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PubMed1997

Increased synaptic availability of norepinephrine following desipramine is not essential for increases in GR mRNA. Short communication.

Male Sprague-Dawley rats were treated for 7 days with the norepinephrine (NE) uptake inhibitors desipramine (DMI) or (+)-oxaprotiline or the inactive (-)-enantiomer of oxaprotiline. DMI, as previously reported, significantly increased hippocampal glucocorticoid receptor (GR) mRNA while the equipotent NE uptake inhibitor (+)-oxaprotiline like the inactive (-)-oxaprotiline did not alter hippocampal levels of GR mRNA. The results indicate that an increase in the synaptic availability of NE as a consequence of uptake inhibition is not responsible for the action of DMI on GR gene expression.

Adrenergic Uptake Inhibitors↗
PubMed1992

Paraphilias: a double-blind crossover comparison of clomipramine versus desipramine.

A relationship has been suggested between clinical presentation of paraphilias and obsessive-compulsive disorder (OCD) with respect to the unwanted repetitive nature and insight into the irrationality of the paraphiliac behavior. This has led to speculation that paraphiliac disorders might belong to an "obsessive compulsive spectrum." To address this issue, and because of the striking selective benefit of serotonin reuptake blocking antidepressants (such as clomipramine) in the treatment of OCD, 15 paraphiliacs entered a double-blind crossover comparison of clomipramine vs. desipramine preceded by a 2-week single-blind placebo period. Four subjects responded to placebo and were dropped from the study. Three others failed to complete the study. Although the study is limited by the small number of patients and the heterogeneity of the paraphilias, the observed benefit from both tricyclics (over the initial placebo) encourages further study. For the 8 subjects completing the protocol, there was no preferential response to the more specific serotonin reuptake inhibitor suggesting a difference in underlying pathophysiology between paraphilia and OCD.

Adult↗
PubMed1995

Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreases binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain.

1. The effects of chronic administration of five antidepressant drugs on the benzodiazepine and 5-HT2A binding sites in the same rat brain were assessed. 2. Clomipramine, desipramine, maprotiline, fluoxetine, and phenelzine (all 10 mg/kg/day) were administered s.c. for 21 days by Alzet osmotic minipumps. 3. Results showed that none of the drugs changed the density or affinity of benzodiazepine binding sites, yet at the same dose all the drugs with the exception of fluoxetine decreased binding to 5-HT2A receptors in the same animals.

Animals↗
PubMed1992

Effects of acute and chronic desipramine treatment on somatostatin receptors in brain.

The effects of acute (5 mg/kg, IP twice daily for 2 days) and chronic (5 mg/kg IP twice daily for 21 days) administration of desipramine (DMI) on [125I]-Tyr11-somatostatin binding sites in brain were examined. There was no change in [125I]Tyr11-somatostatin binding in membranes prepared from the frontal cortex, striatum, and hippocampus of rats acutely or chronically treated with DMI as compared to non treated animals. [125I]Tyr11-somatostatin binding was increased in membranes prepared from the rat nucleus accumbens only after chronic DMI administration. Scatchard analysis of the binding data from the nucleus accumbens showed that [125I]Tyr11-somatostatin labels a single population of somatostatin binding sites with an affinity constant, Kd, of 1.8 +/- 0.60 nM and a Bmax of 330 +/- 90 fmol/mg protein. Chronic treatment with DMI increased the Bmax (500 +/- 140 fmol/mg protein) but had no effect on the Kd. This finding shows a regional effect of DMI on [125I]Tyr11-somatostatin binding sites in rat brain and suggests that somatostatin may play a role in the pathophysiology of depression.

Animals↗
PubMed1995

Blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists.

This study examined whether the antidepressant-like effect of serotonin (5-HT)1A receptor agonists in the forced swim test (FST) is mediated by 5-HT1A receptors. The 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and buspirone decreased immobility in the FST. The effect of 8-OH-DPAT was blocked by the 5-HT1A receptor antagonists NAN 190, BMY 7378 and pindolol. The effect of buspirone was blocked by NAN 190 and pindolol. The antagonists produced no effects on their own. The norepinephrine (NE) uptake inhibitor desipramine (DMI) also reduced immobility, and this was also blocked by NAN 190, BMY 7378 and pindolol. The alpha 1, beta 1 and beta 2 adrenergic antagonists prazosin, betaxolol and ICI 118,551 did not block either 8-OH-DPAT or DMI, and produced no effects on their own. These results provide evidence that the antidepressant-like effects of 5-HT1A receptor agonists in the FST are mediated through 5-HT1A receptors, probably located postsynaptically. The finding that the 5-HT1A receptor antagonists blocked the effect of DMI suggests that the NE and 5-HT systems interact in the FST.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

The effect of carbamazepine on the 2-hydroxylation of desipramine.

The effect of carbamazepine (CBZ, 200 mg twice daily for 28 days) on the kinetics of a single oral dose of desipramine (DMI, 100 mg) was investigated in six healthy volunteers. Compared with a control session, treatment with CBZ caused a marked increase in DMI apparent oral clearance (from 1.05 +/- 0.40 to 1.38 +/- 0.52 1 h per kg, means +/- SD, P < 0.01) and a significant shortening in DMI half-life (from 22.1 +/- 3.5 to 17.8 +/- 3.5 h, P < 0.01). The amount of 2-hydroxydesipramine (2-OH-DMI) excreted in urine over a 24-h period was significantly increased during CBZ intake (from 75 +/- 15 to 92 +/- 16 mumol, P < 0.01). These findings suggest that CBZ induces the 2-hydroxylation of DMI, a reaction primarily catalyzed by the polymorphic CYP2D6 isozyme. This interaction may have considerable practical significance.

Adult↗
PubMed2003

Differential effects of K(ATP) channel blockers on [(3)H]-noradrenaline overflow after short- and long-term exposure to (+)-oxaprotiline or desipramine.

To test whether prolonged uptake blockade can lead to changes in the function of ATP-dependent potassium (K(ATP)) channels we investigated in rat neocortex slices the effects of K(ATP) channel blockers on electrically evoked [(3)H]-noradrenaline ([(3)H]-NA) overflow after short- (45 min) and long-term (210 min) exposure to the NA uptake blockers (+)-oxaprotiline or desipramine (1 microM each). The K(ATP) channel blocker glibenclamide (1 micro M) increased the evoked [(3)H]-NA overflow by 42% after short-term uptake inhibition. This effect was confirmed by tolbutamide and glipizide, two other K(ATP) channel antagonists. The evoked [(3)H]-NA overflow was enhanced by 73% following short-term uptake blockade (15 min) and by 110% following long-term blockade (180 min). After long-term blockade (210 min), however, glibenclamide failed to further enhance the overflow of [(3)H]-NA. The alpha(2)-autoreceptor-mediated feedback control was not involved in the glibenclamide-induced increase in [(3)H]-NA overflow after short-term uptake blockade or in the increase in [(3)H]-NA overflow due to long-term uptake blockade per se. The Na(+)/K(+)-ATPase inhibitor ouabain diminished the glibenclamide-induced enhancement of [(3)H]-NA overflow after short-term uptake blockade, suggesting that an operative Na(+)/K(+)-ATPase is the prerequisite of activation of K(ATP) channels. These results suggest that short-term uptake blockade activates the Na(+)/K(+)-ATPase, thereby reducing intracellular ATP which allows transient opening of K(ATP) channels. Activation of the Na(+)/K(+)-ATPase may increase the Na(+) gradient, probably over the membrane of noradrenergic nerve terminals. The resulting hyperpolarisation leads to inhibition of the evoked overflow which can be reversed, i.e. enhanced, by K(ATP) channel blockers. In contrast, longer lasting uptake blockade seems to reduce the activity of the Na(+)/K(+)-ATPase and hence the consumption of ATP. As a consequence, reduced Na(+) and K(+) gradients may facilitate transmitter release. Closure of K(ATP) channels by accumulating ATP may further promote membrane depolarisation and transmitter release. The unexpected effect of longer exposure to uptake blockers could be somehow related to the clinical time latency of the antidepressant efficacy of monoamine uptake blockers.

Adenosine Triphosphate↗
PubMed2005

Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex.

RATIONALE: The density of tyrosine hydroxylase-immunoreactive (TH-IR) axons in the prefrontal cortex of schizophrenic subjects may be reduced by as much as 50% in the deep cortical layers (Am J Psychiatry 156:1580-1589, 1999). Previously, we demonstrated that approximately 60% loss of TH-IR axons in the rat medial prefrontal cortex (mPFC) decreases local basal and stress-evoked extracellular dopamine (DA) concentrations, suggesting that moderate loss of DA axons in the mPFC is sufficient to alter the neurochemical activity of the remaining DA neurons (Neuroscience 93:497-505, 1999). OBJECTIVES: To further assess the functional consequences of partial mPFC DA depletion, we examined the effects of 6-hydroxydopamine lesions of the rat mPFC on behavior in a T-maze delayed-response task. We also assessed whether chronic administration of the norepinephrine (NE) uptake inhibitor, desipramine (DMI), attenuates lesion-induced deficits in T-maze performance. Previous research indicates that inhibition of NE transport in the mPFC results in a concomitant increase in extracellular DA and NE. RESULTS: Moderate loss of mPFC DA and NE (approximately 50 and 10% loss, respectively) was sufficient to impair delayed-response behavior, in part due to an increase in perseverative responding. Chronic DMI treatment (3 mg/kg delivered via osmotic pumps) impaired performance of control rats but attenuated the deficits in delayed-response behavior in rats previously sustaining loss of mPFC DA and NE (approximately 75 and 35% loss, respectively). CONCLUSION: These data suggest that moderate loss of DA and NE in the prefrontal cortex is sufficient to impair cognitive function, and these behavioral effects are attenuated by inhibition of the NE transporter.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Synthesis and positron emission tomography evaluation of three norepinephrine transporter radioligands: [C-11]desipramine, [C-11]talopram and [C-11]talsupram.

Desipramine (DMI), talopram and talsupram, three of the most potent norepinephrine transporter (NET) inhibitors reported to date, were radiolabeled in high yields and at high specific radioactivity (58-75 GBq/micromol) by the methylation of nor-precursors with [C-11]methyl triflate. The regional brain distribution of each radioligand following intravenous injection into cynomolgus monkey was examined in vivo with positron emission tomography (PET). For all three radioligands, the regional brain distribution of radioactivity was slightly heterogeneous, with higher uptake of radioactivity in the mesencephalon, thalamus and lower brainstem than in striatum. The rank order of maximal brain radioactivity (as percentage of injected dose) was [C-11]DMI (2.7%) > [C-11]talsupram (1.3%) > [C-11]talopram (0.7%). The appearance of radioactive metabolites in plasma was similar for each radioligand (75-85% of radioactivity in plasma at 45 min). These metabolites were all more polar than their parent radioligand. The data show that these radioligands are inferior to existing radioligands for the study of brain NET with PET in vivo.

Animals↗
PubMed1986

Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors.

The effects of the antidepressant drug desipramine (DMI) on the density of beta-adrenoceptor sites were studied on intact cultured human cells: skin fibroblasts, lung fibroblasts and macrophages. Direct binding studies were performed with the radioligand 3H-CGP 12177, a hydrophilic beta-adrenergic antagonist. The confluent cell cultures were exposed to DMI and all three cell types showed a dose-dependent decrease in the number of beta-adrenergic binding sites. This receptor desensitisation was only seen after chronic exposure of the cells to DMI. The extent of desensitisation was comparable to that seen in brain following chronic treatment of rats with DMI. The affinity of the binding sites to the radioligand was not affected by the antidepressant drug action. From these results we suggest that the in vivo effect of antidepressant drugs on postsynaptic beta-adrenoceptor density, at least in part, reflects a primary drug action and not only an adaptive change to presynaptic events.

Cell Line↗
PubMed1986

The effect of neuroleptics on imipramine demethylation in rat liver microsomes and imipramine and desipramine level in the rat brain.

A study of the cytochrome P-450 level and imipramine (IMI) demethylase activity in liver microsomes of rats treated concurrently with IMI and chlorpromazine (CPZ) or IMI and chlorprothixene (CPX) for two weeks were carried out. Concomitant administration of IMI and CPZ or IMI and CPX elevated the cytochrome P-450 level and accelerated IMI demethylation in in vitro study. Kinetic study of IMI demethylation carried out in the absence or in the presence of CPZ or CPX revealed that those neuroleptics inhibited IMI demethylation via competitive mechanism. Simultaneously with the enzymatic study the brain level of IMI and its demethylated metabolite desipramine (DMI) was assessed. It was found that 1 hr after withdrawal of IMI and CPZ or IMI and CPX the brain level of IMI was elevated in comparison with that of IMI treated animals, and the ratio between DMI/IMI brain concentration was decreased. When the assessment of IMI and DMI brain level was performed 24 hr after withdrawal of IMI and CPZ or IMI and CPX, there was no difference between the concentration of IMI and DMI in both, experimental and control animals.

Animals↗
PubMed1987

Subcellular distribution of the antidepressant drug desipramine in cultured human fibroblasts after chronic administration. Drug-effect on the subcellular distribution of accumulated phospholipids.

Desipramine (DMI) is an important antidepressant drug and a lysosomotropic substance. In cultured fibroblasts it interferes with lysosomal functions, e.g. phospholipid degradation. Chronic exposure of cells with DMI induces storage of phospholipids. Subcellular fractionations of cultured human fibroblasts that had been exposed to a short pulse of 3H-DMI showed accumulation of DMI in two acidic compartments, one of high density represented the lysosomes and one of much lower density may contain pinosomes. In chronically exposed cells DMI accumulated in the subcellular fractions of lower density only. DMI induced an important shift of lysosomal enzymes from vesicles of high density to the ones of lower density. Phospholipids were accumulating in those vesicles of lower density as well as in the fractions that contained plasma membranes. DMI also accumulated in one part of the Golgi vesicles of acute and chronically exposed cells. In the latter phospholipids and arylsulfatase A activity were also accumulating. DMI possibly interferes with membrane recycling. This eventually could induce changes in phospholipid content and composition in the plasma membrane which may have important implications for membrane functions.

Cell Fractionation↗
PubMed1988

Organ-specific, qualitative changes in the phospholipid composition of rats after chronic administration of the antidepressant drug desipramine.

Rats were chronically treated with daily i.p. injections of 10 mg/kg desipramine for 21 days. A 30% decrease in the number of beta-adrenoceptors was observed in brain. A receptor desensitization of similar extent was noted in submaxillary glands and lung. No change in beta-adrenoceptor number was present in heart. Total phospholipid contents were not altered in these organs after chronic drug treatment. However, organ-specific changes were found in the phospholipid composition of submaxillary glands, lung and liver but not in whole brain and heart. The changes were variable but an increase in phosphatidylinositol and decreases in phosphatidylethanolamine and sphingomyelin were consistent. Possible alterations in the phospholipid composition of the brain might have been masked by the large and stable pool of myelin phospholipids. A casual relationship between changes in the phospholipid composition and beta-adrenoceptor desensitization is discussed.

Animals↗
PubMed1990

Single and multiple desipramine exposures of cultured cells. Changes in cellular anisotropy and in lipid composition of whole cells and of plasma membranes.

Effects of the antidepressant drug desipramine (DMI) on fluorescence anisotropy were studied in living cultured human fibroblasts, rat brain astrocytes and rat ROC-1 hybridoma cells (oligodendrocytes x C6). Fluorescence anisotropy, a measure for fluidity, was measured by means of a fluorescence polarization technique using a set of n-(9-anthroyloxy) fatty acids as markers. Apparent fluorescence anisotropies were determined in cells following single or multiple dose exposures to 5 microM DMI at 37 degrees and compared to control cells. In all three cell types single doses of DMI led to significant decreases in anisotropies of the deeper layers (12-AS) of the membranes only, suggesting increases in fluidity. Repeated exposures to 5 microM DMI led to cell specific, significant changes in anisotropies of the superficial membrane layers, as determined by 2-AP, 6-, 7- and 9-AS. The resulting anisotropy values of the three different cell types became more alike than prior to DMI exposure. Alterations in anisotropies were accompanied with changes in the phospholipid patterns of whole cells and isolated plasma membrane vesicles. The changes of PC/PE ratios were consistent with changes observed in fluorescence anisotropies. Such alterations may be individual regulatory responses of the cells to the chronic presence of the drug within the membranes.

Animals↗
PubMed1996

Inhibition of microsomal cytochromes P450 in rat liver by the tricyclic antidepressant drug desipramine and its primary oxidized metabolites.

N-Monoalkyl substituted tricyclic antidepressants like desipramine (DES) undergo cytochrome P450 (P450)-mediated biotransformation in liver to produce inhibitory metabolite-intermediate (MI) complexes with the enzyme. However, additional oxidation pathways that generate isolable metabolites have also been identified, so that the relationship between MI complexation and total oxidative metabolism is unclear. The present study investigated the capacity of DES and three putative metabolites (2-hydroxy- and 10-hydroxy-DES and N,N-didesmethylimipramine; DIDES) to elicit MI complexation and inhibit P450-dependent activities in rat liver. MI complexation of P450 was produced by DES, but not with the three metabolites, in NADPH-supplemented microsomes. Consistent with this finding, inhibition of testosterone hydroxylation pathways was enhanced markedly by prior incubation of DES with NADPH and microsomes. Direct addition of DIDES to incubations resulted in significant inhibition of P450 activities (IC50s of 35 and 29 microM against estradiol 6 beta- and 16 alpha-hydroxylation mediated by P450s 3A2 and 2C11, respectively). Neither 2-hydroxy- nor 10-hydroxy-DES directly inhibited testosterone hydroxylation (IC50s > 100 microM). However, after a preincubation step between these metabolites and NADPH-fortified microsomes, enhanced inhibition of reactions mediated by P450 3A2 and P450 2C11/2A1 was produced by 2-hydroxy-DES and 10-hydroxy-DES, respectively. Metabolism of DES to DIDES and 2-hydroxy-DES was estimated as 7.77 +/- 0.48 nmol/mg protein/hr (10-hydroxy-DES was not detected). It is likely that secondary oxidized metabolites derived from 2-hydroxy-DES, as well as the primary metabolite DIDES, may contribute to the inhibition of P450 activity during DES biotransformation. These results indicate that the 2-hydroxy-, 10-hydroxy-, and N-desmethyl-metabolites of DES are not involved in MI complexation, but complexation is not the sole mechanism by which DES inhibits microsomal drug oxidation that may lead to pharmacokinetic drug interactions.

Animals↗
PubMed1996

Effects of recombinant drug-specific single chain antibody Fv fragment on [3H]-desipramine distribution in rats.

Tricyclic antidepressant overdose can be reversed in rats by drug-specific antibody Fab fragments, but the required Fab dose may itself by toxic. We studied the potential use of a smaller, recombinant desipramine (DMI)-specific single chain Fv fragment (B9-sFv) for this purpose. Anesthetized rats received a tracer (subtoxic) dose of [3H]-DMI followed in 15 min by B9-IgG, B9-Fab, B9-sFv (0.1 mumol of binding sites) or BSA. Each of the active treatments produced a rapid and substantial increase in the serum radiolabel concentration, whereas BSA did not (P < 0.001). The increase in serum radiolabel concentration 1 min after treatment was 13.3-fold with B9-IgG, 10.0-fold with B9-Fab and 7.3-fold with B9-sFv. Serum antibody concentrations were also highest after B9-IgG and lower with B9-Fab or B9-sFv. The 24-hr urinary excretion of radiolabel did not differ among groups, but was extensive even in the BSA group and probably represented the excretion of DMI metabolites. B9-sFv concentrations in urine or buffer at 37 degrees declined by >90% over 24 hr, but this fragment was much more stable in serum, retaining 70% of its activity after 96 hr. These data demonstrate that B9-sFv can alter markedly the distribution of [3H]-DMI in vivo. The rapidity of this effect, and its magnitude in comparison with Fab fragment or IgG, suggest that further study of B9-sFv as a treatment of DMI overdose is warranted.

Analysis of Variance↗