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PubMed1989

The thyroid axis and desipramine treatment in depression.

Although there has been much recent investigation of the role of thyroid function in affective illness, few studies have addressed the effects of the tricyclic antidepressants on the pituitary-thyroid axis. In the present study, thyroid functions (TFTs) and thyrotropin-releasing hormone (TRH) stimulation of thyroid-stimulating hormone (TSH) were measured before and after treatment with desipramine (DMI) in 13 men with a diagnosis of major depressive disorder. All subjects had normal TFTs and baseline TSH measured in a drug-free state at the initiation of the study. Both mean free thyroxine index and baseline TSH decreased after DMI treatment. The amount of decrease in baseline TSH correlated with increase in delta TSH. Four subjects had blunted delta TSH (delta TSH less than or equal to 5 microIU/ml); three of these subjects "normalized" with treatment (delta TSH less than or equal to 5 microIU/ml; greater than or equal to 20 microIU/ml). Two subjects had a high delta TSH, and both "normalized" during treatment. The decrease in both free T4 index and TSH suggests a down-regulation of the thyroid axis at the hypothalamic level. "Normalization" of subtle dysregulation of the thyroid axis is suggested as a mechanism of antidepressant therapy in the treatment of some depressions.

Adult↗

PubMed1991

Response of depression to very high plasma levels of imipramine plus desipramine.

Forty-five depressed patients were treated with imipramine for 6 weeks. Seven of 7 patients (100%) who had plasma levels of imipramine plus desipramine greater than 500 ng/ml showed a 50% or greater improvement in Hamilton depression scores compared with 23 of 38 patients (60%) with plasma levels less than 500 ng/ml (p less than 0.057).

Adult↗

PubMed1994

Attenuation of hormone responses to the 5-HT1A agonist ipsapirone by long-term treatment with fluoxetine, but not desipramine, in male rats.

The present study had two objectives: (1) to provide information on neuroendocrine challenge tests that can lead to diagnostic tests in humans; and (2) to confirm our previous observation that chronic fluoxetine selectively inhibits serotonin (5-HT1A) receptor function. We determined the effect of chronic fluoxetine and desipramine (DMI) on the hormone response to ipsapirone, a 5-HT1A agonist and a potential anxiolytic drug. Ipsapirone increased oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, and prolactin, but not renin or vasopressin concentrations in plasma. Chronic fluoxetine, but not DMI, significantly inhibited the effect of ipsapirone on plasma oxytocin, ACTH and corticosterone concentrations. Chronic fluoxetine also reduced the Bmax for 3H-8-hydroxy-2-(dipropylamino) tetralin (3H-8-OH-DPAT) labelled 5-HT1A receptors in the midbrain. Neither antidepressant altered the density or affinity of 5-HT uptake sites. In conclusion, the present results confirm our previous results using 8-OH-DPAT as a challenge, and suggest that chronic 5-HT uptake inhibition results in adaptive changes leading to decreased function of the 5-HT1A receptor system. Finally, because ipsapirone may be administered to humans, it might be usable to evaluate 5-HT1A receptor function in depressed patients.

Adrenocorticotropic Hormone↗

PubMed1985

Effect of chronic desipramine treatment on adrenoceptor modulation of [3H]dopamine release from rat nucleus accumbens slices.

The effects of alpha 2- and beta-adrenoceptor agonists on the 25 mM K+-induced release of [3H]dopamine [( 3H]DA) from the nucleus accumbens slices of chronic desipramine (DMI)- and saline-treated rats were investigated using a superfusion technique. The K+-induced release of [3H]DA from nucleus accumbens slices was shown to be Ca2+ dependent and to be enhanced by ascorbic acid. In experiments with isoproterenol, ascorbic acid was added to the superfusion media in order to prevent the otherwise rapid oxidation of the drug. The K+-induced release of [3H]DA from nucleus accumbens slices of saline-treated rats was significantly decreased by the alpha 2-adrenoceptor agonist, clonidine (10 microM; 89 +/- 2.4% of control values; P less than 0.002), and significantly enhanced by the beta-adrenoceptor agonist, isoproterenol (1 and 10 microM; 122 +/- 4.3 and 171 +/- 2.9% of control values, P less than 0.002 and P less than 0.001, respectively). The basal release of [3H]DA was strongly enhanced by 10 microM but not 1 microM isoproterenol. Chronic DMI pretreatment (10 mg/kg i.p. for 28 days) did not significantly alter the K+-induced release of [3H]DA. Chronic DMI treatment attenuated the alpha 2-adrenoceptor-mediated inhibition of [3H]DA release, while the beta-adrenoceptor-mediated stimulation remained unchanged. The net effect of chronic DMI treatment therefore would appear to be a facilitation of dopaminergic neurotransmission in the mesolimbic system. This is consistent with behavioural evidence which suggests that the function of the mesolimbic dopaminergic reward system is facilitated by chronic treatment with antidepressant drugs.

Animals↗

PubMed1986

Clorgyline and desipramine alter the sensitivity of [3H]noradrenaline release to calcium but not to clonidine.

Synaptosomes (P2) were prepared from cerebral cortices of control rats and from those which had received clorgyline (1 mg/kg/day for 21-28 days) or desipramine (10 mg/kg/day for 21-28 days). Following incubation with [3H]noradrenaline (500 nM/15 min, 37 degrees C), aliquots of the synaptosomes were gently filtered onto Whatman GF/A filters and superfused with Krebs buffer (pH 7.5, 37 degrees C) for a maximum period of 2 h. During this time, the basal efflux of tritiated materials (approximately 75% noradrenaline) together with K+-evoked release of the amine and metabolites, were measured. Chronic antidepressant drug regimens increased the K+-stimulated release, but its attenuation by clonidine was not altered. Thus, chronic antidepressant drug regimens do not apparently alter presynaptic alpha 2-adrenoceptors. These results suggest that the reported antidepressant drug induced decreases in [3H]clonidine binding, occur on sites which are postsynaptic to noradrenergic neurones. Following the chronic antidepressant drug regimens, the sensitivity of the [3H]noradrenaline release process to Ca2+ is significantly increased. This change may explain the enhanced K+-evoked release which follows the antidepressant drug regimens. It is proposed that this increased sensitivity of the [3H]noradrenaline release process may be an adaptation to the decrease in neuronal firing which have been reported following antidepressant drug treatments.

Animals↗

PubMed1987

The modulatory effect of neurotensin on [3H]dopamine release from rat nucleus accumbens slices is enhanced after chronic desipramine treatment.

In the presence of the reuptake blocker, nomifensine (1 microM), neurotensin caused a dose-dependent increase in the 25 mM K+-evoked release of [3H]dopamine ([3H]-DA) from rat nucleus accumbens slices. Chronic desipramine (DMI)-treatment (20 mg DMI/kg/day, orally for 28 days) caused a significant reduction in the K+-stimulated release of [3H]DA from rat nucleus accumbens slices. This could possibly have resulted from increased DA autoreceptor-mediated inhibition of DA release. Superfusion of the DMI-treated rat tissue with buffer-containing neurotensin (100 nM) resulted in an increase in the K+-evoked release of [3H]DA to a level which was higher than that observed with tissue obtained from untreated rats. A similar enhanced effect of neurotensin on DA release was observed when the DA agonist, apomorphine (APO), and ascorbate were included in the superfusion buffer. These findings are consistent with DMI treatment giving rise to impaired DA release possibly due to DA autoreceptor-mediated inhibition of DA release and cancellation of this effect by neurotensin.

Animals↗

PubMed1987

Chronic administration of desipramine or nialamide decreases wet-dog shakes in rats produced by the TRH-analog MK-771.

The effect of chronic administration of the tricyclic antidepressant, desipramine, or the monoamine oxidase inhibitor (MAOI), nialamide, on the ability of the TRH analog, MK-771, to induce wet-dog shakes in rats was examined. MK-771 at a dose of 3 mg/kg produced significantly fewer wet-dog shakes in those animals treated repeatedly with either nialamide or DMI in comparison to those animals treated chronically with saline. Acute administration of these antidepressant compounds did not alter the ability of MK-771 to produce wet-dog shakes in rats. The results of these experiments indicate that TRH responsiveness in the CNS is reduced by chronic but not acute antidepressant drug treatment, and suggest that TRH may be involved in antidepressant drug action.

Animals↗

PubMed1992

Effects of repeated administration of desipramine or electroconvulsive shock on norepinephrine uptake sites measured by [3H]nisoxetine autoradiography.

To determine if repeated administration of desipramine (DMI) or electroconvulsive shock (ECS) regulate uptake sites for norepinephrine (NE) in rat brain, the binding of [3H]nisoxetine ([3H]NIS) was measured using quantitative autoradiography. Groups of animals were given DMI intraperitoneally, either a single injection or repeated doses of 10 mg/kg once daily for 21 days and were killed 48 h after the last injection. Another group of rats received ECS daily for 12 days (150 mA, 300 ms, 60 Hz) and was killed 24 h after the last shock. Repeated administration of DMI caused statistically significant decreases (20-40%) in the binding of [3H]NIS in 8 out of 17 brain regions measured; these areas included the hippocampus, thalamus and the amygdala. Acute treatment with DMI had no effect on the binding of [3H]NIS in any of the regions analyzed except the centrolateral nucleus of the amygdala. By contrast, except for the paraventricular nucleus of the thalamus where ECS caused a modest (20%) increase in binding, no other brain region was affected by ECS. Thus it appears that repeated administration of DMI and chronic ECS treatment have different effects on the binding of [3H]NIS to uptake sites for NE in rat brain.

Animals↗

PubMed1993

Long-term fluoxetine, but not desipramine, inhibits the ACTH and oxytocin responses to the 5-HT1A agonist, 8-OH-DPAT, in male rats.

The present studies determined whether serotonin 5-HT1A receptor-mediated function is modified by chronic exposure to antidepressants. Hormone responses to the 5-HT1A agonist, 8-OH-DPAT, were evaluated after long-term exposure to two antidepressants, the 5-HT uptake blocker, fluoxetine, and the norepinephrine uptake blocker, desipramine (DMI). In addition, the density and affinity of 5-HT1A receptors in the hypothalamus and cerebral cortex were measured. Male rats received fluoxetine (10 mg/kg i.p.), DMI (5 mg/kg i.p.) or saline injections once daily for 21 days. 8-OH-DPAT (0-500 micrograms/kg s.c.) was administered 18 h after the final antidepressant injection and 15 min before sacrifice. 8-OH-DPAT significantly increased plasma ACTH, corticosterone, oxytocin and prolactin, but not renin or vasopressin concentrations. Chronic injections of fluoxetine inhibited the ACTH, corticosterone and oxytocin responses to 8-OH-DPAT, suggesting reduced 5-HT1A receptor function. In contrast, chronic DMI did not alter the hormone responses to 8-OH-DPAT. The density and affinity of 5-HT1A receptors in the frontal cortex or hypothalamus were not altered by either fluoxetine or DMI. To verify that the observed effects require prolonged exposure to fluoxetine, rats received a single injection of fluoxetine (10 mg/kg, i.p.), 3 h before 8-OH-DPAT (0-500 micrograms/kg s.c.). Acute fluoxetine did not reduce any of the hormone responses to 8-OH-DPAT. In conclusion, the results suggest that chronic, but not acute, exposure to fluoxetine decreases 5-HT1A receptor function. This effect is not seen in rats chronically exposed to DMI.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Norepinephrine transporter mRNA is elevated in the locus coeruleus following short- and long-term desipramine treatment.

In situ hybridization for the norepinephrine transporter (NET) mRNA was performed in animals receiving short-term (2 days) and long-term (4 weeks) treatment with desipramine (DMI; 10 mg/kg, intraperitoneal). Following short-term and long-term DMI treatment, a significant (P < 0.05) increase in hybridization of 35S-labeled oligonucleotides to NET mRNA in the locus coeruleus was observed compared to that observed in vehicle-treated animals. The mechanism of this increase in transporter mRNA or its involvement in the therapeutic effects of anti-depressants remains to be determined.

Animals↗

PubMed1994

Catecholamine release in the rat hypothalamic paraventricular nucleus in response to haemorrhage, desipramine and potassium.

In vivo microdialysis and HPLC were used to measure catecholamine release in the rat hypothalamic paraventricular nucleus (PVN) during haemorrhage. The effects of noradrenaline uptake blockade with 1 microM desipramine (DMI) and a depolarising concentration of potassium (100 mM) through the probe were also examined. Dialysis probes implanted in the PVN of urethane anesthetised rats were perfused with modified Ringer solution at 1.1 microliter/min. Thirty minute collections were analysed for DOPA, noradrenaline, DOPAC, HVA and 5-HIAA. Basal concentrations, in the absence of DMI, were: DOPA 203.6 +/- 44.0 pg/ml, noradrenaline 128.0 +/- 20.4 pg/ml; DOPAC 5.6 +/- 0.7, HVA 5.1 +/- 2.2 and 5-HIAA 87.2 +/- 17.8 ng/ml. Basal noradrenaline was doubled in the presence of DMI while basal and stimulated DOPA, DOPAC, HVA and 5-HIAA were not affected by DMI. Haemorrhage resulted in a significant noradrenaline release (48% over resting levels) in the presence of DMI (n = 10, P < 0.05); in the absence of DMI, a smaller and non-significant increase (30% over basal levels) was observed. Potassium-induced depolarisation caused a significant two- and four-fold increase in noradrenaline release (P < 0.001), with decreases in the dopamine metabolites DOPAC (31%, 44%) and HVA (35%, 28%), and the serotonin metabolite, 5-HIAA (41%, 33%), in the presence and absence of DMI, respectively. The catecholamine precursor DOPA did not vary throughout either experiment. The results indicate that haemorrhage induces a 48% increase in noradrenaline release in the rat PVN which provides evidence for a role of noradrenergic projections to the PVN in cardiovascular control.

Animals↗

PubMed1995

REM sleep inhibition by desipramine: evidence for an alpha-1 adrenergic mechanism.

The acute administration of drugs that block norepinephrine (NE) reuptake suppresses rapid eye movement (REM) sleep in cats and other mammals. The mechanism is presumed to involve NE acting on cells in a pontine REM sleep-generator region. Postsynaptic noradrenergic receptor mechanisms have not been identified. In the present experiments, we tested the ability of the alpha-1 antagonist prazosin and the beta antagonist propranolol to reverse the REM sleep suppression produced by the NE reuptake blocker desipramine (DMI) in the cat. DMI reduced the number of REM sleep episodes, the REM percentage (REM sleep time/total sleep time), and the average REM sleep episode duration. The co-administration of prazosin, but not propranolol, increased the REM percentage and the average REM sleep episode duration toward the placebo level. The co-administration of the peripherally-acting, anti-hypertensive agent hydralazine did not reverse the DMI-induced REM sleep suppression. While the identity of the brain region(s) involved in mediating the alpha-1 noradrenergic suppression of REM sleep by DMI remains unclear, there is reason to consider forebrain structures including the amygdala as well as the pontine areas that generally have been implicated in REM sleep control.

Adrenergic Uptake Inhibitors↗

PubMed1981

Simultaneous liquid chromatographic analysis of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and nordoxepin.

A simultaneous method for the therapeutic monitoring of amitriptyline, doxepin, imipramine, and their active demethylated metabolites nortriptyline, nordoxepin, and desipramine, respectively, in plasma or serum by reversed-phase liquid chromatography (RPLC) is presented. The drugs and the internal standard (loxapine) are first extracted from 2 ml of serum into butylchloride at pH 14, and then back extracted into 200 microliter of 0.025 mol/l hydrochloric acid. An aliquot of the aqueous acid phase is injected into the chromatograph and eluted with acetonitrile-phosphate buffer (21: 79, by vol.) containing 0.6 nl of n-nonylamine per liter of phosphate buffer. The drugs are eluted in a total chromatographic time of approximately 13 min at ambient temperature and detected at 200 nm. A sensitivity of 5 microgram/l of serum for each drug is obtained. Recoveries for these drugs ranged from 77% to 103%; and the coefficient of variation (day-to-day) ranged from 4.2 to 7.8. Of 35 basic or neutral drugs tested for possible interference, only propoxyphene interferes with the analysis of nortriptyline.

Amitriptyline↗

PubMed1976

Catecholamine release by intracerebral perfusion of 6-hydroxydopamine and desipramine.

The rate of catecholamine release at perfusion sites in the diencephalon of the unanesthetized rat during the perfusion of a solution of 6-hydroxydopamine (6-OHDA) or desipramine (DMI). Endogenous stores of norepinephrine (NE) and dopamine (DA) were first tagged by the cerebral microinjection of 14C- or 3H-labelled NE or DA. After successive control perfusates were collected with a push-pull cannula system, 6-OHDA, in a concentration of 5.0, 0.5, or 0.1 mg/ml, was perfused at 20-23 mul/min through a site in the rat'e brain. The compound induced a dose-related release of both NE and DA. In control experiments, 6-OHDA exerted a non-specific releasing effect on 3H-inulin which was not dose dependent. In addition, DMI, an NE reuptake inhibitor in a concentration of 10.0, 2.0 or 0.5 mg/ml, was perfused through 23 sites in the brain following the injection of labelled NE. DMI enhanced the recovery of NE in the push-pull effluent at the 10.0 mg/ml concentration only. However, an augmented efflux of 3H-inulin was also observed during the perfusion of the highest concentration of DMI. These results support the view that 6-OHDA releases catecholamines from endogenous storage sites, but also indicate a strong non-specific releasing action of this compound possibly at extracellular or non-catecholaminergic loci.

Animals↗

PubMed1977

Effects of phentolamine, phenoxybenzamine and desipramine on clonidine-induced blockade of cardiac acceleration in the dog.

Clonidine reduced cardiac acceleration induced by low frequency electrical stimulation of cardiac sympathetic nerve fibers in anesthetized and vagotomized dogs. This effect of clonidine was abolished by short periods of high frequency electrical stimulation. The inhibitory effect of clonidine was observed with 10- as well as with 90-sec periods of electrical stimulation of sympathetic nerve fibers; it was antagonized by phentolamine, phenoxybenzamine and desipramine. This suggests the presence of alpha-adrenoceptors at the peripheral sympathetic nerve ending in the dog.

Animals↗

PubMed1978

Effects of single and multiple doses of desipramine (DMI) on endogenous levels of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rat brain.

A single administration of desipramine (DMI) (10 mg/kg, i. p.) decreased brain levels and probenecid-induced accumulation rate of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rats. To investigate the mechanism of this action, the interaction of DMI with NA receptor blockers and its effects on electrical stimulation were evaluated. It was found that phenoxybenzamine (20 mg/kg) or chlorpromazine (10 mg/kg) completely prevented the DMI-induced decrease in MOPEG-SO4 brain levels. On the other hand, DMI did not antagonize the increase in MOPEG-SO4 induced in the cortex-hippocampus by stimulation of the locus coeruleus. These observations indicate that the effect of DMI on MOPEG-SO4 is more likely to be due to a reduction of neuronal impulse flow mediated by a negative feed-back mechanism resulting from impairment of reuptake than to a direct effect on NA catabolism. In contrast to the effect of a single dose, the repeated administration of DMI (10 mg/kg, twice a day for 3 days) did not significantly reduce the rate of probenecid-induced accumulation of MOPEG-SO4. This development of tolerance to the metabolite-decreasing effects of DMI indicates that complex adaptive changes occur in the NA system upon repeated DMI administration.

Animals↗

PubMed1978

The in vivo binding of [3H]-desipramine and [3H]-chlorpromazine to areas in the rat brain.

The distribution of [3H]-desipramine (DMI) and of [3H]-chlorpromazine (CPZ) in rat brain was determined by the incorporation of radioactivity into various regions of the brain and by autoradiography of transverse cryostat sections. The label from [3H]-DMI was rapidly distributed in all brain regions, reaching peak levels within 30 min and considerably decreasing 1--4 h after injection. Following the selective destruction of catecholaminergic nerve terminals by intracerebral administration of 6-hydroxydopamine, a marked reduction in the incorporation of DMI, but not of CPZ, was evident in all brain areas investigated. The autoradiographed sections clearly demonstrated a preferential uptake of both drugs by the caudate nucleus. These findings suggest that DMI might be largely bound to presynaptic dopamine and norepinephrine terminals, while the CPZ binding involves postsynaptic sites.

Animals↗

PubMed1979

Electrophysiological effects of desipramine on guinea pig papillary muscles.

The effects of desipramine (DMI) in concentrations between 1 x 10(-7) M and 1 x 10(-4) M on various electrophysiological parameters were evaluated in ventricular papillary muscles of guinea pig. At concentrations less than 5 x 10(-5) M, DMI produced a significant shortening in the action potential duration (APD) measured at both 50% and 100% of repolarization. At 1 x 10(-4) M, the terminal portion of repolarization was so prolonged that the total APD was not significantly different from control values. DMI (greater than 1 X 10(-5) M) did not change the resting potential but significantly, decreased the overshoot potential, the amplitude, and the maximum rate of rise of phase O depolarization (Vmax) and shifted the membrane responsiveness and membrane reactivation curves downward and to the right. The effective refractory period (ERP) was shortened or lengthened, the effect being dependent on the concentration, but always made the ERP long relative to APD. DMI, (1 X 10(-5) M and 5 x 10(-5) M), attenuated and abolished the spontaneous activity and the Ca-mediated action potentials induced in ventricular muscle fibers. The mechanisms responsible for DMI's in vivo arrhythmogenic or antiarrhythmic effects are discussed. In terms of changes in ion conductance most effects can be explained by a reduction in sodium and calcium conductance.

Action Potentials↗