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PubMed1993

A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder.

OBJECTIVE: To determine whether clomipramine hydrochloride, a serotonin reuptake blocker with unique anti-obsessional properties, is differentially effective for obsessive-compulsive and stereotyped motor behaviors in autistic disorder compared with placebo and with the noradrenergic tricyclic antidepressant agent, desipramine hydrochloride. DESIGN: Following a 2-week, single-blind placebo washout phase, 12 autistic subjects completed a 10-week, double-blind, crossover comparison of clomipramine and placebo, and 12 different subjects completed a similar comparison of clomipramine and desipramine. SETTING: Outpatient clinic. PATIENTS: A referral sample of 30 male and female autistic patients were enrolled, and 24 completed the study. MEASURES: Key outcome measures were the Autism Relevant Subscale of the Children's Psychiatric Rating Scale, the Modified Comprehensive Psychopathological Rating Scale-Obsessive-Compulsive Disorder Subscale, and the Clinical Global Impressions Scale. RESULTS: Clomipramine was superior to both placebo and desipramine on ratings of autistic symptoms (including stereotypies), anger, and compulsive, ritualized behaviors (P < .05), with no differences between desipramine and placebo. Clomipramine was equal to desipramine and both tricyclic agents were superior to placebo for amelioration of hyperactivity. CONCLUSION: Biological links between compulsions and stereotyped, repetitive behaviors in autistic disorder should be explored.

Adolescent↗

PubMed1994

A monoclonal anti-idiotypic antibody to opioid receptors labels desipramine-induced opioid binding sites on rat C6 glioma cells and attenuates thymidine incorporation into DNA.

Treatment of rat C6 glioma cells with the tricyclic antidepressant desipramine induces opioid binding. Here the distribution of these opioid-binding sites on C6 cell membranes and a functional property were investigated. Immunohistochemical examination of C6 cells was performed using a monoclonal anti-idiotypic antibody to opioid receptors (Ab2AOR). Ab2AOR uniformly labeled > 97% of the cells exposed to desipramine over their entire surface. The opioid-receptor antagonist naltrexone completely blocked Ab2AOR binding. Ab2AOR, which has opioid agonist properties, also inhibited DNA synthesis in desipramine-treated but not in naive C6 cells. Similarly, morphine blocked C6 cell proliferation only after desipramine treatment. The antineurotrophic action of Ab2AOR was reversed by naltrexone and was insensitive to pertussis toxin. These findings demonstrate that Ab2AOR suppresses the proliferation of C6 glioma cells by binding to desipramine-induced opioid receptors.

Animals↗

PubMed1998

Isolation of partially purified P450 2D18 and characterization of activity toward the tricyclic antidepressants imipramine and desipramine.

Previous reports have shown that rat brain microsomes are capable of metabolizing tricyclic antidepressants such as imipramine. Subsequent studies have shown that the protein products of several clones isolated from rat brain cDNA libraries are capable of metabolizing imipramine to both its active metabolite, desipramine, and its inactive hydroxylated metabolites. We report here the overexpression and partial purification of P450 2D18 using the baculovirus expression system and the incorporation of a C-terminal [His]4 tag. P450 2D18 was partially purified to a specific content of 4.8 nmol/mg protein and shown to be electrophoretically pure. The apparent KM values for P450 2D18 toward imipramine and desipramine were 374 and 314 microM, respectively. While apparent KM values were similar, P450 2D18 was shown to have a fivefold increased Vmax (2.2 nmol/min/nmol P450) for imipramine compared to desipramine (0.44 nmol/min/nmol P450), suggesting a primary involvement in the activation of imipramine to desipramine. We also examined the effect of the CYP2D6 inhibitor quinidine, the CYP3A inhibitor ketoconazole, and the dopamine reuptake inhibitor GBR-12935 for their ability to inhibit P450 2D18-mediated metabolism of imipramine. These results, when compared with previous studies using rat brain microsomes, suggest that P450 2D18 may play an important role in the conversion of imipramine to its active metabolite desipramine in the rat brain.

Aryl Hydrocarbon Hydroxylases↗

PubMed1992

Characterization of the [3H]-desipramine binding site of the bovine adrenomedullary plasma membrane.

The specific (i.e. nisoxetine-sensitive) binding of [3H]desipramine was studied in membranes prepared from bovine adrenal medullae. (1) [3H]desipramine bound reversibly and with high affinity (KD = 2.8 nmol/l) to a single class of non-interacting binding sites (Hill coefficient = 0.96); the maximal number of binding sites (Bmax) was 2.1 pmol/mg protein. (2) Binding of [3H]desipramine was dependent on [Na+] and [Cl-]. Increasing the concentrations of these ions increased binding. (3) Substrates and inhibitors of the neuronal noradrenaline transport system (uptake1) inhibited binding of [3H]desipramine with a rank order of potency typical for an interaction with the uptake1 carrier. The characteristics of [3H]desipramine binding remained essentially unchanged after solubilization of adrenomedullary membranes with the non-ionic detergent digitonin. The results indicate that the plasma membrane of bovine adreno-medullary cells is endowed with the neuronal uptake1 transporter.

Adrenal Medulla↗

PubMed1988

Inhibition of neuronal noradrenaline uptake (uptake1) and desipramine binding by N-ethylmaleimide (NEM).

The inhibition of N-ethylmaleimide (NEM) of uptake1 and desipramine binding was studied on clonal rat phaeochromocytoma cells (PC12 cells) in different experimental settings: (1) 3H-noradrenaline uptake into intact PC12 cells; (2) 3H-noradrenaline uptake into isolated PC12 plasma membrane vesicles; (3) 3H-desipramine binding to isolated PC12 plasma membrane vesicles. In plasma membrane vesicles, NEM inhibited 3H-desipramine binding and 3H-noradrenaline uptake with similar potency (the IC50's were 1.36 mmol/l and 1.04 mmol/l, respectively). However, in intact cells, NEM was about 75 times more potent in inhibiting 3H-noradrenaline uptake (IC50 = 0.014 mmol/l). The increased potency of NEM in intact cells is probably due to an inhibition of the Na+/K+-ATPase and not to a direct interaction with the noradrenaline carrier. The inactivation by NEM of 3H-desipramine binding to PC12 plasma membrane vesicles was irreversible. Both an inhibitor (cocaine, 1 mmol/l) and a substrate of uptake1 (amezinium, 1 mmol/l) protected desipramine binding from inactivation. These results are compatible with the hypothesis of a common binding site for substrates and inhibitors of the neuronal noradrenaline carrier.

Adrenal Gland Neoplasms↗

PubMed1975

The effect of amitriptyline, desipramine and imipramine on the vivo brain synthesis of 3H-noradrenaline from 3H-L-dopa in the rat.

3H-L-Dopa was given to rats after a peripheral decarboxylase inhibitor Ro 4-4602 (50 mg/kg) and the effect of 30 min pretreatment with antiptyline (10 mg/kg), desipramine (10 mg/kg) and imipramine (10 mg/kg) on the brain formation of 3H-dopamine, 3H-noradrenaline and their major metabolites was investigated. Desipramine produced a decrease in the level of labelled noradrenaline and its major metabolites free and conjugated 3-methoxy-4-hydroxyphenyleneglycol and 3,4-dihydroxyphenyleneglycol. Imipramine decreased labelled noradrenaline and 3-methoxy-4-hydroxyphenyleneglycol, whereas amitriptyline produced no significant effect on noradrenaline metabolism. The thymoleptic drugs produced no significant effect on endogenous brain noradrenaline and dopamine. These findings provide a strong indication that desipramine and imipramine inhibit the 3H-noradrenaline biosynthesis from 3H-L-Dopamthe effect seems closely related to the well-known membrane inhibitory effect of these drugs, since desipramine produced a more marked effect than imipramine and amitriptyline showed no effect. No conclusive evidence for the precise mechanism of action was obtained but it is possible that the decreased 3H-noradrenaline synthesis is related to interference of desipramine and imipramine with the precursor (s) 3H-L-Dopa or 3H-dopamine at sites of 3H-noradrenaline biosynthesis.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1981

Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression.

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (less than 20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (greater than 20 ng/ml). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a significant (P less than 0.05) positive correlation with age. The mean value of the uptake of 14C-5-HT in the patient's platelets, when measured before the treatment, was significantly (P less than 0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of 14C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of 14C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of 14C-5-HT in rat synaptosomes, but a marked inhibition of uptake of 14C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of 3H-NA in rat synaptosomes incubated in the patient's plasma was strongly inhibited by desipramine treatment but only slightly affected by zimelidine.

Animals↗

PubMed1976

Persistent enhancement of potassium-induced responses of the rat vas deferens by desipramine.

The effect of desipramine on the cumulative dose-response curves of noradrenaline and potassium (K+) was examined on the isolated rat vas deferens. An exposure of 10 min to 10(-7) M desipramine caused a leftward shift and an increase in the maximum response of cumulative dose-response curves of noradrenaline. Desipramine (10(-7) M), in contact with the tissue for 10 min, enhanced responses to cumulative additions of K+ without causing a consistent change in threshold concentrations. Wash-out of desipramine resulted in a rapid loss of enhanced maximum response to noradrenaline while the maximum response to K+ did not show any decrease for up to 120 min after wash-out of drug. One possible explanation for the persistent enhancement of K+-induced responses may be that desipramine causes postjuntional changes which selectively influence contractile responses of this tissue to K+.

Animals↗

PubMed1982

3H-Noradrenaline and 3H-5-hydroxytryptamine release from rat brain slices and its presynaptic alpha-adrenergic modulation after long-term desipramine pretreatment.

The electrically-evoked release of 3H-noradrenaline from superfused cortex and hippocampus slices was strongly enhanced (by about 50%) after long-term (4 weeks) pretreatment with desipramine (10 mg/kg, twice daily). The release-enhancing effect of the alpha-receptor antagonist phentolamine was significantly reduced but the inhibitory effects of exogenous noradrenaline and clonidine on 3H-noradrenaline release were virtually unchanged after chronic desipramine treatment. The K+ -induced release of 3H-noradrenaline from superfused synaptosomes obtained from rats pretreated with desipramine was about 25% higher than that from synaptosomes of control animals. However, noradrenaline inhibited the K+ -induced synaptosomal 3H-noradrenaline release to the same extent (viz. by about 55%) in both cases. The release of 3H-5-hydroxytryptamine induced by 26 mM K+ from cortex and hippocampus slices was not affected by chronic pretreatment with desipramine. In addition, no change was observed in the inhibitory effect of noradrenaline o 3H-5-hydroxytryptamine release. It is concluded that long-term pretreatment with desipramine leads to selective changes in the basic mechanism(s) of noradrenaline release rather than to changes in the sensitivity of presynaptic alpha-adrenoceptors.

Animals↗

PubMed1981

Interaction of desipramine and amitriptyline with adrenergic mechanisms in the human iris in vivo.

Mydriatic responses of the pupil were evoked by locally instilled noradrenaline and methoxamine in eight healthy volunteers. The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine were compared on the mydriatic responses. Both antidepressants potentiated the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by methoxamine, amitriptyline being approximately twice as potent as desipramine. It is suggested that the potentiation of the response to noradrenaline may reflect the blockade of the uptake of noradrenaline into adrenergic nerve terminals, whereas the antagonism of the response to methoxamine may reflect the blockade of postsynaptic alpha-adrenoceptors by the antidepressants. It is argued that the interaction of the antidepressants with adrenergic mechanisms could explain why amitriptyline, a potent anticholinergic agent, causes no significant change in resting pupil diameter, while desipramine, a relatively weaker anticholinergic agent, produces a significant mydriasis.

Adult↗

PubMed1987

Effect of chronic desipramine treatment on neurotransmitter-thyrotropin releasing hormone--thyrotropin interactions in the rat.

Long-term administration of the antidepressant drug, desipramine (20 mg/kg/day, orally for 28 days), decreased the stimulatory effect of the alpha 2-adrenoceptor agonist, clonidine (250 micrograms/kg, i.p.) on thyrotropin (TSH) secretion in the rat, but did not alter basal TSH secretion. beta-Adrenoceptor-mediated inhibition of TSH secretion by isoproterenol (1 mg/kg, i.p.) was unaffected by chronic desipramine treatment, as were the stimulatory effect of TSH-releasing hormone (TRH, 5 micrograms/kg, i.v.) on TSH release and its inhibition by the alpha-adrenoceptor antagonist, phentolamine (2 mg/kg, i.p.). These findings suggest that chronic desipramine treatment induces subsensitivity of alpha 2-adrenoceptors which modulate TSH secretion in the rat while not affecting beta-adrenoceptor-mediated inhibition of TSH release. These findings suggest that pituitary TRH receptors are unchanged but that changes occurred at the hypothalamic level in alpha 2-adrenoceptor-mediated stimulation of TRH release. Although cerebral beta-adrenoceptors have been shown convincingly to be down-regulated after chronic desipramine treatment, their function in the hypothalamic TRH system after 28 days of treatment with desipramine appears to be unimpaired.

Animals↗

PubMed1990

Effects of chronic treatments with amineptine and desipramine on motor responses involving dopaminergic systems.

The acute effects of increasing doses of the antidepressant drugs amineptine (5-40 mg/kg, IP) and desipramine (5-20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87-30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1-1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25-20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1-0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2003

Functional reactivity of central cholinergic systems following desipramine treatments and sleep deprivation.

This study examined the effects of acute and chronic desipramine, 24-h total sleep deprivation (TSD) and 96-h REM sleep deprivation (REMSD) on physostigmine-induced hypothermia, analgesia and behaviour. The effects of acute and chronic desipramine treatment on oxotremorine-induced hypothermia were also examined. Intraperitoneal administration of physostigmine (0.5 mg/kg i.p.) induced hypothermia, analgesia, purposeless chewing movements (chewing) and head tremors. While atropine given in a low dose (1.0 mg/kg i.p. 15 min prior) did not antagonize the hypothermia, chewing and head tremor associated with physostigmine (0.5 mg/kg i.p.), a higher dose of atropine (10 mg/kg i.p. 15 min prior) decreased physostigmine-induced hypothermia, chewing and head tremor behaviour. Chronic (10 or 20 mg/kg i.p. daily for 10 days and withdrawn 24 h prior, chronic DMI) and acute (10 mg/kg, i.p. + 60 min prior, acute DMI) desipramine treatments abolished physostigmine (0.5 mg/kg i.p.)-induced hypothermia compared with saline pretreatment. Interestingly atropine (1 mg/kg i.p. 15 min prior) reversed the inhibitory effect of chronic DMI on hypothermia induced by physostigmine. Acute but not chronic DMI decreased physostigmine-induced chewing and head tremor behaviour. Atropine (1 mg/kg i.p. 15 min prior) increased the inhibitory action of acute DMI on physostigmine-induced chewing behaviour. Acute DMI (10 mg/kg i.p.) decreased oxotremorine (0.1 mg/kg i.p.)-induced hypothermia, while chronic DMI increased the hypothermic effect of oxotremorine. TSD and REMSD did not alter physostigmine (0.5 mg/kg i.p.)-induced hypothermia; however, REMSD and stress decreased physostigmine-induced analgesia and chewing.It is suggested that chronic desipramine treatment decreased physostigmine-induced hypothermia by causing hypersensitivity of pre-synaptic muscarinic receptors, whereas acute desipramine decreased the sensitivity of post-synaptic muscarinic receptors

Adrenergic Uptake Inhibitors↗

PubMed1980

The time course of noradrenergic pre- and postsynaptic activity during chronic desipramine treatment.

The firing of hippocampal cells was studied in rats treated with desipramine 10 mg/kg per day i.p. for various periods of time. These cells were neurophysiologically identified to be noradrenergic postsynaptic by their decreased firing during stimulation of the locus coeruleus (LC). While desipramine given for 1 day produced no change, the drug given for 7, 14, and 21 days produced a 20%, 38% and 89% increase, respectively; only the last increase reached a statistical significance. This time course closely resembles that of the therapeutic action of the drug in depressed patients. Desipramine also altered the firing of norepinephrine-containing cells in the LC. While desipramine given for 1 day produced no change, the drug given for 7, 14 and 21 days produced a 12%, 29% and 34% decrease, respectively; only the last two decrements reached a statistical significance. This time course resembles that of the change in firing of hippocampal cells. Based on this and other data it is suggested that the decrease in the firing of LC cells plays a major role in the increased firing of hippocampal cells obtained after desipramine treatment.

Animals↗

PubMed1980

Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs.

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.

Adrenergic alpha-Agonists↗

PubMed1982

High-affinity [3H]desipramine binding in the peripheral and central nervous system: a specific site associated with the neuronal uptake of noradrenaline.

The specific binding of [3H]desipramine to various brain regions and peripheral tissues of the rat was of high affinity, rapid and reversible. It was inhibited with high affinity only by tricyclic antidepressants and noradrenaline uptake blockers. There was a highly significant correlation between the potencies of a series of drugs for the inhibition of [3H]desipramine binding and for the inhibition of noradrenaline uptake. Substrates for the noradrenaline uptake system however inhibited the binding of [3H]desipramine only at very high concentrations. Postganglionic sympathetic denervation of the submaxillary gland and the heart both resulted in a pronounced decrease in [3H]desipramine binding sites, which paralleled the reduction in endogenous noradrenaline levels. High-affinity [3H]desipramine binding sites thus appear to be localised on noradrenergic nerve endings and are probably closely associated with the neuronal uptake system for noradrenaline.

Animals↗

PubMed1988

Rapid down regulation of beta-adrenoceptors by co-administration of desipramine and fluoxetine.

Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.

Adenosine Triphosphate↗

PubMed1990

Alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test.

The influence of alpha 2-adrenoceptor blockade on the activity of desipramine in an experimental model of depression was studied by using idazoxan and 1-(pyrimidinyl)piperazine (1-PP). The two drugs antagonists at these receptors, were studied for their ability to modify the effect of repeated treatment with the antidepressant, desipramine in the forced swimming test. Idazoxan (0.03, 0.3 and 3 mg/kg s.c.) and 1-PP (0.3 and 3 mg/kg p.o.) given with the last dose of a 7-day schedule of 10 mg/kg i.p. desipramine significantly reduced the effect of the latter on immobility. On its own neither drug modified the immobility time of rats at any dose. Infusion of various concentrations of idazoxan (1.6, 8 and 40 ng/microliters) in the rat locus coeruleus (LC), dose dependently antagonized the effect of desipramine without causing any appreciable change in motor behavior or immobility. The effect of idazoxan (8 ng/microliters) infusion in the LC was completely prevented by administering 6 micrograms 6-hydroxydopamine in the same region 12 days earlier. It thus appears that alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test, presumably by an effect on noradrenaline-containing cells in the LC. The question of how blockade or activation of alpha 2-adrenoceptors, both in the LC and in other sites, could influence antidepressant activity is discussed.

Adrenergic alpha-Antagonists↗