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PubMed1985

Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone.

Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of 14C-methadone and increases in the percentages of total 14C in liver or urine as 14C-water-soluble metabolites (14C-WSM) after the rats were challenged with a test dose of 14C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone.

Analgesia↗
PubMed1991

Pretreatment with drug-specific antibody reduces desipramine cardiotoxicity in rats.

The effect of a drug-specific antibody on desipramine (DMI) cardiotoxicity was studied in rats. Animals were pretreated i.v. with 4.2 g/kg of a monoclonal antibody (anti-TCA) followed by DMI HCl 30 mg/kg i.p. (molar ratio of anti-TCA binding sites to DMI = 0.56). Peak QRS complex prolongation was substantially lower after pretreatment with anti-TCA than after control antibody (70 +/- 14 v. 21 +/- 4%, p less than 0.001). Time to peak toxicity was the same in both groups. Binding of DMI by anti-TCA was demonstrated by a higher serum total DMI concentration and increased DMI binding in serum after anti-TCA compared to controls. The DMI concentration in anti-TCA treated animals was lower in some organs (brain, lung, liver, spleen), but not in others (heart, muscle, kidney, fat). The calculated fraction of the DMI dose bound by anti-TCA was 19.9%. The steepness of the DMI dose-response curve was examined by administering DMI alone (without antibody) at various doses to rats. Compared to 30 mg/kg DMI, a dose reduction of 30-50% was needed to reduce QRS duration to the same extent as anti-TCA pretreatment. We conclude that DMI cardiotoxicity was markedly reduced by the binding of a relative small fraction of the DMI body burden to anti-TCA. This disproportionate effect of DMI binding was not due to the steepness of the DMI dose-response curve, nor to slowing of the rate of DMI distribution to tissues.

Animals↗
PubMed1987

The influence of L-triiodothyronine (T3) on the effects of repeated administration of desipramine or electroconvulsive shock on alpha 2- and beta-adrenoceptor function in the brain of the rat: implications for the potentiation of antidepressant therapy by T3.

Repeated, daily administration of either an electroconvulsive shock (ECS; 110 V, 1 sec) or desipramine (DMI; 5 mg/kg X 2) to rats caused a progressive decrease in the function of presynaptic alpha 2-adrenoceptors, assessed by the hypoactivity (sedation) response to clonidine (0.2 mg/kg). This attenuation required approximately 7 days' administration of either treatment for maximum effect. A single injection of triiodothyronine (T3; 100 micrograms/kg) on day 1 of the treatment markedly accelerated the decreased responses to clonidine induced by DMI or electroconvulsive shock, but did not alter the maximum attenuation. By itself T3 did not affect the hypoactivity responses. alpha 2-Adrenoceptors, measured by the binding of [3H]idazoxan in the cortex, which are believed to be predominantly postsynaptic, were decreased by 14 days of DMI or electroconvulsive shock for 10 days, but not 2 days of either treatment. Triiodothyronine did not influence the decreased number of alpha 2-adrenoceptors induced by DMI or electroconvulsive shock but may have delayed the onset produced by DMI. Binding to beta-adrenoceptors in the cortex was measured using [3H]dihydroalprenolol. This was significantly decreased by 14 days administration of DMI, but not significantly by electroconvulsive shock for 10. Down-regulation of beta-adrenoceptors, induced by DMI was rapid, being observed after 1 day of treatment. Injection of T3 did not influence the final decreases produced by DMI or electroconvulsive shocks but moderately delayed their onset. Triiodothyronine alone caused a 25% reduction in cortical beta-adrenoceptors 24 hr after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The influence of injection of oestradiol to female rats on changes in alpha 2- and beta-adrenoceptor function induced by repeated administration of desipramine or electroconvulsive shock.

Repeated daily administration to female rats of either an electroconvulsive shock (110 V, 1 sec) or desipramine (DMI; 5 mg/kg x 2) caused a progressive decrease in presynaptic alpha 2-adrenoceptor function assessed by the hypoactivity (sedation) response to clonidine (0.5 mg/kg). This reduction was maximal after approximately seven electroshocks or 8-12 days of injection of DMI. Daily administration of oestradiol (100 micrograms s.c.), starting one day prior to the commencement of administration of DMI or treatment with electroshock, markedly accelerated the onset of decreased hypoactivity responses to clonidine, but did not alter the maximum reduction induced by repeated injection of DMI or administration of electroshock. Injection of oestradiol alone had no effect on the responses to clonidine. Administration of DMI for 14 days decreased the number of both alpha 2- and beta-adrenoceptors in the cortex. Cortical beta-, but not alpha 2-adrenoceptors, were also decreased after 4 days of injection of DMI. Two and ten electroshocks moderately increased and decreased cortical alpha 2-adrenoceptors, respectively. beta-Adrenoceptors were also decreased by ten electroshocks, but two were without effect. Simultaneous administration of oestradiol had little influence on the changes in the binding of alpha 2- or beta-adrenoceptors induced by repeated administration of DMI or treatment with electroshock. Oestradiol increased the numbers of cortical alpha 2- and beta-adrenoceptors 3 and 15 days after injection, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The effects of a potential antidepressant, 2,4-dimethyl-5-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione, in an electrophysiological model responsive to desipramine.

The effects of acute and chronic administration desipramine (DMI) and the potential antidepressant, MDL 26,479 (2,4-dimethyl-5-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione) were compared on the sensitivity of Purkinje neurons in the cerebellum of the rat to iontophoretically applied norepinephrine (NE) and gamma-aminobutyric acid (GABA). Neither compound, administered acutely at 10 mg/kg (i.p.), altered the spontaneous firing rate of Purkinje neurons or the depression of the rate caused by iontophoresed NE. However, MDL 26,479 did significantly reduce the enhancement of inhibitory responses to GABA, produced by NE. Administered chronically (10 mg/kg x 21 days, i.p.), neither compound altered the slowing of Purkinje neurons evoked by NE. Chronic treatment with MDL 26,479, but not with DMI, produced a small but significant decrease in average spontaneous firing rate of Purkinje neurons. Both compounds substantially attenuated the enhancement of the inhibitory responses to GABA produced by NE, with MDL 26,479 having a more marked effect than DMI. These effects of MDL 26,479 on the activity of Purkinje neurons are consistent with the compound having antidepressant potential and further suggest, since similar effects were seen after a single dose, that the compound may have a rapid onset of antidepressant action.

Action Potentials↗
PubMed1991

Adrenocorticotropic hormone influences the development of adaptive changes in dopamine autoreceptors induced by chronic administration of desipramine.

The influence of adrenocorticotropic hormone (ACTH) in the adaptive changes on central dopamine (DA) autoreceptors following chronic administration of desipramine (DMI) has been examined in rats. Dopamine had an inhibitory effect on basal and K(+)-induced release of [3H]DA from slices of striatum and n. accumbens of rats treated chronically (10 days) with ACTH (50 IU/kg, s.c.), DMI (10 mg/kg, i.p.) or the combination of ACTH and DMI. In slices of n. accumbens, but not in slices of striatum of rats exposed to the combined treatment of ACTH and DMI, a significant decrease in the inhibitory effect of exogenous DA on stimulated release of [3H]DA was observed. Chronic administration of ACTH or DMI alone had no effect. The effect of the combined treatment with both agents, on the reactivity of these DA receptors was evaluated by means of apomorphine-induced hypoactivity. The administration of ACTH and DMI (5 mg/kg, i.p.) reduced the hypoactivity induced by apomorphine, as compared to hypoactivity in rats treated with ACTH or DMI alone. Experiments with ACTH4-10 revealed that the peptide modified biochemical and behavioural parameters of dopaminergic function, which may implicate a direct action of the peptide on the brain, rather than on the release of adrenal hormones. These findings suggest that ACTH accelerates the onset of DMI-induced adaptive changes on dopamine in the mesolimbic area. However, because the effect of ACTH4-10 on release of adrenocortical hormone was not investigated, the possibility cannot be disregarded that the effect of the peptide was secondary to an enhancement of release of adrenal hormone.

Adrenocorticotropic Hormone↗
PubMed1980

Effects of nomifensine and desipramine on the sequelae of intracerebrally-injected 6-OHDA and 5,6-DHT.

Pretreatment with either nomifensine or desipramine (15 mg/kg) attenuated the depletion of forebrain noradrenaline induced by unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Neither pretreatment influenced the depletions of striatal dopamine induced by medial forebrain bundle lesions with 6-hydroxydopamine or 5,6-dihydroxytryptamine, or contralateral rotational responses to apomorphine in the 6-hydroxydopamine-lesioned animals. Pretreatment with nomifensine attenuated the depletion of striatal dopamine induced by intrastriatal injections of 6-hydroxydopamine, consistent with inhibition of dopamine uptake in vivo. Nomifensine may differently influence distinct axonal and terminal uptake mechanisms for dopamine.

5,6-Dihydroxytryptamine↗
PubMed1982

Effect of lithium upon desipramine enhanced shock-elicited fighting in rats.

Rats were tested for changes in shock-elicited fighting (SEF) following the chronic administration of saline (IP); lithium (Li+) (20 mEq./l tap water) + saline (IP); desipramine (DMI) (15 mg/kg, IP); and DMI + Li+ for 14 days. The repeated test trials indicated a significant decrease in SEF in Li+-saline group (p less than 0.05), a significant increase (p less than p.05) in the DMI group, but no difference in the DMI + Li+ group in comparison to saline controls. Combined treatment with DMI + Li+ significantly reduced (p less than 0.05) SEF in comprison to the DMI group. These results suggest that enhanced aggressivity resulting from chronic DMI administration and measured by SEF can be a useful behavioral model to study the action of lithium.

Aggression↗
PubMed1983

Synergistic effect of propranolol and quipazine on desipramine enhanced shock-elicited fighting in rats.

Changes in shock-elicited fighting (SEF) were measured following single or repeated injections (IP) of dl-propranolol (5 mg/kg, 20 mg/kg) or quipazine (1.25 mg/kg, 2.5 mg/kg) given either alone or in combination to saline or desipramine (DMI) (10 mg/kg) treated rats. DMI + propranolol (20 mg/kg) caused a greater increase in fighting than DMI + saline 18 hours after last dose. Propranolol (20 mg/kg) produced an equal inhibition in both of these groups at 15 min. Propranolol (5 mg/kg) had no effect. Quipazine (2.5 mg/kg) failed to alter DMI induced increase in SEF. The combination of propranolol (5 mg/kg) + quipazine (1.25 mg/kg) blocked the enhanced SEF significantly in DMI treated rats in comparison to DMI + saline treated group. This combination of propranolol + quipazine produced no significant change in SEF in saline treated group in comparison to the pretest level. These results suggested that propranolol + quipazine act synergistically at low doses to inhibit the increased SEF seen in DMI treated rats and might have therapeutic implications for the management of irritable aggression or mania.

Aggression↗
PubMed1983

Effects of adrenergic blockers on the inhibition of muricide by desipramine and noradrenaline injected into the amygdala in olfactory bulbectomized rats.

Muricide in olfactory bulbectomized rats (OB rats) is readily inhibited by systemic administration of desipramine (DMI) or microinjection of DMI and noradrenaline (NA) into the medial amygdaloid nucleus. The present experiment investigated whether the muricide inhibition produced by these forms of drug treatment was mediated by alpha- or beta-noradrenergic receptors in the central nervous system. Muricide inhibition produced by systemic administration of DMI was antagonized by an alpha-blocker phenoxybenzamine but unaffected by a beta-blocker sotalol, although administration of these adrenergic blockers alone had no effect on muricide. Muricide inhibition induced by the microinjection of DMI and NA into the medial amygdaloid nucleus was similarly antagonized by pretreatment of phenoxybenzamine injected into the same site, but sotalol had no effect. Injection of phenoxybenzamine or sotalol alone into the medial amygdaloid nucleus did not elicit any changes in muricide. These findings suggest that mechanisms mediated by brain noradrenergic alpha-receptor play an important role in muricide inhibition by tricyclic antidepressants in rats and that the medial amygdaloid nucleus is an important site of action of these drugs.

Adrenergic alpha-Antagonists↗
PubMed1985

Potentiation of cold-water swim analgesia by acute, but not chronic desipramine administration.

Like other stress responses, cold-water swim (CWS) analgesia can be altered by changes in norepinephrine (NE) availability. While clonidine pretreatment potentiates CWS analgesia, lesions placed in the noradrenergic locus coeruleus reduce this response. Desipramine (DMI) can alter both the availability and receptor function of catecholamines, particularly NE: while both acute and chronic DMI treatments decrease NE reuptake, subsensitivity of beta-adrenergic receptors occurs only after chronic DMI treatment. The present study examined whether acute and chronic DMI treatments differentially alter CWS analgesia as measured by the jump test, CWS hypothermia and basal jump thresholds. The first experiment determined that pretreatment at either 24, 5 and 1 hr or only at 1 hr with DMI doses of 20 and 5 but not 1 mg/kg potentiated CWS analgesia. The second experiment found that chronic DMI pretreatment at a dose of 10 mg/kg administered twice daily over seven days failed to alter CWS analgesia at 1, 24, 48 or 72 hr thereafter. Neither CWS hypothermia nor basal jump thresholds were affected by the acute or chronic DMI injection regimens. The selective potentiation of CWS analgesia by acute DMI pretreatment is discussed in terms of the differential actions of acute and chronic injection regimens upon NE availability, receptor function, and adaptation processes.

Analgesia↗
PubMed1985

Behavioral responses of high and low active male rats to the chronic ingestion of desipramine.

Male rats arbitrarily selected for high and low motor activity (HA and LA-rats) were submitted to the chronic ingestion (30 days) of desipramine (DSP) in doses of about 1.5, 3 and 6 mg/kg/24 hr. Their motor activity was assessed in an animal activity monitor providing a measure of total horizontal movements and vertical movements and in a hole-board providing a measure of locomotion, head-dipping and grooming. There were significant differences between HA and LA-rats in their behavioral response to DSP treatment. At the doses used DSP did not affect horizontal and vertical movements and hole-board locomotion or exploration in HA-rats (Experiment 1). In LA-rats, however (Experiment 2), these motor activities were significantly stimulated by DSP. Such effect was dose dependent; 1.5 mg/kg/24 hr was ineffective while 6 mg/kg/24 hr produced a clear cut reversion of hypoactivity. It is speculated that DSP treatment increased resistance of LA-rats to the mild stress caused by testing.

Animals↗
PubMed1987

Effect of the chronic ingestion of chlorimipramine and desipramine on the hole board response to acute stresses in male rats.

The effect of the chronic ingestion of chlorimipramine (CI) or desipramine (DS) on the alterations of hole board behavior caused by a model stress (2 IP injections of physiological saline) and by a short restraint stress (5 min) is analyzed in this study. The experimental groups ingested about 3 mg/kg/24 hr CI or DS for 15 days. Then some experimental and control rats were assigned to control of drug effects on baseline activity. The remaining rats were submitted to saline stress (Experiment I) or restraint stress (Experiment II). The baseline scores of hole board locomotion, head dipping, grooming and defecation were not affected by DS treatment but locomotion slightly increased in the CI treated group. Saline stress impaired significantly head dipping and caused excessive grooming in control rats. The CI treatment induced almost full protection against these behavioral effects of saline stress but DS treatment was ineffective. Restraint stress was found to cause a pronounced inhibition of head dipping as well as a great increase of the scores of grooming in the control group. The CI treatment clearly attenuated these effects of restraint but DS treatment was not effective. The results suggest that male rats treated chronically with CI tolerated both acute stresses better than untreated rats, and that a similar treatment with DS did not provide protection against the effect of such stresses on hole board responding. Inasmuch as CI and DS have different relative potency at noradrenergic and serotonergic systems, it is speculated that this might be in part responsible for their differences as stress protectors.

Animals↗
PubMed1988

Functional responses to baclofen and 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) in rats repeatedly treated with desipramine.

Subcutaneous chronic desipramine (DMI, 5 mg/kg once daily for 18 consecutive days) prevented subcutaneous THIP (20 mg/kg) reduction in body temperature but did not affect THIP behavioral depressant effect (open-field behavior). Repeated DMI treatment did not affect subcutaneous baclofen (2.5-10 mg/kg) reduction in body temperature and behavioral depression (open-field behavior).

Analgesics↗
PubMed1989

Effects of corticotropin releasing factor, desipramine and haloperidol on a DRL schedule of reinforcement.

Rats were trained on a schedule of differential-reinforcement-of-low-rate (DRL) which has been proposed to be differentially sensitive to antidepressant drugs. Desipramine and haloperidol decreased response rate and increased reinforcement rate. CRF decreased response rate and failed to change reinforcement rate. Amphetamine produced the opposite pattern of increased response rate and decreased reinforcement rate. These results question the specificity of the DRL task as a screen for antidepressants and suggest that drugs that moderately lower response rate may produce a behavioral profile on this task similar to that of tricyclic antidepressants.

Amphetamine↗
PubMed1990

Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus.

Two weeks of chronic desipramine HCl (DMI) (10 mg/kg, IP) treatment did not alter reward or motor/performance components of intracranial self-stimulation (ICSS) as assessed with the rate-frequency method. Acute DMI treatment produced an ICSS reward decrement relative to saline control treatment, which was similar in size on Day 1 and Day 15 of chronic testing. The failure to find a chronic DMI effect on ICSS reward suggests that ICSS in normal rats may not be a valid animal model of depression. A better paradigm may be to test the ability of antidepressants to reverse a chronic reduction in ICSS reward function that is first produced by some other method.

Animals↗
PubMed1993

Juvenile desipramine reduces adult sensitivity to imipramine in two behavioral tests.

The behavioral effects of adult imipramine administration were examined in female rats treated with desipramine as juveniles (JDES), treated with saline as juveniles (JSAL), and untreated as juveniles (JUNT). In the forced swimming test, the juvenile groups displayed similar behavioral effects of imipramine when administered short term following a pretest forced swimming exposure. Similar effects of imipramine were observed when administered long term prior to the only test exposure. When rats were not given a pretest forced swimming test exposure, short-term imipramine had no effect on JDES rats but did influence JSAL and JUNT rats. In the open-field test, short- and long-term imipramine treatment affected the behavior of JUNT and JSAL rats. Short-term imipramine treatment influenced open-field behavior of JDES animals, but long-term imipramine treatment had no effect. These results suggest that JDES treatment may permanently alter the neural mechanism underlying the behavioral effects of antidepressant treatment.

Animals↗
PubMed1980

Efficacy of desipramine in endogenomorphically depressed patients.

This study was designed to test the hypothesis that there are 2 biochemical subgroups of 'endogenously' depressed patients--serotonin-deficient and noradrenalin-deficient groups--which respond differently to antidepressants depending on relative blockade of serotonin vs. norepinephrine (NE) reuptake. Patients with pervasive anhedonia and autonomy of depressed mood (endogenomorphic depressives) were treated first with the noradrenergic agent desipramine (DMI), then, if still depressed, such patients were randomized double-blind to continued DMI or clomipramine (CMI), a primarily serotonergic agent. Of 34 such endogenomorphically depressed patients 2 responded during a placebo period and 5 dropped out. Of 27 patients completing at least 4 weeks of DMI (mean maximum daily dose 283 mg, range 100-400 mg/d), 23 (85.2%) responded. With only 4 nonresponders, the second, or CMI, part of the study had to be abandoned. Since DMI strongly blocks neuronal reuptake of catecholamines with little effect on serotonin reuptake, these results suggest that endogenomorphic depressives may have a relatively homogeneous catecholamine deficiency. Alternatively, DMI may exert its effect by a mechanism other than blockade of EN reuptake. Eleven of the endogenomorphically depressed patients also met Research Diagnostic Criteria for situational depression (reactive). Ten of these 11 responded to DMI suggesting that presence or absence of a precipitant may be irrelevant in predicting response to tricyclic antidepressants in endogenomorphic depressions. Mean blood levels drawn at equivalent DMI dose were 238 ng/ml (range, 48-712) for responders, and 352 ng/ml (range, 160-877) for non-responders, indicating that patients appear to respond to DMI across a wide range of blood levels and suggesting the absence of a narrow therapeutic window.

Adjustment Disorders↗