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PubMed1995

Changes in the regulation of 5-hydroxytryptamine release by alpha2-adrenoceptors in the rat hippocampus after long-term desipramine treatment.

In vivo microdialysis was used to measure the effects of long-term treatment of rats with desipramine upon the regulation by alpha2-adrenoceptors of serotonin (5-hydroxytryptamine, 5-HT) release from the serotonergic neurons in the hippocampus. Rats were injected with saline or desipramine, 10 mg/kg, i.p., every 12 h for 14 days. When added to the perfusion solution, brimonidine, an alpha2-adrenoceptor agonist, significantly inhibited the K+-evoked release of 5-HT in the hippocampi of saline-treated, control rats. This action of brimonidine was prevented by pretreating the rats with idazoxan, an alpha2-adrenoceptor antagonist. Long-term desipramine treatment significantly reduced the inhibitory effect of brimonidine upon the K+-evoked 5-HT release. With long-term administration of desipramine, noradrenaline content in the hippocampi was significantly decreased as compared with that of the control rats, whereas the basal noradrenaline concentration in the dialysate was significantly increased. On the other hand, both the 5-HT content of the hippocampus and the basal 5-HT concentration in the dialysate were significantly increased. The present study suggests that long-term administration of desipramine causes a functional subsensitivity of the presynaptic alpha2-adrenoceptors that regulate serotonergic neuronal function in the rat hippocampus. It also supports the concept that changes in the sensitivity of alpha2-adrenoceptors that regulate neurotransmitter release play an important role in the mechanism of antidepressant drug action.

Animals↗

PubMed1984

Effect of desipramine, phenoxybenzamine and yohimbine on beta-adrenoceptors and cyclic AMP production in the rat brain.

In rat brain, the number of beta-adrenoceptors and activity of noradrenaline-dependent adenylate cyclase were examined after treatment with desipramine (7.5 mg kg-1 day-1) for three days alone or in combination with the alpha 2-adrenoceptor antagonist, yohimbine (2 mg kg-1 12 hr-1), or with phenoxybenzamine (7.5 mg kg-1 day-1), which is a more potent inhibitor of alpha 1 than alpha 2-adrenoceptors. The only treatment which significantly decreased the specific binding of the beta-adrenoceptor antagonist, [3H]dihydroalprenolol was the combination of desipramine with yohimbine. Desipramine alone and desipramine with yohimbine also significantly reduced the formation of cyclic AMP in response to incubation with noradrenaline, the response to the drug combination being accounted for by addition of the individual effects of the drugs. The results showed that decreases in the activity of noradrenaline-dependent adenylate cyclase could become apparent before decreases in beta-adrenoceptor numbers. Whether these rapid changes in noradrenaline-dependent adenylate cyclase or in numbers of beta-adrenoceptors which are produced by combination of desipramine with an alpha 2-adrenoceptor antagonist, are of therapeutic value remains to be elucidated.

Adenylyl Cyclases↗

PubMed1990

Antinociceptive effect of intrathecally-administered desipramine and zimelidine in rats.

The effect of intrathecally (i.th.) administered desipramine and zimelidine, in doses of 5, 10 and 50 micrograms, were investigated in the tail-flick test with simultaneous measurement of the temperature of the tail skin and in the increasing temperature hot-plate test. A constant negative correlation between the temperature of the tail skin and tail-flick latency, as described previously, was found. For all doses tested, desipramine induced longer tail-flick latencies, 10 min after injection than vehicle and the temperature of the tail skin tended to increase less in this group than in controls. After adjustment of the tail-flick latencies for the changes in the temperature of the tail skin, an antinociceptive effect of desipramine was still found. For zimelidine, only the largest dose (50 micrograms) was found to be antinociceptive, after adjustment for the tail skin temperature. In the increasing temperature hot-plate test, no antinociceptive effect of these antidepressants was found. For desipramine and zimelidine, the effect in the tail-flick test, 10 min after injection, indicates that the antinociceptive effect of these drugs may have, at least partly, a spinal site of action. In the increasing temperature hot-plate test, the response is integrated supraspinally. This may partly explain the lack of effect in this test when desipramine and zimelidine were administered intrathecally.

Analgesics↗

PubMed1986

Antagonism by dopamine, but not noradrenaline receptor blockers of the anti-immobility activity of desipramine after different treatment schedules in the rat.

The effect of antidopaminergic and antiadrenergic agents on the anti-immobility activity of desipramine after different schedules of treatment was studied in rats. 0.5 mg/kg i.p. haloperidol and 100 mg/kg i.p. sulpiride antagonized the anti-immobility effect of three injections of 10 mg/kg desipramine. Similar results were obtained after 7 or 21 daily doses of 10 mg/kg desipramine. Neither 5 mg/kg i.p. propranolol nor 3 mg/kg s.c. prazosin had any effect on desipramine after the various treatment schedules. It is suggested that DA mechanisms are involved in the anti-immobility effect of repeated desipramine in the rat. A possible role of beta-adrenergic receptors in the development of this effect is discussed.

Animals↗

PubMed1991

Desipramine enhances isolation-induced aggressive behavior in mice.

Effects of desipramine on aggressive behavior induced by long-term (6-7 weeks) isolation of mice were examined. Aggressive behavior was measured as duration of biting attack and/or wrestling during a 20-min observation period. Desipramine (5, 10 and 20 mg/kg, IP) and imipramine (10 and 20 mg/kg, IP) dose-dependently increased the duration of aggressive behavior in isolated mice, without inducing aggressive behavior in group-housed animals. Desipramine-induced increase in aggressive behavior was blocked by phentolamine (3 mg/kg, IP) and yohimbine (0.3 mg/kg, IP), but not prazosin (0.5 mg/kg, IP). Clonidine (0.001 mg/kg, IP), an alpha 2 agonist, significantly blocked desipramine-induced enhancement of aggressive behavior in isolated mice without affecting the basal aggression. These data suggest that long-term isolation may induce functional changes in the sensitivity of alpha 2 receptor in the noradrenergic system and that desipramine enhancement of aggressive behavior in isolated mice is modulated by drugs acting onto alpha 2 noradrenergic receptors.

Aggression↗

PubMed1994

Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice.

The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice.

Aggression↗

PubMed1983

Dissimilar responses of cortical neurons to chronic trazodone or desipramine treatment.

The effects of acute and chronic trazodone or desipramine treatment on the spontaneous firing rate of cortical neurons in chloral hydrate anesthetized rats were determined. Either trazodone (30 or 60 mg/kg, po) or desipramine (5 or 10 mg/kg, po) was administered daily for periods of up to 11 or 16 days respectively. A significant reduction in the firing rate of cortical neurons was observed after acute and chronic 10 mg/kg desipramine treatment. Chronic treatment with 5 mg/kg desipramine had no effect on activity. Neither acute nor chronic treatment with trazodone produced any significant alteration in cortical unit activity. The results suggest that the spontaneous activity of randomly encountered cortical neurons is not involved in the mechanism of the therapeutic action produced by chronic treatment with the two clinically effective antidepressants. The response of the cortical neurons to antidepressant treatment might help differentiate the relative effects of the drugs on monoaminergic receptors. Also, the depressant effect of desipramine on the spontaneous rate of cortical neurons does not appear to be a specific effect of chronic treatment since it occurred after a single dose.

Animals↗

PubMed1989

The apparent antinociceptive effect of desipramine and zimelidine in the tail flick test in rats is mainly caused by changes in tail skin temperature.

Tricyclic antidepressants have shown antinociceptive properties in some, but not in all, animal studies using the tail flick test. Tail flick latency has been found to be strongly negatively correlated to tail skin temperature with its highest correlation found when the temperature is measured close to the heated spot. The selective 5-HT reuptake inhibitor zimelidine, as well as the noradrenaline reuptake inhibitor desipramine, increased tail flick latencies. However, this increase could largely be explained by a concomitant reduction in tail skin temperature. The highest dose of desipramine investigated (25 mg/kg) seemed to possess antinociceptive properties in this test also after correction for the fall in tail skin temperature. Lower doses of desipramine (5 and 15 mg/kg) and zimelidine (5, 20 and 30 mg/kg) were either inactive or their effect on tail flick latency could be explained by the fall in tail skin temperature. The apparent antinociceptive effect of zimelidine in the tail flick test thus seems to be due to an effect on tail skin temperature. Desipramine also seems to have its main effect due to a similar mechanism; however, the highest dose of desipramine used induced significant antinociception.

Analgesics↗

PubMed1992

Effects of a single oral dose of desipramine on postoperative morphine analgesia.

Drugs that block norepinephrine reuptake offer promise as opioid potentiators, because norepinephrine mediates opioid analgesia but not side effects such as sedation or nausea. In a two-by-two factorial design, we randomized 62 inpatients with pain following major surgery to receive either desipramine, 50 mg by mouth, or placebo at 6 a.m. on the first day after surgery. At their first request of pain medication after 8 a.m., they were given intravenous morphine, either 0.033 mg/kg or 0.10 mg/kg. Pain relief and side effects were assessed for 4 hr; peak relief on the visual analog scale (VAS) was the primary outcome variable. Pain relief, side effect scores, and time to remedication were significantly greater with the higher dose than with the lower dose of morphine, verifying assay sensitivity, but desipramine pretreatment did not significantly enhance morphine analgesia. The mean increase in peak VAS relief score after desipramine pretreatment, relative to placebo, was 6%; the 95% confidence interval for this estimate ranged from a 21% reduction to a 34% increase in pain relief. These results differ from a previous report that 1 week of pretreatment with desipramine, 75 mg per day, potentiated postoperative morphine analgesia. We conclude that if desipramine potentiation of opioid analgesia occurs in humans, its demonstration may require higher doses or chronic treatment.

Administration, Oral↗

PubMed2004

Relationship between the antinociceptive response to desipramine and changes in GABAB receptor function and subunit expression in the dorsal horn of the rat spinal cord.

Although tricyclic antidepressants are among the drugs of choice for the treatment of neuropathic pain, their mechanism of action in this regard remains unknown. Because previous reports suggest these agents may influence gamma-aminobutyric acid (GABA) neurotransmission, and GABAB receptors are known to participate in the transmission of pain impulses, the present experiments were undertaken to examine whether the administration of desipramine alters GABAB receptor subunit expression and function in the dorsal horn of the rat spinal cord. For the study, rats were injected (i.p.) once daily with desipramine (15 mg/kg) for 7 consecutive days, during which their thermal withdrawal threshold was monitored, and after which GABAB receptor function, and the levels of GABAB receptor subunit mRNA, were quantified in the spinal cord dorsal horn. The results indicate that 4-7 days of continuous administration of desipramine are necessary to observe a significant increase in the thermal pain threshold. Moreover, it was found that 7 days of treatment with desipramine enhances GABAB receptor function, as measured by baclofen-stimulated [35S]GTPgammaS binding, and increases mRNA expression for the GABAB(1a) and GABAB(2), but not GABAB(1b), subunits. These findings suggest the antinociceptive effect of desipramine is accompanied by a change in spinal cord GABAB receptor sensitivity that could be an important component in the analgesic response to this agent.

Analgesics↗

PubMed2005

Desipramine treatment of cocaine-dependent patients with depression: a placebo-controlled trial.

OBJECTIVE: The aim of this study was to test the hypothesis that desipramine would be an effective treatment in cocaine abusers with current depressive disorders. METHOD: This was a randomized, 12-week, double-blind, 'placebo-controlled trial of outpatients (N = 111) meeting DSM-III-R criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with desipramine, up to 300 mg per day, or matching placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included the Clinical Global Impression Scale, self-reported cocaine use and craving, urine toxicology, and the Hamilton Depression Scale (biweekly). Summary measures of mood and cocaine use outcome were compared between treatment groups with chi2- or t-tests. Dichotomous summary measures of depression response and cocaine response were the primary outcomes. Mixed effect models were also fit to explore the relationship of cocaine use to mood improvement and treatment over weeks in the trial. RESULTS: Desipramine was associated with a higher rate of depression response (51%, 28/55) than placebo (32%, 18/56) (p < 0.05), but treatment groups did not differ in rate of cocaine response. Depression improvement was associated with improvement in cocaine use. Desipramine was associated with more dropouts due to side effects and medical adverse events, while placebo was associated with more dropouts due to psychiatric worsening. CONCLUSIONS: Desipramine was an effective treatment for depression among cocaine-dependent patients. Improvement in mood was associated with improvement in cocaine abuse, but a direct effect of medication on cocaine outcome was not clearly established and rates of sustained abstinence were low. Future research should examine newer antidepressant medications with more benign side effect profiles and combinations of behavioral and pharmacological treatments to maximize effects on cocaine use.

Adult↗

PubMed2003

Regulation of GAP-43 expression by chronic desipramine treatment in rat cultured hippocampal cells.

BACKGROUND: The importance of molecular and cellular changes in hippocampus in major depression and in the mechanism of action of antidepressants has become increasingly clear. Identification of novel targets for antidepressants in hippocampus is important to understanding their therapeutic effects. METHODS: We used cDNA microarray to measure the expression patterns of multiple genes in primary cultured rat hippocampal cells. In situ hybridization and Northern and immunoblotting analysis were used to determine brain regional distribution and mRNA and protein levels of target genes. RESULTS: After comparing hybridized signals between control and desipramine treated groups, we found that chronic treatment with desipramine increased the expression of six genes and decreased the expression of two genes. One of the upregulated genes is growth associated protein GAP-43. In situ hybridization revealed that desipramine increased GAP-43 gene expression in dentate gyrus but not other brain regions. Northern and immunoblotting analysis revealed that desipramine increased GAP-43 mRNA and protein levels. GAP-43 expression is also increased by another antidepressant, tranylcypromine, but not by lithium or haloperidol. CONCLUSIONS: Because GAP-43 regulates growth of axons and modulates the formation of new connections, our findings suggest that desipramine may have an effect on neuronal plasticity in the central nervous system.

Animals↗

PubMed1997

Effects of long-term treatment with desipramine on microtubule proteins in rat cerebral cortex.

The molecular mechanism of the action of antidepressants beyond the receptor level has not yet been elucidated. We have investigated the effects of long-term treatment with desipramine on the phosphorylation state of microtubule-associated protein 2 (MAP2) and microtubule assembly in the rat cerebral cortex. Phosphorylation of MAP2 was detected by immunoblotting after immunoprecipitation of MAP2 in the soluble fraction. The degree of phosphorylation of serine residues of MAP2 was significantly increased after chronic administration of desipramine without changes in the total concentration of MAP2. Microtubule assembly in crude brain extracts was monitored in terms of changes in turbidity measured at 350 nm using a spectrophotometer. Chronic but not acute treatment with desipramine inhibited microtubule assembly, assayed in the presence of a phosphatase inhibitor, calyculin A, whereas the inhibition was completely nullified in the absence of calyculin A. Desipramine had no direct effect on microtubule assembly in vitro. These results raise the possibility that the changes in the degree of phosphorylation of MAP2 and microtubule assembly represent intracellular modifications involved in functional changes elicited by long-term treatment with desipramine.

Adrenergic Uptake Inhibitors↗

PubMed1999

Effect of desipramine on spontaneous arterial pressure oscillations in the rat.

There has been no previous report on the effect of the noradrenaline uptake inhibitor desipramine on short-term variability of arterial pressure. Mean arterial pressure was recorded in 9 conscious resting rats during 4 consecutive 30-min periods: (1) under baseline conditions, (2) after desipramine administration (2 mg/kg i.v., followed by 1 mg/kg every hour), then after (3) cardiac autonomic blockade with methylatropine and atenolol, and (4) alpha-adrenoceptor blockade with phentolamine. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205-s time series. Desipramine did not change the mean level and overall variability of mean arterial pressure. However, spectral power in the mid-frequency (0.3-0.5 Hz) band containing the Mayer waves was reduced by more than 80%, and power in the low-frequency (0.05-0.2 Hz) band was enhanced by approximately 50%, especially due to the appearance of a major oscillation centred at 0.095 +/- 0.005 Hz. This slow oscillation was further enhanced after cardiac autonomic blockade and was abolished after alpha-adrenoceptor blockade. In conclusion, desipramine profoundly alters short-term arterial pressure variability in resting rats, mainly by shifting vasomotor waves from 0.4 to 0.1 Hz. Desipramine may prove a valuable pharmacological tool to study the dynamic aspects of arterial pressure control.

Adrenergic Uptake Inhibitors↗

PubMed2000

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.

Aging↗

PubMed2000

Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in spontaneously hypertensive and Wistar-Kyoto rats.

Spontaneously Hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats differ in their emotional responses to stress and antidepressant administration. We have analysed different neurochemical and psychoneuroendocrine responses to repeated pretreatments with fluoxetine, imipramine or desipramine (10 mg/kg p.o. daily for 4 weeks) in SHRs and WKY rats exposed to a daily 2-h restraint episode for the last 5 days of antidepressant administration. Following a 24-h wash-out period, WKY rats displayed higher plasma antidepressant and antidepressant metabolite levels than SHRs. Fluoxetine pretreatment decreased [(3)H]citalopram binding at midbrain serotonin (5-HT) transporters, whereas tricyclic and/or fluoxetine decreased [(3)H]ketanserin binding at cortical 5-HT(2A) receptors, [(3)H]CGP-12177 binding at cortical ss-adrenoceptors, and [(3)H]nisoxetine binding at midbrain noradrenaline (NA) transporters in both strains. None of the antidepressants affected [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin binding at hippocampal 5-HT(1A) receptors. In WKY rats, repeated restraint triggered a desipramine-sensitive 140% increase in hypothalamus [(3)H]nisoxetine binding; moreover, plasma adrenocorticotropin-releasing hormone responses to a 5-min open field test were amplified by prior repeated restraint in both strains, but desipramine prevented such an amplification in WKY rats only. However, neither elevated plus-maze nor open field behaviors of SHRs and WKY rats were affected by desipramine pretreatment. Thus, the SHR and WKY rat strains may prove useful in understanding how genetic differences in noradrenergic responses to repeated stress and desipramine treatment impact on adaptive processes.

Adrenocorticotropic Hormone↗

PubMed2000

An analysis of submandibular salivary gland function with desipramine and age in female NIA Fischer 344 rats.

Dry mouth is one of the major side effects of cyclic antidepressants, which are still a dominating group of psychotherapeutic drugs used in the treatment of depression. In this study we analyzed the effects of 28 day tricyclic antidepressant administration and the reversibility of this treatment following a 15 day washout period on different parameters in submandibular gland function in aging rats. We postulated that desipramine would decrease gland function, accented with age, and delay recovery in senescent animals. In contrast to body weight, desipramine had no effect on glandular wet weight. While glandular DNA synthesis was changed with age and treatment, the concentration of total membrane and soluble proteins was not affected. Flow rate was significantly changed with age, but desipramine increased salivary flow in the youngest animals only. Neither age nor treatment influenced salivary protein concentrations, but the total amount of proteins secreted, revealed perturbation with age. SDS- polyacrylamide gel analysis revealed changes in protein expression with treatment and age. Desipramine decreased epidermal growth factor (EGF) levels in all age groups, but increased the secretion of peroxidase and lysozyme. Analysis of total RNA showed a pronounced decrease with age. These data indicate that desipramine has profound effects on submandibular salivary gland function.

Aging↗

PubMed2001

Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression.

BACKGROUND: Depression is associated with activation of the inflammatory response system (IRS). In humans, antidepressants significantly increase the production of interleukin-10 (IL-10), a negative immunoregulatory cytokine. The aims of the present study were to examine the effects of desipramine, a tricyclic antidepressant, on the IRS in C57BL/6 mice with and without exposure to chronic mild stress (CMS). METHODS: We examined the effects of desipramine on the cytotoxic activity of natural killer (NK) cells, the proliferative responses of lymphocytes after stimulation with IL-1, IL-2, lipopolysaccharide (LPS), concanavaline-A (Con-A), phytohaemagglutinin-P (PHA), pokeweed mitogen (PWM), and anti-CD3 monoclonal antibodies, the production of IL-2, IL-4, IL-10 and interferon-gamma (IFNgamma) by T lymphocytes and the ability of B cells to proliferate after stimulation by lipopolysaccharide (LPS). RESULTS: Prolonged treatment of C57BL/6 mice subjected to CMS with desipramine increases the ability of T cells to produce IL-10 and the ability of B cells to proliferate after stimulation with LPS; and significantly decreases the cytotoxic activity of NK cells and the proliferative responses of lymphocytes after stimulation with Con-A, PHA and anti-CD3 monoclonal antibodies. Repeated administration of desipramine to non-stressed mice increases the activity of T lymphocytes, lowers that of B lymphocytes, increases the production of IL-10 by T cells and has no significant effect on the activity of NK cells. CONCLUSION: Prolonged desipramine treatment of stressed and non-stressed C57BL/6 mice induces an increase in the production of IL-10, an anti-inflammatory cytokine.

Animals↗