examined in 16 enuretic children and adolescents and compared to that in 22 healthy subjects of similar ages. A significant reduction was observed in the number of 3H-imipramine binding sites, while the dissociation constants (Kd) did not differ significantly in the platelets of enuretics as compared to controls. 3H-Imipramine binding values did not discriminate between familial and nonfamilial enuresis. These results may indicate that an alteration in the serotonin transporter in peripheral or central neuronal levels might be involved in the pathophysiology of nocturnal enuresis.

Adolescent↗
PubMed1989

Selective breeding in rats for extreme densities of platelet 3H-imipramine binding sites: evidence against a trait hypothesis.

Some investigators suggest that the number of platelet 3H-imipramine binding sites is genetically determined and that the reduced 3H-imipramine binding observed in some studies of depression represents a trait marker. Others believe that 3H-imipramine binding is state-dependent because 3H-imipramine binding has been reported to normalize after clinical recovery. We used a genetic selection paradigm in rats to approach this question from another direction. While breeding 10 generations of rats, we used either extremely high or extremely low density of platelet 3H-imipramine binding sites as a selection criterion. We were unsuccessful in producing two distinct rat sublines. These data do not support a predominant genetic influence on 3H-imipramine binding.

Animals↗
PubMed1989

3H-imipramine binding in the frontal cortex of suicides.

Imipramine binding (desipramine- and serotonin-sensitive) was determined in the frontal cortex of suicide victims and nonpsychiatric controls who died due to medical disease or accidents. There were no differences in Kd or Bmax of imipramine binding between controls and suicides. The Kd and Bmax values of serotonin-sensitive imipramine binding were significantly lower than desipramine-sensitive imipramine binding, both in controls and suicides. There were significant correlations between Kd and Bmax of serotonin-sensitive imipramine binding and desipramine-sensitive imipramine binding in suicides but not in controls.

Adolescent↗
PubMed1983

Distribution of imipramine binding sites in the rat brain studied by quantitative autoradiography.

The distribution of imipramine binding sites in rat brain was examined by the LKB film method of autoradiography. Brain sections were labeled in vitro with [3H]imipramine in the presence or absence of 100 microM unlabeled desmethylimipramine to define non-specific binding. The binding of [3H]imipramine to brain sections was saturable, specific and of a high affinity (2-6 nM). There were very high levels of imipramine binding sites in the dorsal and medial raphe nuclei and over the superficial layers of the superior colliculus. Moderately high concentrations were observed in the olfactory tubercule, interpeduncular nucleus and substantia nigra, among others. There were low levels of binding sites over white matter and in the ventral thalamus. The distribution of imipramine binding sites parallels the distribution of serotonin terminals in rat brain. These results are consistent with the hypothesis that the high affinity imipramine binding site is associated with the presynaptic uptake site for serotonin.

Animals↗
PubMed1988

Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine.

[3H]Imipramine and [3H]paroxetine were used to label sites associated with serotonin uptake mechanisms in post-mortem brain tissue from control subjects. The anatomical localization of these sites was examined by autoradiography and densities measured by microdensitometry. We found [3H]imipramine binding to increase with age in the cortex and amygdala, but to be independent of gender and post-mortem delay. Preliminary results indicate that the binding of both [3H]imipramine and [3H]paroxetine is diminished in the brain of patients treated with imipramine. The distribution of [3H]imipramine and [3H]paroxetine high-affinity binding sites was very similar, and correlated well with the distribution of serotonergic presynaptic markers in the brain. The highest densities of binding sites were found in the raphé nuclei and the midline thalamic nuclei. Other structures presenting high levels of binding were the substantia nigra, nucleus interpeduncularis, locus coeruleus, nucleus nervi hypoglossi, nucleus nervi facialis, mammillary bodies and other parts of the hypothalamus. In contrast, regions such as the neocortex, hippocampus, amygdala and cerebellum showed low densities of [3H]imipramine and [3H]paroxetine binding sites. This distribution seems to indicate that the ascending serotonergic pathways are the main site of action of antidepressants.

Aged↗
PubMed1996

Cerebral metabolism of imipramine and a purified flavin-containing monooxygenase from human brain.

Flavin-containing monooxygenase (FMO), previously reported both from hepatic and extrahepatic tissues, including brain, catalyze the oxidation of certain xenobiotics and drugs that contain a nucleophilic heteroatom. Psychoactive drugs, including the antidepressant imipramine, are substrates for the brain FMO. Since FMO-mediated metabolism of these drugs might contribute to local pharmacodynamic modulation within the human brain, the metabolism of imipramine by human brain FMO was studied in further detail. In the present study, the FMO activity was determined in human brain microsomes by estimating the actual amount of imipramine N-oxide formed. It was then compared with the corresponding activity measured using substrate (imipramine)-stimulated rates of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation, which was significantly higher than the activity estimated as the amount of N-oxide assayed using high-pressure liquid chromatography (HPLC). The brain FMO activity was measurable only in the presence of detergents (sodium cholate or Lubrol PX) or in microsomes that were freeze-thawed several times. The activity was inhibited by an antibody to rabbit pulmonary FMO, but an antiserum to the rat liver NADPH cytochrome P-450 reductase had no effect indicating that cytochrome P-450 was not involved in the above metabolic pathway. The optimum pH for N-oxidation of imipramine was found to be 8.5; thermolability experiments indicated that the FMO activity was completely lost only after the incubation of brain microsomes at 45 degrees C for 20 minutes. An FMO purified to apparent homogeneity from a human brain had a molecular weight of 71,000 Da. The purified enzyme cross-reacted with the antibody to rabbit pulmonary FMO and efficiently catalyzed the metabolism of imipramine to its N-oxide. The human brain clearly contains an active FMO system, and it is conceivable that such enzymes are significantly involved in the local metabolism and modulation of pharmacological and/or toxic effects of certain xenobiotics, including psychoactive drugs.

Antidepressive Agents, Tricyclic↗
PubMed2004

Differential effect of imipramine and related compounds on Mg2+ efflux from rat erythrocytes.

The effect of imipramine on Mg2+ efflux in NaCl medium (Na+/Mg2+ antiport), on Mg2+ efflux in choline.Cl medium (choline/Mg2+ antiport) and on Mg2+ efflux in sucrose medium (Cl- -coupled Mg2+ efflux) was investigated in rat erythrocytes. In non-Mg2+-loaded rat erythrocytes, imipramine stimulated Na+/Mg2+ antiport but inhibited choline/Mg2+ antiport and Cl- -coupled Mg2+ efflux. The same effect could be obtained by several other compounds structurally related to imipramine. These drugs contain a cyclic hydrophobic ring structure to which a four-membered secondary or tertiary amine side chain is attached. At a physiological pH, the amine side chain expresses a cationic choline-like structure. The inhibitory effect on choline/Mg2+ antiport is lost when the amine side chain is modified or abandoned, pointing to competition of the choline-like side chain with choline or another cation at the unspecific choline antiporter or at the Cl- -coupled Mg2+ efflux. Other related drugs either stimulated Na+/Mg2+ antiport and choline/Mg2+ antiport, or they were ineffective. For stimulation of Na+/Mg2+ antiport and choline/Mg2+ antiport, there is no specific common structural motif of the drugs tested. The effects of imipramine on Na+/Mg2+ antiport and choline/Mg2+ antiport are not mediated by PKCalpha but are caused by a direct reaction of imipramine with these transporters. By increasing the intracellular Mg2+ concentration, the stimulation of Na+/Mg2+ antiport at a physiological intracellular Mg2+ concentration changed to an inhibition of Na+/Mg2+ antiport. This effect can be explained by the hypothesis that Mg2+ loading induced an allosteric transition of the Mg2+/Mg2+ exchanger with low Na+/Mg2+ antiport capacity to the Na+/Mg2+ antiporter with high Na+/Mg2+ antiport capacity. Both forms of the Mg2+ exchanger may be differently affected by imipramine.

Animals↗