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PubMed1987

Effects of chronic amitriptyline and desipramine on food intake and body weight in rats.

Long-term treatment with tricyclic antidepressant drugs (TCAs) can induce excessive body weight gain in a significant proportion of patients. Such weight gains, which appear to be largely independent of clinical improvement, are in many cases severe enough to interfere with continuation of treatment. In efforts to model this effect in experimental animals, seven experiments were performed in which two commonly used TCAs, amitriptyline and desipramine, were administered chronically to rats. Despite manipulations of drug dosages (2.5 mg-17 mg/kg), route of administration (intraperitoneal, subcutaneous, oral; daily injections vs. continuous release from osmotic pumps), diet composition and palatability (regular Purina Chow pellets or powder with or without added high fat and high carbohydrate sources; high vs. low protein diets) and animal sex and housing conditions (single vs. group housing), chronic TCA treatment was never observed to increase daily food intake or rates of body weight gain. Desipramine treatment invariably caused decreased food intake and weight loss. Amitriptyline treatment either caused no change in food intake and body weight or slightly reduced levels in comparison to vehicle-treated controls. However, both amitriptyline- and desipramine-treated rats showed a potentiation of acute caloric intake after a single systemic injection of the glucoprivic agent 2-deoxy-D-glucose. These results are considered against the background of human clinical observations. Possible reasons for the differences between human and animal data are discussed.

Amitriptyline↗

PubMed1985

Effect of desipramine on control of ventilation and depression scores in patients with severe chronic obstructive pulmonary disease.

Decreased ventilatory responses to carbon dioxide (CO2) correlate with elevated scores on tests for depression in normal subjects and with episodes of endogenous depression in psychiatric patients. Patients with severe chronic obstructive pulmonary disease (COPD) frequently develop resting hypercapnia due to impaired ventilatory mechanics or drive, and may also have elevated scores on tests for depression. Tricyclic antidepressant drugs can improve ventilatory mechanics and possibly drive. We hypothesized that antidepressant drugs might enhance ventilatory drive and improve arterial blood gases in patients with severe COPD and that these improvements might correlate with improvement in depression scores. Therefore, we studied the effects of desipramine versus placebo on spirometry, resting arterial blood gases, hypercapnic ventilatory and mouth occlusion pressure responses, and scores on the Beck and Zung self-rated depression scales. In our patients the resting arterial CO2 (PaCO2) was found to depend almost equally on ventilatory mechanics and drive. In addition, patients with higher depression scores tended to have a lower PaCO2 when the severity of airways obstruction was taken into consideration. In a 16-week, double-blind, crossover comparison of desipramine with placebo, both treatments led to significant improvement in depression scores. Desipramine had no effects on resting PaCO2, spirometry, or ventilatory control.

Aged↗

PubMed1992

Effect of chronic antidepressant treatment with adinazolam and desipramine on melatonin output.

Output of melatonin or its main metabolite, 6-sulphatoxy melatonin, provides an index of noradrenergic activity in the pineal gland, which is of interest in major depression and during its treatment with antidepressants. Fifteen female depressed outpatients did not differ in levels of 24-hour urinary 6-sulphatoxy melatonin compared with 13 female control subjects. However, a subgroup of the depressed patients (n = 9) who were treated with desipramine showed a significant elevation of 6-sulphatoxy melatonin levels after 1 week of treatment and a return to baseline levels after 6 weeks. There was also a significant negative correlation between 6-sulphatoxy melatonin levels and symptom severity as measured by the Hamilton Rating Scale for Depression after 3 weeks of treatment with desipramine. The other subgroup of depressed patients (n = 6) were treated with adinazolam, a benzodiazepine with antidepressant properties. Despite comparable antidepressant effects to those achieved with desipramine, adinazolam was not associated with any apparent change in 6-sulphatoxy melatonin output during 6 weeks of treatment. There was also no correlation between 6-sulphatoxy melatonin levels and symptom severity.

Adult↗

PubMed1982

Elevation in analgetic effect and plasma levels of morphine by desipramine in rats.

Pretreatment of rats with desipramine (30 mg/kg, s.c.) enhanced both peak intensity and duration of morphine sulfate (5 mg/kg, s.c.) analgesia as determined by measurement of tail flick latency. Morphine concentrations in plasma were also significantly elevated after desipramine. Increased narcotic analgetic responses following desipramine pretreatment appear related to higher circulating levels of unmetabolized morphine.

Animals↗

PubMed1986

Desipramine enhances opiate postoperative analgesia.

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.

Amitriptyline↗

PubMed1992

Desipramine potentiates spinal antinociception by 5-hydroxytryptamine, morphine and adenosine.

The effects of pretreatment with desipramine, a selective noradrenaline (NA) uptake blocker, on spinal antinociception by 5-hydroxytryptamine (5-HT), morphine and an adenosine analog (NECA) in the rat hot-plate test were examined to determine if endogenous NA is involved in the spinal action of these agents. Desipramine, 25 mg/kg, had no significant intrinsic effect in the hot-plate test but potentiated spinal antinociception by NA and 5-HT. Potentiation was more prominent at higher doses of NA and 5-HT. Desipramine also enhanced the action of morphine and NECA, but, in these instances, the greatest enhancement occurred at lower doses. These results, in conjunction with others, suggest that 5-HT releases NA from the spinal cord while morphine and NECA interact synergistically with endogenously released NA.

Adenosine↗

PubMed1994

Long-term in vivo desipramine or estrogen treatment fails to affect serotonin-induced outward current in hippocampal pyramidal cells of the rat.

The effect of castration combined with either long-term treatment with the tricyclic antidepressant drug desipramine or the sex steroid 17 beta-estradiol on serotonin responses in area CA1 of the hippocampus of male and female rats was examined. Using single-electrode current and voltage-clamp techniques serotonin-induced hyperpolarizations and outward currents were recorded from hippocampal pyramidal cells. Neither in male nor in female castrated rats treatment effects were observed on the magnitude of the 5-hydroxytryptamine 1A mediated outward currents (0.26 nA) and membrane hyperpolarizations (11 mV) induced by superfusion of serotonin (15 microM), or on the effect of serotonin on the afterhyperpolarization and extracellularly recorded population spike. In voltage-clamp experiments using microelectrodes filled with potassium-chloride, but not with potassium-acetate, the sole observable effect was that the membrane resistance drop due to application of serotonin was significantly larger in the ovariectomized group (31% approximately 19 M omega) as compared to the ovariectomized/estrogen supplemented group (23% approximately 15 M omega). Spiperone (3 microM) completely antagonized the serotonin-induced outward currents and input resistance changes under all treatments. Apart from these changes the majority of passive and active membrane properties of cells from ovariectomized animals were not affected by chronic desipramine or steroid treatment. Neither did castration alone, nor in combination with long-term 17 beta-estradiol treatment, affect CA1 pyramidal cell membrane properties of male rats. Since we attained physiological levels of 17 beta-estradiol in the blood plasma (30-50 pg/ml) using subcutaneous silastic implants containing a mixture of cholesterol/estrogen, we conclude that both long-term estrogen and long-term desipramine treatment do not affect serotonergic neurotransmission in CA1 of the rat hippocampus.

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

PubMed1990

Beta-adrenoceptor and post-receptor components show different rates of desensitization to desipramine.

Both 3-day and 15-day desipramine treatments (10 mg/kg, once daily) significantly reduced beta 1- but not beta 2-adrenoceptor and isoproterenol-stimulated adenylyl cyclase activities in rat cortical, hippocampal and amygdaloid membrane preparations. In contrast, 15-day but not 3-day desipramine treatment resulted in a significant reduction in NaF-, GppNHp- and forskolin-stimulated adenylyl cyclase activity. The results suggest that post-beta-adrenoceptor component desensitization occurs more slowly than receptor downregulation in response to desipramine.

Adenylyl Cyclases↗

PubMed2006

Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze.

Antidepressants are usually prescribed for the treatment of depression but more recently have also been recommended for the treatment of anxiety disorders. The purpose of this study was to investigate the anxiogenic- or anxiolytic-like effects of an acute administration of antidepressants (serotonergic and noradrenergic compounds) in male Wistar rats submitted to the elevated plus-maze. Fluoxetine (2.5, 5, 10, 15mg/kg), paroxetine (0.1, 0.5, 3, 12mg/kg) and desipramine (2.5, 5, 10mg/kg) or their vehicles were administered intraperitoneally 30min prior to testing. Diazepam (0.5, 1.5, 2.5mg/kg) was used as a positive comparator for anxiolytic effect. In comparison with control animals, the percentage of time the rats treated with fluoxetine (5 and 10mg/kg) and paroxetine (3 and 12mg/kg) spent in the open arms decreased. The percent of inactive time spent in the open arms also decreased in rats given fluoxetine (5 and 10mg/kg) and paroxetine (12mg/kg). Desipramine was inactive on all these parameters. In conclusion, acute treatment with fluoxetine and paroxetine, but not with desipramine, produced a pattern of anxiety behavior. Thus, the pharmacological mechanism appears to be due more to serotonergic than adrenergic neurotransmission. The elevated plus-maze exhibits good sensitivity for detecting anxiogenic effects of antidepressant drugs and the conventional parameters are sufficient and reliable for detecting such effects.

Analysis of Variance↗

PubMed2004

Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine.

Atomoxetine is a selective norepinephrine (NE) reuptake blocker that has recently been marketed for the treatment of attention deficit hyperactivity disorder. The purpose of the present study was to evaluate the self-administration of atomoxetine in an animal model predictive of abuse liability in humans. Rhesus monkeys (N = 5) were prepared with chronic intravenous catheters and allowed to self-administer cocaine or saline during alternating baseline sessions. When behavior was stable, atomoxetine (0.03-3.0 mg/kg per injection), desipramine (0.1-3.0 mg/kg per injection), methylphenidate (0.001-0.1 mg/kg per injection), or their vehicles were substituted for baseline conditions. Methylphenidate consistently maintained responding above the levels maintained by its vehicle. Atomoxetine and desipramine failed to reliably maintain self-administration above vehicle levels in four of five individual monkeys. These results predict that atomoxetine, in contrast to methylphenidate but like desipramine, will lack reinforcing effects and abuse potential in humans.

Animals↗

PubMed2004

Alpha-tocopherol influences the lipid membrane affinity of desipramine in a pH-dependent manner.

Phopholipidosis is a lipid storage disorder caused by cationic amphiphilic drugs (CADs) characterized by the lysosomal accumulation of phospholipids and drug. alpha-Tocopherol (alpha-Toc) has a reversible effect on phospholipidosis in rats and cell culture. We studied the influence of alpha-Toc on the partitioning of the CAD desipramine in a liposome/buffer system using equilibrium dialysis with the following lipid compositions: egg phosphatidylcholine (PhC) or wheat germ phosphatidylinositol (PhI) or a combination of PhC, PhI and cholesterol, containing between 1.5 and 20% (mol per mol total lipids) of alpha-Toc, alpha-tocopherol acetate (alpha-TocAc), 2,2,5,7,8-pentamethyl-6-chromanol (PMC) or cholesterol. alpha-Toc (1.5%) enhanced the partition coefficient of neutral desipramine by up to 1.1 log units while it had no influence on the partitioning of the ionized compound. In the PhC liposome system, at pH 7.4 logD increased with increasing alpha-Toc concentrations but was unchanged at pH 4.5. Similar effects were found with PMC while alpha-TocAc or cholesterol, between 1.5 and 20%, had no influence on the partitioning of desipramine. From these results we postulate that in vivo, alpha-Toc could mediate a redistribution of CADs from lysosomal membranes (pH approximately 4.5) to membranes and lipoproteins at physiological pH.

Antidepressive Agents, Tricyclic↗

PubMed2006

The involvement of endogenous opioid mechanisms in the antinociceptive effects induced by antidepressant drugs, desipramine and trimipramine.

The present study was designed to investigate the involvement of endogenous opioid systems in the antinociception induced by the antidepressant drugs, desipramine and trimipramine. For this purpose, the antinociceptive effects of desipramine (7.5 and 15.0 mg/kg i.p.) and trimipramine (5.0 and 10.0 mg/kg i.p.) were compared to that induced by morphine (0.2 and 2.0 mg/kg i.p.) in the tail-clip model in mice. Naloxone (0.3 and 3.0 mg/kg i.p.), a non-specific opioid receptor antagonist, inhibited morphine-induced antinociception in mice, whereas the antinociceptive effects of antidepressant drugs were found to be resistant to naloxone blockade to some extent, since only the higher concentration of naloxone (3.0 mg/kg i.p.) caused significant inhibition of the effects of antidepressant drugs. In contrast, naltrindole (1.0 mg/kg i.p.), a specific delta-receptor antagonist, inhibited antinociception induced by desipramine and trimipramine in this test, while it inhibited the antinociceptive effect of morphine only partly. None of the opioid antagonists produced a significant effect in the tail-clip experiment when they were injected alone. Based on these findings, we concluded that endogenous opioids are involved in the antinociceptive effects of the antidepressant drugs using different mechanisms.

Analgesics↗

PubMed2000

Noradrenergic lesion antagonizes desipramine-induced adaptation of NMDA receptors.

Repeated administration of the tricyclic antidepressant, desipramine, for 28 days to mice effected a decrease in the potency of glycine to displace [3H]5,7-dichlorokynurenic acid (5,7-DCKA) in mouse cortical homogenates. Pre-treatment with the noradrenergic neurotoxin DSP-4, while having no effect alone, attenuated the desipramine-induced effect. The present findings support a norepinephrine-dependent adaptation of the NMDA receptor complex in vivo following chronic desipramine treatment. The inter-relationship of norepinephrine and glutamate transmission may provide insight into the mechanism underlying the action of antidepressant drugs.

Adaptation, Physiological↗

PubMed1982

Simultaneous analysis of imipramine and its metabolite desipramine in biological fluids.

A method for the simultaneous quantitation of imipramine and its N-demethylated metabolite desipramine at the nanogram level in a single gas chromatograph peak is presented, utilizing gas chromatography-mass spectrometry with selected ion recording. The assay is specific and quantitation is achieved using [2H4]imipramine as the internal standard. The method involves the in situ methylation of desipramine with [2H2]formaldehyde and sodium borohydride to give [2H2]imipramine. Quantitation is then achieved by selected ion recording at m/z 280, 282 and 284, whence the ratio of the ion currents at 280/284 and at 282/284 gives the quantities of imipramine and desipramine respectively.

Desipramine↗

PubMed2001

Effect of ACTH on the imipramine- and desipramine-induced decrease in duration of immobility time as measured in a rat forced swimming test.

In a rat forced swimming test (FS), we examined the effect of repeated injections of ACTH (adrenocorticotropic hormone) for 14 days on the decreased duration of immobility time produced by imipramine and desipramine. Both imipramine (15 and 30 mg/kg, p.o.) and desipramine (15 and 30 mg/kg, p.o.) significantly decreased the duration of immobility time in the FS. On the other hand, ACTH (100 microg/kg, i.p.) alone did not affect the duration of immobility time in FS. When ACTH (100 microg/kg, i.p.) was injected for 14 days before the 15-min swim session, it counteracted the decreased duration of immobility time induced by both imipramine and desipramine. Thus, ACTH seems to play a key role in decreasing the duration of immobility time of antidepressants in this test.

Adrenocorticotropic Hormone↗

PubMed1998

Influence of the antidepressants desipramine and fluoxetine on tryptophan-2,3-dioxygenase in the presence of exogenous melatonin.

The effects of desipramine and fluoxetine were examined on rat hepatic tryptophan-2,3-dioxygenase activity in the presence or absence of exogenous melatonin. Male Wistar rats were treated intraperitoneally over 8 days. The antidepressants were also administered individually and their impact on the enzyme noted. Desipramine reduced basal hepatic tryptophan-2,3-dioxygenase activity in the liver while fluoxetine had no observable effect. However, fluoxetine also prevented the hemin induced elevation in total enzyme activity. Exogenous melatonin (0.25mg/kg/day) for 8 days counteracted the inhibitory effects of both desipramine and fluoxetine at concentrations of 2.5mg/kg/day. Total enzyme activity was restored when melatonin was administered in combination with either drug. The experimental findings indicate that there is chemical antagonism at the surface of the enzyme between melatonin and the antidepressants that abolishes the observed inhibitory effects of the administered compounds.

Animals↗

PubMedDate not supplied

Antimalarial effect in vitro and lack of modulating effect of desipramine and imipramine.

Based on previous studies in vitro of the modulating effect of desipramine on chloroquine-resistance of Plasmodium falciparum, the effect of desipramine and imipramine on freshly isolated resistant Brazilian strains of the parasite was investigated. Both drugs in therapeutic doses showed an unexpected antimalarial effect in vitro in duplicate tests (IC50 = 44.26 and 46.53 micrograms/L for desipramine, and 83.93 and 41.26 micrograms/L for imipramine), but no reversal of resistance when added to cultures together with chloroquine.

Animals↗

PubMedDate not supplied

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.

Animals↗