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At least 793 records · Page 44Linked to original sources
PubMed1998

Effects of rearing condition on HPA axis response to fluoxetine and desipramine treatment over repeated social separations in young rhesus monkeys.

Normal hypothalamic-pituitary-adrenal (HPA) axis activity is disrupted in several types of human psychiatric disorders, and has been widely reported to be altered as a result of early experience in rodents. In this study the effects of early social experience on later response of the HPA axis to separations from cagemates and pharmacologic treatments were examined in rhesus monkeys. HPA axis activity was measured in mother-reared and peer-reared monkey infants in conjunction with six repeated separations from and reunions with their cagemates. Within each rearing group, infants were assigned to one of three treatment groups that received continuous treatment with either fluoxetine (2 mg/kg), desipramine (DMI, 5 mg/kg) or placebo (saline) beginning 2 weeks prior to separations. At 2 weeks after drug treatment, fluoxetine increased ACTH and cortisol in the treated groups, while DMI decreased ACTH and cortisol in both treated groups; however, these effects were not persistent over the separations. While these treatment effects tended to be more pronounced in the mother-reared group, the rearing groups did not show a clearly differential response to either of the treatments. The most prominent finding was that mother-reared monkeys showed significantly higher ACTH and cortisol levels than peer-reared monkeys over all samples, an effect that may have mitigated a potential rearing group difference in treatment response. The results add to growing evidence for the influence of primate mothers on the functional development of psychobiological systems in their infants, and suggest that the HPA axis is among the more sensitive of these systems to postnatal experience.

Adrenocorticotropic Hormone↗
PubMed1996

Effects of locally administered desipramine on myocardial interstitial norepinephrine levels.

We investigated whether locally administered neuronal uptake blockade with desipramine (DMI) modified basal myocardial interstitial norepinephrine (NE) levels and stimulation-induced NE responses. Using the dialysis technique, dialysates were sampled from the midwall of the left ventricle in anesthetized cats. Dialysate NE concentrations, as an index of myocardial interstitial NE level, were measured by high performance liquid chromatography. Through the dialysis probe, local administration of DMI (10(-4) mol/l) increased the dialysate NE level from 24.6 +/- 12.2 to 127.8 +/- 37.4 and from 11.9 +/- 5.4 to 64.9 +/- 28.7 pg/ml regardless of whether stellate ganglia were intact or transected. The arterial pressure and heart rate responses to electrical stimulation of the stellate ganglia were not altered by DMI. Control nerve stimulation increased dialysate NE concentrations to 214.5 +/- 100.0 and 57.5 +/- 22.0 pg/ml at 5 Hz and 2 Hz, respectively. During local administration of DMI, nerve stimulation-induced NE response increased to 997.5 +/- 202.0 at 5 Hz and to 436.0 +/- 68.5 pg/ml at 2 Hz. We conclude that local administration of DMI caused marked rises in basal myocardial interstitial NE concentrations and responses to cardiac sympathetic activation.

Adrenergic Uptake Inhibitors↗
PubMed2003

Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder.

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Attention↗
PubMed1999

The involvement of an opiate mechanism in the sensitized behavioral deficit induced by early chronic variable stress: influence of desipramine.

The influence of early chronic variable stress (CVS) associated with persistent desipramine (DMI) administration was examined on escape performance. Animals were exposed to CVS and 1 day later administered DMI (5 mg/kg, i.p. twice a day) or vehicle (VH) during six consecutive days. Escape performance was assessed over 24 h following inescapable shock (IS) exposure. Higher escape failures were observed in CVS shocked rats compared with unstressed shocked animals. DMI normalized escape failures in both groups. In order to investigate the role of an endogenous opiate mechanism presumably activated by CVS exposure in this behavioral deficit, rats were administered naltrexone (NAL, 2 mg/kg i.p.) or VH prior to each daily stressor of the CVS regime. NAL pretreatment blocked escape failures performed only by CVS shocked rats. In addition, animals were daily administered morphine (MOR, 10 mg/kg, i.p.) or VH during seven consecutive days and subsequently administered DMI. A significant increase in escape deficit in shocked rats was observed after chronic MOR but not following the associated treatment with MOR and DMI. These behavioral data suggest that early experience with a CVS facilitated the onset of escape deficit induced by a brief IS event, an effect that can be prevented by chronic DMI. Furthermore, this sensitized escape deficit response seems to be partially modulated by the previous activation of an opiate mechanism.

Adrenergic Uptake Inhibitors↗
PubMed2003

Intraaccumbens dopaminergic lesion suppresses desipramine effects in the forced swim test but not in the neuronal activity of lateral septal nucleus.

The nucleus accumbens (NAcc) function is related to locomotor activity, while the lateral septal nucleus (LSN) is related to the motivational aspects of behavior. Thus, a dopaminergic lesion of the NAcc blocks the antiimmobility effect of desipramine (DMI) and this tricyclic increases the firing rate of the LSN; however, it is unknown whether a relation exists between a dopaminergic lesion of the NAcc and the response of LSN neurons to DMI treatment. Therefore, we conducted a longitudinal study to further explore the participation of NAcc dopaminergic terminals in the immobility reduction exerted by DMI in the forced swim test and its relation to the firing rate of the LSN, at the same time exploring motor and motivational aspects of DMI-dopaminergic relationships in the animals. A dopaminergic lesion was bilaterally produced by 6-hydroxydopamine (6-OHDA) injection into the NAcc of adult ovariectomized Wistar rats pretreated with DMI (25 mg/kg ip, 30 min before lesion to protect NA terminals but to destroy DA endings). Treatments with DMI or saline began 24 h after stereotaxic surgery. The results showed that DMI once a day during 9 days (10 mg/kg) reduced immobility in the forced swim test in the sham-lesion group (P<.02); however, in the dopaminergic lesion group submitted to DMI treatment, immobility remained at control level in agreement with other reports. DMI increased the firing rate of the LSN (P<.001) independently of the 6-OHDA lesion. In conclusion, the dopaminergic terminals of the NAcc seem to be essential for the motor manifestation associated with motivation induced by DMI in the forced swim test, given that the antiimmobility actions of DMI are blocked after a dopaminergic NAcc lesion; however, the effect on the firing rate of LSN neurons is still present.

Animals↗
PubMed1996

Raphe-septal neurons changes in sensitivity to desipramine following an early septal lesion in the rat.

1. The electrophysiological responsivity to desipramine (DMI) applied by systemic or local route was tested in Wistar female rats submitted to a wide lesion in the lateral septal area on the 8th day after birth. 2. One year after a septal lesion, the dorsal raphe nucleus (DRN) stimulation produced an initial brief response in lateral septal and CA1/CA3 neurons. In the control and sham-lesion groups, most recordings showed only this initial brief response (non-late responding neurons); however, in the lesion group most of the recorded neurons showed an afterdischarge. 3. DMI (2.14 mg/kg, 21 days, i.p.) increased the firing rate in septal and CA1/CA3 non-late responding neurons. In the equivalent septal neurons from lesion group, DMI produced the inverse effect, i.e., a decreased firing rate. 4. In septal non-late responding neurons, DMI (2 mM; 10-15 nAmps, 0.5 sec) applied by microiontophoresis increased the firing rate only after long-term systemic DMI impregnation. The response to locally applied DMI did not occur in the lesion group even after long-term DMI treatment. 5. In conclusion, an early lateral septal lesion canceled the response of intermediate-dorsal septal neurons to DMI applied by systemic and local routes.

Animals↗
PubMed1998

Bupropion and desipramine increase dopamine transporter mRNA expression in the ventral tegmental area/substantia nigra of rat brain.

1. Regulation of dopamine transporter (DAT) mRNA was studied in rats treated with the DAT blocker bupropion (BUP; 15 or 30 mg/kg tid x 2d), the norepinephrine transporter blocker desipramine (DMI; 10 mg/kg/d x 2d), or saline. 2. mRNA expression was assessed via in situ hybridization histochemistry. 3. BUP and DMI both increased DAT mRNA expression in the ventral tegmental area/substantia nigra. 4. These findings suggest that DAT mRNA expression in the brain may be regulated by both noradrenergic and dopaminergic mechanisms.

Animals↗
PubMed1998

Desipramine restricts estral cycle oscillations in swimming.

1. Desipramine (DMI) is a tricyclic antidepressant which reduces the immobility in rats forced to swim; however, it is unknown whether estral cycle phases impinge on DMI actions on immobility in daily swimming tests during several weeks. 2. In female wistar rats, vaginal smears taken before testing defined four estral phases. Afterwards, the authors assessed the latency for the first period of immobility in five-min forced swim tests practiced on 21-day DMI (DMI group), 21-day washout saline given after a 21-day DMI treatment (washout-saline group), or non-treated rats (control group). 3. We observed a longer latency for the first period of immobility in proestrus-estrus from the control and washout-saline groups. The 21-day treatment with DMI (2.1 mg/kg i.p., once a day) significantly (p < 0.001) increased the latency by about 160% from control regardless of the estral cycle phase. 4. It is concluded that proestrus-estrus relates to increased struggling behavior. DMI enhances struggling behavior independently of hormonal state.

Animals↗
PubMed2003

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients.

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

Adult↗
PubMed1980

Technical considerations in the gas chromatographic analysis of desipramine.

Procedures are presented for minimizing variability in and interferences with the gas chromatographic determination of desipramine in plasms. Careful consideration of procedures for sample collection and storage, drug separation from matrix components, and chromatography appears to be a prerequisite for avoiding inaccurate and imprecise determinations of this antidepressant, especially at levels below 20 micrograms/l. Numerous pitfalls are examined and optimal conditions for obviating them are presented.

Blood Specimen Collection↗
PubMed2002

Imipramine hydrochloride and desipramine hydrochloride as new reagents for detection of microamounts of blood in urine.

Benzidine and o-tolidine, the hazardous carcinogens are still in use for the detection of blood in urine. Development of safer substitutes are of paramount importance. Unfortunately, the alternate available reagents lack specificity, sensitivity and reproducibility. Imipramine hydrochloride (IPH) and desipramine hydrochloride (DPH) are proposed as new reagents for the detection of blood in urine. Both the reagents impact to blood a green-blue to blue color, in the presence of acetic acid and hydrogen peroxide and the development of this color is explored under laboratory conditions. IPH or DPH compares favorably with benzidine and multistix methods. Both the reagents are relatively inexpensive, and have required sensitivity and stability. The proposed reagents offer advantages of relatively low sensitivity to endogenous vegetable peroxidases; hence, the test can be performed on samples taken from patients who are on a normal diet and the results are reproducible. Besides, the reagents, are non-carcinogenic and can replace benzidine and o-tolidine without any extra procedural difficulties as they also exhibit a similar blue color.

Acetates↗
PubMed1999

A double-blind crossover comparison of clomipramine and desipramine in the treatment of panic disorder.

OBJECTIVE: To compare the efficacy of clomipramine hydrochloride (CMI), a serotonin reuptake inhibitor with the noradrenergic tricyclic antidepressant agent, and desipramine hydrochloride (DMI) for patients with panic disorder (PD). METHOD: Following a 2-week, single-blind placebo washout phase, 17 PD outpatients completed a 16-week, double-blind, crossover comparison of CMI and DMI. Key outcome measures included panic attacks frequency, the NIMH Global Scales for Anxiety, Depression and Impairment, Hamilton Anxiety Scale (Psychic and Somatic Subscales), Zung Anxiety Inventory (Raw and Index Subscales) and the Spielberger State Anxiety Scale. RESULTS: Both CMI and DMI led to significant improvement from baseline placebo state in panic attacks frequency and behavioral ratings (p<0.001). CMI led to a greater reduction in the frequency of panic attacks (p=0.028) and was superior to DMI on ratings of anxiety: NIMH Global Anxiety, Zung Anxiety Scale (Raw and Index) and the Spielberger Anxiety Scale. No difference was found between the drugs on the NIMH Global Impairment Scale and the Hamilton Somatic and Psychic Scales. CONCLUSION: Both drugs appeared to have significant therapeutic effects in patients with PD, but CMI appeared to be more effective. The effectiveness of the serotonergic drug suggests that the role of the serotonergic system in the pathogenesis of PD should be further explored.

Adult↗
PubMed2000

MAO-A and MAO-B activities in rat striatum, frontal cortex and liver are unaltered after long-term treatment with fluvoxamine and desipramine.

In the course of investigating the mechanisms underlying the beneficial effect of fluvoxamine augmentation on negative symptoms of schizophrenia, the authors found a reduction in human platelet monoamine oxidase-B activity after 5 weeks of treatment. This unexpected finding raised the possibility that MAO activity may be one of the factors altered by chronic tricyclic or SSRI antidepressant treatment. The current study examined the effect of long-term administration, up to 6 weeks, of fluvoxamine, desipramine or saline on MAO-A and MAO-B activities in rat striatum, frontal cortex and liver. No differences were noted between drug-treated groups and their saline-treated controls. The hypothesis that long-term treatment with tricyclic and SSRI antidepressants alters MAO activity was not supported. MAO is not among proteins whose activity may be altered by chronic tricyclic or SSRI antidepressant treatment.

Animals↗
PubMed1997

Synthesis of 11C-labeled desipramine and its metabolite 2-hydroxydesipramine: potential radiotracers for PET studies of the norepinephrine transporter.

The antidepressant desipramine (DMI) and its principal metabolite 2-hydroxydesipramine (HDMI) have been radiolabeled with 11C for PET studies. The normethyl precursors of DMI and HDMI were synthesized from iminodibenzyl in 35% and 11% overall yield, respectively. Direct methylation of the normethyl precursor with [11C]CH3I, followed by HPLC purification, provided [11C]DMI and [11C]HDMI in 18-30% and 15-23% decay-corrected radiochemical yields, respectively, in a 45 min synthesis time from end of bombardment. The specific activities of the two radiotracers were >1459 Ci/mmol at the end of synthesis. [11C]DMI and [11C]HDMI have potential utility as PET radiotracers for the norepinephrine transporter.

Carbon Radioisotopes↗
PubMed2003

Desipramine treatment reduces the long-term behavioural and neurochemical sequelae of early-life maternal separation.

Primate and rodent models of maternal separation have shown that repeated postnatal separation of young from the mother results in long-term changes to neurohormonal systems relevant to depression. To date, however, it remains unclear whether rodents that experience postnatal maternal separation display specific behavioural or biochemical features of depression in adulthood and whether these changes can be prevented by treatment with antidepressant drugs. We report here that maternally separated mice showed significantly shorter swim times on the forced swim test and significantly lower levels of brain-derived neurotrophic factor in dentate gyrus and CA3 regions of the hippocampus compared to control mice when assessed in adulthood. Neither of these differences was apparent in maternally separated mice that received chronic treatment with the antidepressant desipramine after maternal separation. These results suggest that intervention following early stress may eliminate the long-term vulnerability to behavioural and biochemical dysfunction that occurs following this early chronic stress.

Animals↗
PubMed1994

Surface ionization organic mass spectrometry of imipramine, desipramine, clomipramine, and lidocaine.

Surface ionization organic mass spectrometry (SIOMS) has been performed on some clinically important drugs (imipramine, desipramine, clomipramine, lidocaine) by using quadrupole mass spectroscopy in which the thermal ion source has a rhenium oxide emitter. The mass spectra were presented, interpreted in a purely empirical way, by means of evidence from previous investigations, and then compared to conventional EI techniques. Sensitivity and selectivity have also been studied, demonstrating that (a) these drug compounds are efficiently surface-ionized, (b) experimental results rationalize the high sensitivity of the surface ionization detector (SID) of gas chromatography (GC) for the examined drugs, and (c) the GC/SIOMS coupling can be used for sensitive and selective detection of the drugs in the serum. An approach to detection of these drugs in serum by GC/SIOMS and GC with SID is described. The characteristics of both methods provide a reliable, sensitive, and selective method, which is needed for low concentration level measurements in complex mixtures.

Clomipramine↗
PubMed1998

Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo.

Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean Km value of 11.7 microM (range: 9.9-15.3 microM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 microM (range: 0.13-0.18 microM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.

Antidepressive Agents, Tricyclic↗
PubMed2004

The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function.

The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake. Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI. [3H]DMI trapped in membranes was displaceable by the structurally unrelated NET inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the NET. A similar cellular retention was observed following incubation of cells with nisoxetine. The results demonstrate that DMI and nisoxetine are persistently retained in cell membranes, at least partly in association with the NET. The retention and slow diffusion of DMI and nisoxetine from membranes may contribute to their pharmacological and modulatory action on NET.

Adrenergic Uptake Inhibitors↗