Increased antidepressant-like effect of desipramine combined with central stimulants (caffeine and amphetamine) in mice

Desipramine is a widely used antidepressive agent that inhibits the reuptake of noradrenaline and serotonin, and central stimulants such as caffeine and amphetamine help to release noradrenaline and serotonin. This work aimed to evaluate whether the combination of these agents could produce a stronger antidepressant-like effect than either of the drugs alone. To this end, male mice were treated with different doses of desipramine, caffeine, amphetamine, desipramine-caffeine and desipramine-amphetamine. The results showed that all drugs produced decreased immobility time in the forced swimming model. The combined treatment of desipramine (0.31, 1.0 or 3.1 mg/kg i.p.) with caffeine or amphetamine (0.31 or 1 mg/kg i.p.) reduced immobility time greater than either of those drugs alone. The combined treatment of desipramine (0.31, 1 and 3.1 mg/kg i.p.) with amphetamine or caffeine (0.1 and 1 mg/kg i.p.) did not increase the motor activity significantly compared to the control. These results also suggested that drugs which promote the release of noradrenaline and serotonin could increase antidepressant-like effect of desipramine.     

Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade

Parietal and occipital cortices, while densely innervated by noradrenalin 2 (NA) projections, possess a comparatively sparse dopamine 2 (DA) innervation, even sparser than the prefrontal cortex. We previously reported that reboxetine and desipramine, two selective norepinephrine transporter (NET) blockers, at doses that maximally increase DA in the prefrontal cortex, do not increase DA in the parietal and occipital cortices. In the present study, we performed a full dose-response study of the effect of systemic reboxetine and desipramine on DA and NA in dialysates from the parietal and occipital cortices. Seven doses of reboxetine (0.1, 0.25, 0.5, 1.0, 2.5, 5.0 and 10 mg/kg) and four doses of desipramine (0.25, 1.0, 2.5 and 5.0 mg/kg) were tested. Reboxetine and desipramine differentially affected dialysate DA as compared with NA. Reboxetine increased DA maximally by about 100% after doses of 0.25-0.5 mg/kg and showed a bell-shaped dose-response function in both areas; desipramine did not affect DA in the parietal cortex and increased it in the occipital cortex only at 2.5 mg/kg. NA was maximally increased by 275% by 0.5-2.5 mg/kg reboxetine and by about 300% by 5.0 mg/kg desipramine with a more linear dose-response curve. The mechanism of peculiar dose-response function of dialysate DA after reboxetine and desipramine was further investigated by testing the effect of drugs on dialysate DA and NA under alpha(2) receptor blockade. Under local perfusion of the occipital cortex with idazoxan, an otherwise ineffective dose of reboxetine and desipramine (5 mg/kg) became effective in raising extracellular DA. In contrast, the effect of reboxetine on NA was potentiated, while that of desipramine was not affected. These results suggest that, in the parietal and occipital cortices, extracellular NA, raised by NET blockade, exerts a preferential inhibitory influence on DA release by acting on local alpha(2) receptors, thus accounting for the bell-shaped feature of the dose-response function of drugs on dialysate DA in these areas.     

Simultaneous determination of lofepramine and desipramine by a high-performance liquid chromatographic method used for therapeutic drug monitoring

A simple reversed-phase HPLC method with ultraviolet detection for the simultaneous measurement of lofepramine and desipramine is described. Only a single alkaline extraction was used, with clomipramine as internal standard. The column used was to Supelco PCN column, and the mobile phase was acetonitrile-methanol-0.015 M phosphate buffer (120:35:100, v/v). The average recoveries were 78.8% for desipramine and 103.8% for lofepramine, and limits of quantitation were 25 and 5 nmol/1, respectively. The inter-assay C.V.s for lofepramine and desipramine were 6.0 and 7.6%, respectively. The method is specific and has excellent accuracy, and has been used for therapeutic drug monitoring of patients with depressions treated with lofepramine. Mean steady-state plasma concentrations found for lofepramine and desipramine were 8.5 ± 6.1 and 123.6 ± 120.6 nmol/l, respectively. It is concluded that lofepramine in itself has an antidepressive effect.     

A Microdialysis Study of the Regulation of Endogenous Noradrenaline Release in the Rat Hippocampus

In vivo microdialysis was used to investigate the regulation of noradrenaline release in rat hippocampus. Idazoxan, an alpha 2-adrenoreceptor antagonist (1-10 mg/kg), increased noradrenaline release in a dose-dependent manner. Inhibition of noradrenaline uptake by desipramine (0.05-20 microM; via the probe) also increased the extracellular content of the transmitter. In the presence of this increased noradrenaline content (desipramine via the probe), the effect of a low dose of idazoxan (1 mg/kg) was potentiated. Local perfusion of idazoxan (1-500 microM) in the hippocampus also increased noradrenaline release but not to the same extent as following systemic administration. In the presence of desipramine, unlike the systemic injection of idazoxan, local perfusion did not potentiate noradrenaline release. The data are consistent with the regulation of extracellular noradrenaline content in the hippocampus by neuronal uptake and to a lesser extent by presynaptic autoreceptors.     

Desipramine inhibits histamine H1 receptor-induced Ca2+ signaling in rat hypothalamic cells

The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca(2+) evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca(2+) increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca(2+) increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants.     

Vasopressinergic neurons in rats during ontogenesis: reaction to salt-loading and its modulation by noradrenergic afferents

Salt-loading in adult mammals stimulates vasopressin secretion by vasopressinergic neurons of the supraoptic nucleus that is under control by a number of hormones and neurotransmitters including noradrenalin. This study was aimed to determine at what period of ontogenesis the vasopressinergic neurons begin to respond to salt-loading and when the noradrenergic control of this process is switched on. Rats on the 21st embryonic day (E), the 3rd postnatal day (P) and P13 were salt-loaded, sometimes under simultaneous treatment with prasozin, an inhibitor of al -adrenoreceptors. Thereafter, the hypothalamic nuclei of the animals were processed for immunocytochemistry and in situ hybridization. Salt-loading provoked increased synthesis of vasopressin mRNA and, most probably, vasopressin itself in rats in all studied age groups. Under salt-loading, the intraneuronal content of vasopressin increased significantly at E21 and P3, whereas it did not change at P13. No change in the intracellular contents of vasopressin mRNA and vasopressin was observed in foetuses following salt-loading and treatment with prasozin though the same treatment provoked an increase of both parameters at P3. These data show that noradrenalin provides an inhibitory control of vasopressin expression at least since P3. Thus, vasopressinergic neurons begin to respond to salt-loading at the since P3. Thus, life by the increased expression of vasopressin that is postnatally under the inhibitory control by noradrenalin.     

Chronic desipramine treatment increases activity of noradrenergic postsynaptic cells

Chronic administration of tricyclic antidepressant drugs has been shown to exert multiple influences on various mechanisms of noradrenergic nervous systems. To determine the overall effect of these influences, this study examined the effect of long-term desipramine administration on the firing rate of noradrenergic postsynaptic neurons, specifically, those in the rat hippocampus that were inhibited by the nucleus locus coeruleus. Daily injections for 3 weeks of 5 or 10 mg/kg desipramine resulted in a 32% or 49% increase, respectively, of hippocampal cell activity, suggesting that long-term desipramine treatment is antagonistic to noradrenergic functions.     

TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment

Adult hippocampal neurogenesis is stimulated by chronic administration of antidepressants (ADs) and by voluntary exercise. Neural progenitor cells (NPCs) in the dentate gyrus (DG) that are capable of continuous proliferation and neuronal differentiation are the source of such structural plasticity. Here we report that mice lacking the receptor tyrosine kinase TrkB in hippocampal NPCs have impaired proliferation and neurogenesis. When exposed to chronic ADs or wheel-running, no increase in proliferation or neurogenesis is observed. Ablation of TrkB also renders these mice behaviorally insensitive to antidepressive treatment in depression- and anxiety-like paradigms. In contrast, mice lacking TrkB only in differentiated DG neurons display typical neurogenesis and respond normally to chronic ADs. Thus, our data establish an essential cell-autonomous role for TrkB in regulating hippocampal neurogenesis and behavioral sensitivity to antidepressive treatments, and support the notion that impairment of the neurogenic niche is an etiological factor for refractory responses to an antidepressive regimen.     

The effect of GABA-ergic agents on the development of a neurogenic stomach lesion in rats

Neurogenic gastric lesions in rats were induced by combination of immobilization with 3-h long electrostimulation. After this stress a distinct decrease of noradrenalin and creatine phosphate content and then the activation of lipid peroxidation (LPO) in the stomach tissue was recorded. If the stress treatment was preceded by application of piracetam and fenibute, gastric tissue trophic was protected by way of prevention from a decrease of the content of noradrenalin, creatine phosphate and the activation of LPO.     

The mechanism of action of peptides acting on smooth muscle. II. Relationships between angiotensin II and adrenergic systems with reference to blood pressure regulation]

To explore the molecular and subcellular effects of Angiotensin II during the early phase of an experimental hypertension, biochemical and morphological changes induced by continued administration of subpressoric Angiotensin II doses were traced in rats. After the treatment, the endogenous noradrenalin and dopamine content was changed in various brain regions, the turnover rate of noradrenalin was lowered, and the neuronal 3H noradrenalin uptake was delayed and reduced. Electron microscopy revealed an increase in number and granulation of adrenergic vesicles in the hypothalamus, and characteristic changes at pre- and postsynaptic membrane complexes. The interaction between central effects of angiotensin II and the adrenergic system presumably involves disturbance at the level of neuronal membranes.     

Desipramine induced changes in salivary proteins, cultivable oral microbiota and gingival health in aging female NIA Fischer 344 rats

Cyclic antidepressants are still a dominating group of psychotherapeutic drugs used in the treatment of depression. One of their major side effect is salivary gland dysfunction (oral dryness, xerostomia), leading in humans to increased oral disease and dysfunction of speech, chewing, swallowing and taste. The purpose of this study was to assess the effects of the long-term administration of the tricyclic antidepressant desipramine and the reversibility of this treatment following a 15 d washout period on specific salivary proteins, composition of oral microbiota, and oral health (gingivitis) of aging female F344 rats. Total salivary proteins showed decreased concentrations with age and desipramine. Similar SDS/PAGE protein profiles appeared in all phases but in different relative amounts with age and treatment. While certain proteins maintained steady levels (lactoferrin) or decreased with age and treatment (amylase), the synthesis of proline-rich proteins, high molecular weight mucin-type glycoproteins, and lysozyme was induced with desipramine and age. The oral microbiota was significantly changed with age and the administration of the antidepressant. The incidence of gingivitis with desipramine was highest in the oldest animals, For the different parameters measured, recovery was delayed with age. These data indicate, that desipramine has profound effects on salivary protein secretion. This may partially explain the changes in microbiota and the increased incidence of gingivitis.     

Microelectrophoretic study of unit responses of the rabbit amygdaloid nucleus to acetylcholine and noradrenaline

Responses of 152 neurons of the basal and lateral nuclei of the amygdala and of the anterior amygdaloid field to microelectrophoretic application of acetylcholine and noradrenalin, in the case of 115 neurons to both substances, were investigated in immobilized, unanesthetized rabbit. In the basal nucleus 35% of neurons tested responded to acetylcholine, most often by an increase in discharge frequency (34%), and 63% of cells responded to noradrenalin, most of them giving inhibitory responses (53%). A response to only one of the two substances applied in turn was given by 45% of neurons. Among neurons responding to both acetylcholine and noradrenalin, 23% of cells did so in the opposite direction and only 11% in the same direction.     

Down-regulation of norepinephrine transporter expression on membrane surface induced by chronic administration of desipramine and the antagonism by co-administration of local anesthetics in mice

We have previously shown that chronic administration of the antidepressant desipramine, a norepinephrine transporter (NET) inhibitor to mice markedly enhanced convulsions induced by local anesthetics and that behavioral sensitization may be relevant to decreased [(3)H]norepinephrine uptake by the isolated hippocampus. The co-administration of local anesthetics with desipramine reversed the behavioral sensitization and down-regulation of NET function induced by desipramine. The present study aimed to elucidate whether chronic treatment with desipramine regulates the expression of NET protein examined in membrane fractions in various brain regions and whether co-administration of local anesthetics affects the desipramine-induced alteration of NET expression. Desipramine with or without local anesthetics was injected intraperitoneally once a day for 5 days. The animals were decapitated 48 h after the last administration of drugs and the whole cell fraction, membrane fraction and cell-surface protein fraction were prepared. [(3)H]nisoxetine binding was significantly reduced in the P2 fraction of the hippocampus by chronic administration of desipramine, and the reduction was overcome by co-administration of lidocaine with desipramine. Immunoreactive NET was detected by SDS-PAGE and immunoblotting in the murine hippocampus. NET protein expression in the whole cell fraction and membrane fraction was not affected by treatment with any drugs. However, administration of desipramine significantly reduced the amount of immunoreactive NET in the cell-surface protein fraction. This reduction was blocked by simultaneous injection of lidocaine, bupivacaine or tricaine. These results indicate that the NET down-regulation indicated by the reduction of [(3)H]nisoxetine binding was induced by administration of desipramine via decrease of NET localization on the cell surface. The antagonistic actions of local anesthetics against NET down-regulation by desipramine were related to alterations of the cell-surface localization of NET.     

Repetitive transcranial magnetic stimulation in a patient suffering from depression and rheumatoid arthritis: evidence for immunomodulatory effects

Repetitive transcranial magnetic stimulation (rTMS) has been suggested as antidepressive treatment strategy. The mechanism of action by which the antidepressive effect is brought about remains unclear at present. Here, we report findings in a patient suffering from recurrent major depression and rheumatoid arthritis. Improvement of depressive symptoms during 20 Hz rTMS of the left dorsolateral prefrontal cortex was repeatedly associated with a systemic inflammatory reaction, suggesting that rTMS induced an immunomodulatory effect.     

Effect of the Tricyclic Antidepressant Desipramine on β-Adrenergic Receptors in Cultured Rat Glioma C6 Cells

Rat glioma C6 cells, cultured in the presence of the tricyclic antidepressant desipramine, lost a significant number of beta-adrenergic receptors in a time- and dose-dependent manner. A similar loss was observed whether binding was determined on intact cells with the hydrophilic beta-adrenergic antagonist (+/-)-[3H]4-(3-tert-butylamino-2-hydroxypropoxyl)benzimidazole-2-o n HCl ([3H]CGP-12177) or on cell lysates with the more hydrophobic antagonists [125I]iodocyanopindolol or [3H]dihydroalprenolol. When stimulated with the agonist isoproterenol, desipramine-treated cells accumulated less cyclic AMP than control cells. The affinity of the beta-adrenergic receptors for either antagonist or agonist was unchanged after desipramine treatment. Desipramine interacted only weakly with the receptors and competed for [125I]iodocyanopindolol binding with a Ki of 30 microM. The presence in the culture medium of alprenolol or propranolol, potent beta-adrenergic antagonists, however, did not prevent the reduction in receptors by desipramine. Desipramine also caused a loss of beta-adrenergic receptors from cells maintained in serum-free medium and the cells themselves did not contain or secrete endogenous catecholamines. Although desipramine is a potent inhibitor of catecholamine uptake, it appears unlikely that the observed loss of beta-adrenergic receptors in rat glioma C6 cells exposed to the drug is due to an increase in extracellular catecholamine levels or to a direct interaction with the receptors.     

Increased cardiac production of dihydroxyphenylalanine (DOPA) during sympathetic stimulation in anaesthetized dogs.

Entry of dihydroxyphenylalanine (DOPA) into plasma from specific organs may reflect regional activity of tyrosine hydroxylase, the enzyme responsible for the immediate synthesis of DOPA and rate-limiting for subsequent formation of catecholamines. Therefore, cardiac spillovers of DOPA, noradrenaline and the intraneuronal metabolite of noradrenaline, dihydroxyphenylglycol (DHPG), were examined during two periods of graded electrical stimulation of the sympathetic nerves to the heart in anesthetized dogs. Responses were examined before and after neuronal uptake blockade with desipramine. Cardiac spillover of DOPA increased by 1.8- and 4.4-fold during sympathetic stimulation before desipramine and by 1.6- and 3.3-fold after desipramine. Fold increases in cardiac spillover of DOPA were much lower than but positively related with fold increases in noradrenaline spillover (5.9- and 13.8-fold increases before and 9.0- and 15.8-fold increases after desipramine). Increases in cardiac spillover of DHPG (1.5- and 2.3-fold increases) were blocked by desipramine so that fold changes in spillover of DOPA were greater than and poorly related to changes in spillover of DHPG. Fold increases in cardiac spillover of DOPA showed a close one-to-one positive relationship with fold increases in the sum of cardiac spillovers of noradrenaline and dihydroxyphenylglycol before and after desipramine. For a given fold increase in noradrenaline release, transmitter turnover is increased fractionally and noradrenaline synthesis need also only increase fractionally to maintain transmitter stores constant. The close relationship between fold increases in cardiac spillover of DOPA and combined spillovers of noradrenaline and DHPG is consistent with regulation of tyrosine hydroxylase activity to match changes in noradrenaline synthesis with changes in noradrenaline turnover. Changes in cardiac spillover of DOPA appear to reflect local changes in tyrosine hydroxylase activity.     

Catecholamine effects on cardiac remodelling,oxidative stress and fibrosis in experimental heart failure

The aim of the study was to assess the relationships between oxidative stress, cardiac remodelling and fibrosis on an experimental model of heart failure with adrenergic stimulation. Large myocardial infarction (approximately 50% of the left ventricle myocardium) was obtained by ligation of the left coronary artery of normotensive male Wistar rats. Sham animals were submitted to left thoracotomy without coronary ligation. In order to perform cardiac stimulation by catecholamines, mini-osmotic pumps were implanted in animals 10 weeks after surgery to deliver noradrenalin for a 2-week period. At the end of this period, the following investigations were performed: haemodynamics, morphometry, fibrosis quantification, plasma and tissue catecholamine assay and oxidative stress status. Coronary ligation induced dilatation of left ventricle with compensatory hypertrophy of the right ventricle and of the remaining left ventricle myocardium. This remodelling process was associated in non-infarcted myocardium with increased collagen infiltration and increased oxidative stress. Ten weeks after surgery, the chronic administration of noradrenalin for 2 weeks did not increase oxidative stress. Noradrenalin, however, induced inotropic stimulation and myocardial hypertrophy, but to a lesser extent in infarcted rats compared to sham rats. Our results suggest that noradrenalin infusion to levels in excess of those seen post-infarction is associated with fibrosis and oxidative stress. Moreover, noradrenalin in infarcted animals caused additional fibrosis without further increasing oxidative stress. The mechanism of catecholamine-induced fibrosis may thus involve different processes such as ischaemia, increased mechanical stress, cytokines and neurohormones.     

Effect of long-term administration of antidepressants on the lipid composition of brain plasma membranes

The connection between changes in lipid pattern in brain plasma membranes and long-term administration of therapeutically effective doses of antidepressants has not been sufficiently demonstrated so far. Therefore, we analyzed effect of antidepressants that differ in pharmacological selectivity on membrane lipid composition in the rat brain tissue. Laboratory rats were given desipramine, maprotiline, citalopram, moclobemide or lithium for a 4-week period. We observed a significant decrease in phosphatidylethanolamine representation after administration of maprotiline, citalopram and moclobemide when compared with controls. Membrane cholesterol content was decreased after desipramine administration and increased after citalopram or lithium treatment. Electroneutral phospholipids were decreased after the administration of all tested antidepressants except for desipramine. Decrease in phosphatidylserine was found following long-term administration of maprotiline or desipramine; relative representation of phosphatidylinositol was reduced after lithium treatment. Statistically significant negative correlation between cholesterol and electroneutral phospholipids was discovered. Membrane microviscosity evaluated by fluorescence anisotropy of membrane probes was only slightly decreased after desipramine and increased after citalopram administration. Hypothesis was supported that changes in brain neurotransmission produced by antidepressants could be, at least partially, associated with adaptive changes in membrane cholesterol and phospholipids.     

Effect of desipramine on Ca2+ levels and growth in renal tubular cells

The in vitro effect of desipramine on renal tubular cell is unknown. In Madin-Darby canine kidney (MDCK) cells, the effect of desipramine on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2. Desipramine (>25 microM) caused a rapid and sustained rise of [Ca2+]i in a concentration-dependent manner (EC50=50 microM). Desipramine-induced [Ca2+]i rise was prevented by 40% by removal of extracellular Ca2+ but was not altered by L-type Ca2+ channel blockers. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which desipramine failed to release more Ca2+; in addition, pretreatment with desipramine partly decreased thapsigargin-induced [Ca2+]i increase. U73122, an inhibitor of phospholipase C, did not change desipramine-induced [Ca2+]i rise. Incubation with 10-100 microM desipramine enhances or inhibits cell proliferation in a concentration- and time-dependent manner. The inhibitory effect of desipramine on proliferation was not extracellular Ca2+-dependent. Apoptosis appears to contribute to desipramine-induced cell death. Together, these findings suggest that desipramine increases baseline [Ca2+]i in renal tubular cells by evoking both extracellular Ca2+ influx and intracellular Ca2+ release, and can cause apoptosis.