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PubMed1989

Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of enkephalin-degrading peptidases.

The implication that opioid peptides are involved in the action of the antidepressants imipramine and iprindole was investigated in mice by using the forced swimming test as an experimental model of depression. Both the drugs were found to shorten the immobility time in this test. This effect of imipramine and iprindole was reversed by the opiate antagonist naloxone. Moreover, when subeffective doses of either imipramine or iprindole were given together with an intracerebroventricular injection of an inhibitor of their degradation (thiorphan or bestatin), the immobility time was again decreased. Interestingly, the reduction of the time of immobility was found to be not related to the effect of the drugs on locomotor activity. These data might be taken as further evidence for the involvement of opioid peptides in the pharmacological action of antidepressant drugs.

Animals↗
PubMed1985

The effects of imipramine and iprindole on the metabolism of octopamine in the rat.

Acute injections of imipramine and iprindole in rats produced significant decreases in the concentration of p-hydroxyphenylglycol (pHPG), a neutral metabolite of octopamine in brain at 6 and 24 hr after the administration of drugs. The 24-hr urinary levels of both free and total pHPG were reduced to 25-29% of control with acute administration of imipramine, while iprindole produced a 30% decrease in free pHPG. With chronic administration of imipramine, concentrations of pHPG in brain returned to normal, while the 24-hr urinary levels were still decreased (to 24%). Octopamine in brain was unaltered after both single and repeated injections of imipramine. Thus, these data suggest that the turnover of octopamine in brain is reduced after acute administration of imipramine and iprindole, while after chronic treatment with imipramine, turnover of octopamine in brain has returned to control levels.

Animals↗
PubMed1996

Effects of neonatally administered iprindole on adult behaviors of rats.

In past studies, administration of the antidepressant drugs clorimipramine, zimeldine, or desipramine to neonatal rats produced abnormalities in adult rats that modeled some behavioral and/or REM sleep features of human endogenous depression. Although these three drugs affected different neurotransmitter systems, all caused REM sleep deprivation (RSD). This suggested the hypothesis that RSD of neonatal rats caused their adult depression. One prediction of this hypothesis is that neonatally administered iprindole, an antidepressant drug that does not produce RSD, will not produce adult rats that model depression. The present study tested this hypothesis. Iprindole was administered to neonatal experimental rats and saline was administered to neonatal control rats. When the rats matured, compared with control rats, experimental rats were not significantly different in aggressive behavior (shock induced fighting), sexual behaviors, open field locomotion, and REM sleep. In our previous studies on rats, all these adult behaviors were affected in a depressive-like way by neonatally administered clorimipramine. Because iprindole does not decrease REM sleep, the present results support the hypothesis that in rats neonatal RSD causes adult depression.

Aggression↗
PubMed1991

Interactions of iprindole with fenfluramine metabolism in rat brain and liver.

An assay procedure utilizing electron-capture gas chromatography was developed for simultaneous analysis of fenfluramine and norfenfluramine. This method was applied to brain and liver samples from rats which had been injected with fenfluramine with or without pretreatment with iprindole. The tissues from rats treated with fenfluramine showed extensive formation of norfenfluramine, consistent with findings reported previously in the literature. Pretreatment with iprindole led to an increase in brain and liver levels of fenfluramine, and, unexpectedly, to a marked decrease in levels of norfenfluramine in these tissues. These findings suggest that iprindole blocks N-deethylation and that it may be a useful tool with which to study the effects of fenfluramine in the absence of norfenfluramine. The results also emphasize the importance of considering drug-drug interactions in future research on fenfluramine.

Animals↗
PubMed1983

Effects of a single dose of methamphetamine and iprindole on the serotonergic and dopaminergic system of the rat brain.

A single dose (17.5 mg/kg i.p.) of methamphetamine was administered to iprindole-treated (10 mg/kg i.p.) rats. Forebrain concentrations of methamphetamine and amphetamine were significantly increased in iprindole-treated rats 1 and 6 hr after injection; in contrast to rats pretreated with saline, both amines were also detected after 18 hr. Three and 7 days after injection, significant decreases were seen in tryptophan hydroxylase (TPH) activity and serotonin concentrations in the cerebral cortex, neostriatum and hypothalamus. Hypothalamic TPH activity had recovered by 14 days. Neostriatal tyrosine hydroxylase activity and dopamine concentrations were significantly depressed at all time points examined. Iprindole alone produced a significant increase in cortical TPH activity after 1 day. After 3 days, TPH activity was significantly decreased when compared with control, whereas serotonin and 5-hydroxyindoleacetic acid concentrations were significantly increased. This study demonstrates that persistence of methamphetamine and/or amphetamine at the site of action is important for neurotoxicity.

Amphetamines↗
PubMed1980

Development of and recovery from subsensitivity of the noradrenergic cyclic AMP generating system in brain. Effect of amphetamine following inhibition of its aromatic hydroxylation by iprindole.

Amphetamine given intraperitoneally (10 mg/kg b.i.d.) for 2 days did not alter either the basal level of cyclic AMP or the neurohormonal response of the cylcic AMP generating system to noradrenaline (NA). The same doses of amphetamine caused a significant reduction in the responsiveness to NA and the beta-adrenergic agonist isoprenaline following the inhibition of the aromatic hydroxylation by iprindole. The EC50 values (concentration of NA which causes half maximal cyclic AMP stimulation) were not significantly changed: 9.5 micro M (controls) and 11 micro M (iprindole + amphetamine). Following discontinuation of the drugs, the recovery from adrenergic subsensitivity to NA was complete within 1 week in the limbic forebrain while the adrenergic responsiveness in the cortex was still only 65% of its control value 3 weeks following discontinuation of the drugs. The subsensitivity in both limbic forebrain and cortex was linked to a decreased Bmax value of specific 3H-dihydroalprenolol binding without changes in the Kd values. The different rates of recovery from noradrenergic subsensitivity in limbic forebrain and cortex following withdrawal of the drugs were reflected in the density of beta-adrenergic receptors in the two brain regions. Since inhibition of the aromatic hydroxylation of amphetamine markedly prolongs the half life of the drug and prevents the accumulation of p-hydroxynorephedrine (a potential NA antagonist), the results support the view that homospecific down-regulation of the NA receptor coupled adenylate cyclase system in brain depends on a sustained and unhindered NA receptor interaction.

Adenylyl Cyclases↗
PubMed1984

Nerve terminal degeneration after a single injection of D-amphetamine in iprindole-treated rats: relation to selective long-lasting dopamine depletion.

A single injection of D-amphetamine has recently been shown to produce long-lasting dopamine (DA) deficits in rats pretreated with iprindole, an agent which interferes with the metabolism of amphetamine and prolongs its half-life. The basis for these persistent DA deficits has not been determined. The present results suggest that amphetamine produces prolonged DA depletions in iprindole-treated rats by destroying DA nerve terminals.

Animals↗
PubMed1981

Differential actions of mianserin and iprindole on the sensitivity of cortical neurons to noradrenaline: effect of chronic treatment.

The sensitivity of cingulate cortical neurons to microiontophoretically administered noradrenaline (NA) was compared in groups of rats treated with one or other of the two antidepressants mianserin (30 mg/kg s.c.) or iprindole (10 mg/kg i.p.) either acutely or chronically, for 10 and 28 days respectively. In the rats treated chronically with mianserin, the neurons were significantly less sensitive to NA than those of the acutely treated animals. By contrast, chronic administration of iprindole did not significantly affect neuronal sensitivity to NA.

Animals↗
PubMed1992

MK801 antagonism of the prolonged depletion of striatal dopamine by amphetamine in iprindole-treated rats.

The administration of amphetamine to rats pretreated with iprindole to inhibit the metabolism of amphetamine results in a long-lasting depletion of striatal dopamine and its metabolites, DOPAC and HVA. Pretreatment with MK801, a noncompetitive antagonist of the NMDA (N-methyl-D-aspartate) subclass of excitatory amino acid receptors, antagonized the depletion of striatal dopamine, DOPAC and HVA 3 days after a single dose of amphetamine in iprindole-treated rats. MK801 pretreatment was effective up to 4 hours but not at 8 or 24 hours in preventing amphetamine effects on striatal dopamine, DOPAC and HVA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine.

(+) Amphetamine was more potent (-) amphetamine in causing persistent depletion of striatal dopamine in iprindole-treated rats. This effect of amphetamine was not mimicked by EXP561, a structurally related compound that is more potent than amphetamine as an inhibitor of dopamine uptake. The depletion of striatal dopamine at 1 week after amphetamine injection in iprindole-treated rats was prevented by amfonelic acid, an inhibitor of uptake into dopamine neurons. The depletion of dopamine by amphetamine was prevented when amfonelic acid was given at the same time as amphetamine or as long as 4 hr after amphetamine but not when amfonelic acid was given 24-48 hr after amphetamine. Amfonelic acid antagonized the depletion of dopamine by amphetamine but not the depletion of serotonin by p-chloroamphetamine; fluoxetine antagonized the depletion of serotonin by p-chloroamphetamine but not the depletion of dopamine by amphetamine. Pretreatment with alpha-methyl-tyrosine to block dopamine synthesis antagonized the persistent depletion of dopamine by amphetamine, but pretreatment with an inhibitor of monoamine oxidase to increase that dopamine concentration had no effect. The possibility that prolonged release of dopamine from intraneuronal storage granules leads to deleterious effects on dopamine neurons is discussed.

Amphetamines↗
PubMed1984

The effects of a single dose of amphetamine and iprindole on the serotonergic system of the rat brain.

Rats treated with iprindole (IPR) (10 mg/kg, i.p.) were given a single dose (15 mg/kg, i.p.) of amphetamine (AMP). Marked decreases in the activity of tryptophan hydroxylase (TPH) were observed in both the cerebral cortex and neostriatum after 6 hr, with maximum depression observed at 24 hr. Enzyme activity had returned to control levels in neostriatum after 3 days and in cerebral cortex after 7 days. Levels of serotonin (5-HT) in both the cerebral cortex and neostriatum were significantly lowered at 24 hr but had recovered by 72 hr. Levels of tryptophan (TRP) in the cortex were significantly elevated after 6 hr, recovering by 24 hr. In the neostriatum, the activity of tyrosine hydroxylase (TH) was significantly depressed by 24 hr and remained so for 7 days. Concentrations of dopamine (DA) were decreased at all times examined. This study clarifies the differences previously observed in the response of the serotonergic system to amphetamine or methamphetamine (METH) in iprindole-treated rats.

Animals↗
PubMed1981

Brain monoamine oxidase activity after in vivo-chronic iprindole treatment.

The effects of chronic administration of three different doses of iprindole on the monoamine oxidase activity and neurotransmitter content were studied in the cerebral cortex, the mesencephalon and the cerebellum of mouse brain. The treatment inhibited mitochondrial monoamine oxidase activity of all three brain regions studied, although a dose-response inhibitory effect was found only in the mesencephalon. Brain regional serotonin contents were markedly increased after iprindole treatment. The 5-hydroxyindoleacetic acid contents showed a significant decrease only in the cerebral cortex. Neither dopamine nor norepinephrine brain regional contents were significantly altered. On the basis of these results it is suggested that a substrate-specific inhibition of monoamine oxidase is involved in the mechanism of action of this tricyclic antidepressant.

Animals↗
PubMed1982

The acute effects of amitriptyline, iprindole and trazodone on blood pressure and heart rate in rats.

The cardiovascular effects of the tricyclic anti-depressant amitriptyline, a monoamine uptake inhibitor, and iprindole and trazodone, two novel anti-depressants of unknown mechanism, were monitored in urethane anesthetized rats following intravenous (IV) or intracerebroventricular (IVT) injection. Amitriptyline (2 mg IV or 0.25 mg IVT) produced hypotension that might reflect an action of norepinephrine on the anterior hypothalamus. Iprindole (2 mg IV) produced hypertension and (0.25 mg IVT) tachycardia that is consistent with a partial beta-agonist mechanism. Trazodone (1 mg IV or 0.25 mg IVT) produced hypotension and bradycardia that is consistent with the activation of noradrenergic neurons in the anterior hypothalamus perhaps as a result of trazodone acting on presynaptic alpha 2 receptors or on presynaptic serotonin receptors to increase the release of norepinephrine. All three of these anti-depressants have the potential to precipitate cardiovascular complications, particularly in patients with pre-existing cardiovascular abnormalities.

Amitriptyline↗
PubMed1985

Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study.

The authors administered lithium carbonate, 900 mg/day, in an open study to seven patients with a major unipolar depression refractory to 3-week treatment with iprindole, 90 mg/day, a tricyclic antidepressant devoid of any action on monoaminergic reuptake. All patients showed clinically significant improvement within 48 hours. Since iprindole induces in the animal a sensitization of forebrain neurons to serotonin (5-HT), as do other tricyclic antidepressants, and lithium enhances the activity of 5-HT neurons, the authors propose that an enhanced release of 5-HT on sensitized target neurons might underlie the rapid antidepressant effect in tricyclic-refractory depression when lithium is added to the treatment regimen.

Adult↗
PubMed1979

The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat.

1. Absorption of a single oral dose of [14C]iprindole was rapid in rats, rhesus monkeys, miniature swine, dogs and human volunteers. In all species except the rat, most of the radioactivity in the blood resided in the plasma. Small amounts of unchanged iprindole were detected in the plasma of rats and rhesus monkeys but not in man and miniature swine. 2. Radioactivity was excreted mainly in the urine of man, miniature swine and rhesus monkey, but in the faeces of rat and dog. 3. Urinary radioactivity was associated with basic (free and conjugated), acidic and highly polar, water soluble metabolites. At least 20 metabolites as well as small amounts of unchanged drug were detected in the basic fractions of each species' urine. 4. Many of these metabolites were common to all species; however, qualitative as well as quantitative differences were apparent. Mass-spectrometric analysis of several metabolites indicated N-demethylation and oxidation of the alicylic ring or a combination of both pathways.

Animals↗
PubMed1981

Iprindole-induced phospholipidosis in rat alveolar macrophages: alterations in oxygen consumption and release of oxidants.

Rats chronically treated with the cationic amphipilic drug iprindole developed a phospholipid storage disorder in their pulmonary alveolar macrophages (AMs). AMs from these iprindole-treated rats (IP-AMs) were compared to AMs from control rats (C-AMs) regarding oxygen consumption and the release of two reactive oxygen species, superoxide anion and hydrogen peroxide. Responses of C-AMs and IP-AMs were compared at rest and when stimulated by unopsonized or opsonized zymosan. Opsonization was not necessary in order to induce respiratory burst-associated phenomena in either cell type; in fact in all cases, for given cell type responses to unopsonized zymosan were virtually identical to those of opsonized zymosan. When at rest, IP-AMs consumed oxygen at a rate nearly identical to that of C-AMs. When stimulated with zymosan particles, IP-AMs consumed more oxygen than controls. However, when superoxide anion and hydrogen peroxide, two products of the respiratory burst were measured, IP-AMs released less of these species than C-AMs when at rest and when particle stimulated. Despite the lower total release of these species by the IP-AMs, the zymosan-induced release (stimulated minus resting levels) was greater for these cells than C-AMs. Therefore, the IP-AMs were found to be more responsive to the zymosan particle than C-AMs. The results indicate marked changes in the release of reactive oxygen species from the AMs following induction of phospholipidosis.

Animals↗
PubMed1994

The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine.

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid beta-adrenergic receptor down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague-Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR-HCl (11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection for free (R)-and (S)-FLU and (R)- and (S)-NFLU after extraction and reaction with (-)-(S)-N-(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)-FLU alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Alterations in peripheral nerves of rats treated with chlorphentermine or with iprindole.

This study deals with the effects of two amphiphilic lipidosis-inducing drugs (chlorphentermine, iprindole) upon the ultrastructure of peripheral nerves of rats. After prolonged drug treatment the preterminal and terminal axoplasm of motor and sensory nerves within skeletal muscles contain numerous abnormal inclusions (osmiophilic conglomerates, autophagic vacuoles, lamellated bodies). By contrast, the axons within large peripheral nerves are little effected. The present observations are tentatively interpreted as resulting from interference with catabolic processes involved in the normal turnover of axoplasmic constituents at the nerve terminal. The exact pathogenesis and the functional significance of these alterations remain to be elucidated.

Animals↗