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PubMed1997

Influence of imipramine on the hypothalamic/pituitary/thyroid axis of the rat.

The effects of the tricyclic antidepressant drug imipramine at different levels of the hypothalamic/pituitary/thyroid axis were investigated in the rat. Intraperitoneal (IP) treatment for 14 days with imipramine at 10 mg/kg, but not 2 mg/kg, reduced serum total thyroxine (T4) and triiodothyronine (T3). A similar decrease in serum total T4 was observed in thyroidectomized T4-treated rats, suggesting that imipramine treatment enhances T4 clearance instead of reducing T4 secretion. There were no parallel decreases in serum free T4 and T3 concentrations, due to the simultaneous increase in the free fractions of both T4 and T3 following imipramine treatment. In vitro experiments using equilibrium dialysis indicated that neither imipramine nor its metabolite desipramine directly influenced the binding of T4 or T3 to their transport proteins following addition to normal serum, suggesting an indirect effect of imipramine or desipramine on free hormone concentrations in vivo. Concentrations of T4 and T3 in the brain, liver, and heart were unaffected by imipramine treatment, suggesting that the drug did not affect cellular uptake and metabolism of T4 and T3. Serum concentrations of thyrotropin (TSH) were unaffected by imipramine pretreatment at either dose level, compatible with the fact that serum free T4 and T3 concentrations were not reduced. Moreover, there was no difference in thyrotrope responsiveness to stimulation by TSH-releasing hormone (TRH) and to inhibition by T4 and T3 in rat anterior pituitary cells cultured ex vivo for 18 hours from control and imipramine-treated rats. Furthermore, in vitro exposure of cultured rat anterior pituitary cells to imipramine and desipramine indicated that both agents decreased TSH secretion only at concentrations greater than 10(-6) mol/L. These concentrations of imipramine and desipramine in the culture medium would exceed the free concentrations of these drugs seen in vivo therapeutically. In addition, no direct effects of 10(-6) mol/L imipramine or desipramine on the TSH response to TRH or to T3 were observed in vitro in cultured pituitary cells. A potential indirect effect of imipramine or desipramine on TSH secretion via altered hypothalamic control of thyrotropes does not seem likely, due to the lack of effect of imipramine treatment on serum TSH concentrations in imipramine-treated rats. In conclusion, imipramine treatment reduces serum total T4 and T3 in the rat, with enhanced clearance being the most likely explanation for the effect on T4. There was no evidence for altered tissue T4 or T3 concentrations or for altered thyrotrope function. The enhanced T4 clearance may explain the reduction in total T4 reported for imipramine-treated depressed patients. However, the effects of imipramine treatment on the transport of thyroid hormones in plasma need to be examined in more detail in patients, since interspecies differences in the nature of the transport proteins preclude extrapolation of the present results from the rat.

Animals↗
PubMed2003

Effects of selective serotonin reuptake inhibitors on immobility time in the tail suspension test in streptozotocin-induced diabetic mice.

We examined the effects of fluoxetine and fluvoxamine, selective serotonin reuptake inhibitors (SSRIs), and desipramine, a selective noradrenaline (NA) reuptake inhibitor, given alone or in combination with diazepam on immobility time in the tail suspension test in diabetic mice. Immobility time was significantly longer in diabetic than in nondiabetic mice. Diazepam (0.1 and 0.3 mg/kg s.c.) dose-dependently decreased immobility time in diabetic mice to the level observed in saline-treated nondiabetic mice. However, diazepam had no significant effect on immobility time in nondiabetic mice. Fluoxetine (3-56 mg/kg i.p.) and desipramine (1-30 mg/kg i.p.) produced marked, dose-dependent suppression of immobility time in both nondiabetic and diabetic mice. However, anti-immobility effects of fluoxetine and desipramine in diabetic mice were less than those in nondiabetic mice. Fluvoxamine (3-30 mg/kg i.p.) produced a dose-dependent suppression of immobility time in nondiabetic mice but not in diabetic mice. The anti-immobility effects of fluoxetine, fluvoxamine and desipramine in nondiabetic mice were antagonized by pretreatment with diazepam (0.3 mg/kg s.c.). Furthermore, fluoxetine, fluvoxamine and desipramine had no effect on the immobility time in diazepam (0.3 mg/kg s.c.)-treated diabetic mice. These results indicate that the anti-immobility effects of SSRIs and desipramine are less in diabetic mice than in nondiabetic mice in the tail suspension test. Furthermore, in diabetic mice, SSRIs and selective NA reuptake inhibitors did not affect immobility time even though the prolonged duration of immobility was suppressed by pretreatment with diazepam.

Adrenergic Uptake Inhibitors↗
PubMed2002

In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs.

UNLABELLED: The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and selective noradrenaline (NA) reuptake-inhibitors, which respectively increase swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT-induced swimming prevents dual 5-HT/NA reuptake-inhibition to produce concurrently climbing with swimming. Since adaptative neurochemical processes occur in the treatment of depression, we examined the influence of long-term antidepressant treatment on these interactions. METHODS: (1) Selective [fluoxetine: 10 mg/kg; desipramine: 10 mg/kg] and non-selective [milnacipran: 40 mg/kg; mirtazapine: 20 mg/kg] antidepressants were administered subacutely (3inj) and chronically (17inj) over 16 days. (2) A subacute fluoxetine-desipramine combination (10-10 mg/kg) was administered in rats that were pre-treated with chronic-desipramine (10 mg/kg per day, 14 days). (3) NA-system-mediated interactions were further examined by combining the alpha(2)-receptor agonist clonidine (5, 10, 20, 200 microg/kg) with 10 mg/kg fluoxetine. RESULTS: (1) Long-term treatment with either fluoxetine or desipramine does not modify the behavioural response produced by their subacute administration. (2) In contrast, whereas subacute-milnacipran increases climbing solely, chronic-milnacipran produces greater anti-immobility effects and increases both climbing and swimming behaviours. Similarly, the fluoxetine-desipramine combination produces climbing solely, but increases both climbing and swimming behaviours in animals pre-treated with chronic-desipramine. Chronic but not subacute-mirtazapine increases swimming behaviour. (3) clonidine dose-dependently antagonizes fluoxetine-induced anti-immobility effects and swimming behaviour. CONCLUSIONS: Chronic enhancement of NA-transmission alters NA-system-mediated inhibition of 5-HT-induced behaviour in the FST, which may involve alpha(2)-receptors.

Adrenergic Uptake Inhibitors↗
PubMed1998

Effect of chronic antidepressant treatment on transcription factor binding activity in rat hippocampus and frontal cortex.

1. The effect of chronic antidepressant administration on CRE-, SP1- and GRE-binding activity was studied in rat hippocampus and frontal cortex. 2. Fluoxetine and desipramine (3 and 10 mg/kg/day respectively) were given to rats for 21 consecutive days. The animals were killed 3 hr after the last injection and nuclear extracts were prepared to perform the DNA-protein reaction with consensus CRE, SP1 and GRE oligonucleotides. 3. Gel-shift assays showed that CRE-binding activity was increased in both frontal cortex and hippocampus by chronic fluoxetine treatment. Desipramine, however, only enhanced this activity in the frontal cortex. 4. Chronic fluoxetine decreased SP1-binding activity in the two selected brain regions. Again, desipramine only produced a significant reduction in the frontal cortex. 5. GRE-binding in the hippocampus was only enhanced by desipramine. Since chronic desipramine, and not fluoxetine, is able to increase hippocampal glucocorticoid receptor (GR) expression, interactions of GR with CREB and SP1 may determine the lack of effect of desipramine on binding activity of the two latter transcription factors in this brain region. 6. Overall, the results show a differential and region-specific effect of chronic, and not acute, antidepressant treatment on the DNA-binding activities studied and are consonant with the possible role of changes in gene expression in the mechanism of antidepressant action.

Animals↗
PubMed2001

Idazoxan and 8-OH-DPAT modify the behavioral effects induced by either NA, or 5-HT, or dual NA/5-HT reuptake inhibition in the rat forced swimming test.

The rat forced swimming test (FST) predicts the efficacy of antidepressants, which decrease immobility duration in the test, and can distinguish selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors, which, respectively, increase swimming and climbing behaviors. However, dual 5-HT and NA reuptake-inhibition produces climbing behavior solely, thereby suggesting with other data that the NA-system mediates inhibiting interactions on 5-HT-induced swimming in the FST. Since alpha(2)-adrenoreceptors and 5-HT(1A)-receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the alpha(2)-receptor-antagonist idazoxan and the 5-HT(1A)-receptor-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) would modify the behavioral pattern induced in the FST by either selective or non-selective antidepressant treatments. The rats were treated subacutely (3 injections IP over 48 h) with: (a) idazoxan (0.5-10 mg/kg) alone, and in combination with desipramine (10 mg/kg), or desipramine + fluoxetine (10/10 mg/kg), or the dual serotonin/noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH-DPAT (0.25-1 mg/kg) alone, and in combination with either desipramine (10 mg/kg) or fluoxetine (10 mg/kg). The results indicated: (a) Idazoxan (0.5, 5, 10 mg/kg) produced no anti-immobility effects per se in the FST, antagonized the effects of the NA-reuptake-inhibitor desipramine, and allowed desipramine + fluoxetine, as well as milnacipran, to increase swimming behavior. (b) 8-OH-DPAT produced non-significant effects per se, potentiated desipramine-induced antidepressant-like effects on immobility and climbing, and both antagonized swimming and produced climbing behavior in combination with fluoxetine. Our data support clinical trials suggesting that alpha(2)-receptor-antagonists and 5-HT(1A)-receptor-agonists may be of interest in augmentation strategies for antidepressant treatments. The scoring of active behaviors in the FST appears to be an interesting tool for studying 5-HT/NA interactions induced by antidepressants, as well as for the testing of augmentation strategies.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.

Adult↗
PubMed2002

Alphaxalone, a neurosteroid anesthetic, inhibits norepinephrine transporter function in cultured bovine adrenal medullary cells.

UNLABELLED: We studied the effects of alphaxalone, a neurosteroid anesthetic, on norepinephrine transporter (NET) function in cultured bovine adrenal medullary cells and the effect of a bolus injection of alphaxalone on blood pressure and serum norepinephrine (NE) levels in anesthetized rats. Alphaxalone (10-100 micro M) inhibited the desipramine-sensitive uptake of [(3)H]-NE by bovine adrenal medullary cells in a concentration-dependent manner. Eadie-Hofstee analysis of [(3)H]-NE uptake showed that alphaxalone increased the apparent Michaelis constant without altering the maximal velocity, indicating that inhibition occurred via competition for the NET. Alphaxalone inhibited the specific binding of [(3)H]-desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [(3)H]-desipramine binding revealed that alphaxalone increased the apparent dissociation constant for binding without altering maximal binding, indicating competitive inhibition. Bolus IV administration of alphaxalone had little effect on blood pressure but slightly, and significantly, increased the serum NE levels in anesthetized rats. These findings suggest that alphaxalone competitively inhibits NET function by interfering with both desipramine binding and NE recognition on the NET in adrenal medullary cells and probably in sympathetic neurons. IMPLICATIONS: Alphaxalone inhibited the desipramine-sensitive uptake of [(3)H]-norepinephrine (NE) by interfering with desipramine binding in bovine adrenal medullary cells. A bolus IV administration of alphaxalone slightly and significantly increased the serum NE levels in anesthetized rats. These findings suggest that alphaxalone competitively inhibits NE transporter function probably in sympathetic neurons.

Adrenal Medulla↗
PubMed1994

Sympathomimetic actions of methylenedioxymethamphetamine in rat and rabbit isolated cardiovascular tissues.

The aim of this study was to investigate the actions of methylenedioxymethamphetamine (MDMA) in several isolated cardiovascular tissues. In spontaneously beating rat atria, concentration-dependent positive chronotropic responses to MDMA and amphetamine were blocked by the neuronal-uptake inhibitor desipramine (1 microM) and the beta-adrenoceptor antagonist propranolol (1 microM). In atria incubated with [3H]noradrenaline to label transmitter stores, 10 microM MDMA and 1 microM amphetamine increased the resting outflow of radioactivity, while 1 microM desipramine had no effect on resting outflow. The MDMA- and amphetamine-induced release of radioactivity were blocked by 1 microM desipramine. MDMA, amphetamine and desipramine each enhanced the electrical stimulation-induced (2 Hz, 30-s train) release of radioactivity; the enhancing effects of MDMA and amphetamine were blocked by 1 microM desipramine. In rat isolated perfused hearts, MDMA (1 and 10 microM) increased heart rate by a similar amount to the increase caused by noradrenaline (10 and 50 nM). MDMA also induced dysrhythmias in 7 out of 11 rat isolated perfused heart preparations. In rabbit isolated perfused and superfused ear arteries preloaded with [3H]noradrenaline, MDMA increased the resting release of radioactivity by 230 +/- 18% (n = 6) of control resting release; the increase was accompanied by a rise in perfusion pressure of 17 +/- 7 mmHg (n = 6). MDMA also facilitated the vasoconstrictor responses to noradrenaline (3-9 ng) and perivascular nerve stimulation (1-5 Hz, 10-s train). MDMA-induced vasoconstriction and the facilitation of vasoconstrictor responses to noradrenaline and electrical stimulation were blocked by 1 microM desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1994

Roles of uptake1 and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit.

Anesthetized rabbits were simultaneously infused with [3H]norepinephrine (NE), [3H]epinephrine (Epi), [3H]dopamine (DA), and [3H]isoproterenol (Iso), and their plasma clearances and fractional extractions across the systemic (ERS), as well as pulmonary (ERP), circulation were determined before and after blockade of uptake1 by desipramine (2 mg/kg). Desipramine reduced the clearance of NE, Epi, and DA by 39, 13, and 14%, respectively, but did not affect Iso clearance. Similar results were obtained with respect to the effects of desipramine on ERS. By contrast, desipramine reduced ERP of NE and DA (which for both amines was markedly lower than ERS) by > 70%; its effect on the very low ERP of Epi was not determinable. Comparison of the desipramine-sensitive components of ERS and ERP indicated that for uptake1 NE was the preferred substrate in the systemic circulation and DA was preferred in the pulmonary circulation. In the absence and presence of desipramine, catechol-O-methyltransferase inhibition had no effect on the clearance of NE, Epi, and DA and decreased Iso clearance by 25%. Hence the contribution by uptake1 to the removal of circulating catecholamines depends on the type of amine and on whether the systemic or pulmonary circulation is considered. Moreover catechol-O-methyltransferase does not appear to contribute to the clearance of NE, Epi, and DA but plays a definite role in the removal of circulating Iso.

Animals↗
PubMed1999

Acute and chronic citalopram treatment differently modulates rat exploratory behavior in the exploration box test: no evidence for increased anxiety or changes in the [3H]raclopride binding.

The effect of acute and chronic desipramine (10 mg/kg) and citalopram (10 mg/kg) treatment on rat exploratory behavior in the recently developed exploration box test was studied on 5 consecutive days. Acute desipramine but not citalopram treatment decreased the time spent exploring, the number of line crossings, rears, investigative approaches, entries into the large arena, and sum of exploratory events. After 3 weeks of pretreatment, both desipramine and citalopram attenuated rat exploratory behavior, whereas the number of entries into the large arena was unchanged. In the open field test, acute desipramine or citalopram treatment (5, 10, 15 mg/kg) attenuated rat exploratory behavior in a dose-dependent manner. In the subsequent rota-rod test, neither desipramine nor citalopram treatment (0-20 mg/kg) impaired motor performance capacity. In an additional experiment, [3H]raclopride binding was unchanged after single as well as 3 weeks of desipramine or citalopram treatment in the rat brain neostriatum. Our experiments demonstrate that acute citalopram treatment in the open field test and chronic citalopram treatment in the exploration box test attenuate rat exploratory behavior, but these effects may not be implicated with enhanced anxiety or changed dopamine D2 receptor characteristics.

Adrenergic Uptake Inhibitors↗
PubMed1993

Studies on cytochrome P450 responsible for oxidative metabolism of imipramine in human liver microsomes.

The activity of imipramine 2-hydroxylase highly correlated with that of desipramine 2-hydroxylase but not with that of desipramine N-demethylase. The correlation was also found between N-demethylation and 2-hydroxylation when imipramine was used as a substrate, whereas no correlation was observed between them when desipramine was used in place of imipramine. Both activities of desipramine and imipramine 2-hydroxylase were markedly inhibited by quinidine but not by quinine. Although the activity of imipramine N-demethylase was slightly inhibited by both quinidine and quinine, the activity of desipramine N-demethylase was unaffected under the same conditions. The activity of imipramine N-demethylase was roughly correlated with the amounts of P450 3A4 immunochemically determined and the activities of testosterone 6 beta-hydroxylase in human liver microsomes. The P450 3A4 catalyzed imipramine N-demethylation much more efficiently than 2-hydroxylation in a reconstituted system, whereas neither N-demethylation nor 2-hydroxylation of desipramine was catalyzed by P450 3A4. The activity of imipramine N-demethylase was inhibited, to various extents, by anti-P450 3A4 antibodies in human liver microsomes. Taking together these and other results, it is suggested that P450 3A4, other than P450 2Cmp, also partly contributes to N-demethylation of imipramine, depending on human liver microsomes.

Cytochrome P-450 Enzyme Inhibitors↗
PubMedDate not supplied

Possible relationship of the locus coeruleus--hippocampal noradrenergic neurons to depression and mode of action of antidepressant drugs.

Recent studies performed in our laboratory suggest involvement of locus coeruleus (LC) and hippocampal noradrenergic (NE) neurons in the mechanism of depression and mode of action of antidepressants. Both electrolytic and 6-OHDA lesions to the LC abolished desipramine action in forced swim test in rats. The action of desipramine was also reduced in rats pretreated with alpha 1 adrenolytic drugs -- phenoxybenzamine and prazosin. Electrical stimulation of the LC produced, like desipramine, activating effect in forced swim test, the phenomenon never observed in phenoxybenzamine-pretreated animals. Chronic (but not acute) administration of desipramine potentiated activatory effects of intrahippocampal injections of NE and phenylephrine but not isoprenaline in both open field and forced swim test. Depressant effect of intrahippocampal clonidine was reversed by chronic desipramine (in the open field test). The effect of desipramine was partially shared by citalopram.

Animals↗
PubMed1988

Parallel pathway interactions in imipramine metabolism in rats.

The in vitro metabolic inhibitions between imipramine and its metabolites were investigated in rat liver microsomes. A type of precursor-metabolite interaction similar to that shown with lidocaine was observed in imipramine metabolism. Desipramine competitively inhibited the formation of 2-hydroxyimipramine from imipramine. Similarly, imipramine inhibited the formation of 2-hydroxydesipramine from desipramine. As in the cases of those 2-hydroxylations, a competitive inhibitory relationship also existed in the N-demethylation pathways of imipramine and 2-hydroxyimipramine. Studies on age-associated alterations of the metabolic rates of imipramine and its metabolites in rats demonstrated that N-demethylation activities of imipramine and of 2-hydroxyimipramine, which showed a large sex difference (male greater than female) in young rats, decreased markedly only in old male rats, while 2-hydroxylation activities of imipramine and desipramine, with no sex difference at any age, did not show a marked alteration in either sex. These data strongly suggest that the hydroxylation pathways of imipramine and desipramine and the demethylation pathways of imipramine and 2-hydroxyimipramine are each sharing the same species of cytochrome P-450. The in vivo metabolic inhibition between imipramine and desipramine was examined by simultaneous intraportal infusion of imipramine (25 nmol/min) and desipramine (175 nmol/min). The steady-state concentration of imipramine after simultaneous infusion was increased twofold over that after infusion of imipramine alone, without any change in the free fraction in blood.

Aging↗
PubMed2001

Antinociceptive efficacy of antidepressants: assessment of five antidepressants and four monoamine receptors in rats.

PURPOSE: For assessment of the antinociceptive potency of antidepressants, we compared the antinociceptive effects of serotonin selective reuptake inhibitors (SSRIs) and classical tricyclic antidepressants (TCAs) in rats. We also attempted to elucidate the monoamine receptor subtypes predominantly involved in the antinociceptive effect of antidepressants. METHODS: Male Wistar rats received SSRIs (sertraline, fluvoxamine, and citalopram) or TCAs (imipramine and desipramine) intraperitoneally, and the reaction time until pain response in the hot plate test and licking time in the formalin test were measured 60 min later. We also observed the effects of prazosin (an alpha(1) antagonist), WB-4101 (a selective alpha(1A) antagonist), yohimbine (an alpha(2) antagonist), WAY-100635 (a selective 5-HT(1A) antagonist), and ketanserin (a 5-HT(2) antagonist), which were simultaneously administered with imipramine or desipramine, on the antidepressant-induced antinociceptive effect in the formalin test. RESULTS: In the hot plate test, desipramine, 20 mg.kg(-1), but not imipramine or sertraline, produced a significant increase in reaction time. In the formalin test, desipramine and imipramine produced significant reductions in the licking time at over 5 mg.kg(-1) and at over 10 mg.kg(-1), respectively. These reductions were nearly complete at 20 mg.kg(-1). On the other hand, both SSRIs induced significant reductions in the licking time only at 20 mg.kg(-1). Prazosin, WB-4101, and ketanserin significantly antagonized the antinociceptive effect of 10 mg.kg(-1) of imipramine. However, imipramine-induced antinociception was not affected by yohimbine and WAY-100635. Prazosin and ketanserin also significantly suppressed antinociception by 5 mg.kg(-1) of desipramine. CONCLUSION: These findings suggest that classical TCAs are likely to have a therapeutic advantage over SSRIs for pain control. In addition, it is likely that central alpha(1) adrenoceptors and 5-HT(2) receptors are predominantly involved in imipramine- and desipramine-induced antinociception.

Journal Article↗
PubMed1995

Inhibitory effects of antidepressants on NMDA-induced currents in Xenopus oocytes injected with rat brain RNA.

Although it has been reported that desipramine affects ion-channel activity of NMDA receptor/ion-channel complexes, the binding sites remain unclear. To identify the binding site, influences of desipramine on NMDA-induced current were examined in Xenopus oocytes injected with rat brain RNA and compared with those of blockers, MK-801, Zn2+ and Mg2+. Application of 100 microM desipramine irreversibly inhibited NMDA-induced inward current as well as 1 microM MK-801. Mg2+ and Zn2+ showed a reversible inhibition. Pretreatment with Mg2+ or Zn2+ abolished the irreversible inhibition of desipramine. In contrast, the irreversible inhibition of desipramine was still observed after application of Mg2+ and Zn2+. These results suggest that Mg2+/Zn2+ and desipramine bind on different sites from each other and affect the cation permeability via different mechanisms. Regarding inhibitory effects of other antidepressant drugs, imipramine and setiptiline were found to markedly inhibit NMDA current, while maprotiline, amitriptyline and lofepramine slightly inhibited the current. Mianserin, a potent antagonist of 5-HT1c receptors, however, had no influence.

Animals↗
PubMed2004

Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

Animals↗
PubMed1977

Effect of lofepramine and other antidepressants on the uptake of 5-hydroxytryptamine and noradrenaline into rat brain monoaminergic neurons.

Lofepramine, (N-methyl-N-[4-chlorobenzoylmethyl]-3-[10,11-dihydro-5H-dibenz(b,f)-azepin-5-yl]-propylamine hydrochloride), is a new antidepressant with low toxicity and no peripheral anticholinergic activity. Its effect on 5-hydroxytryptamine (5-HT) and noradrenaline uptake into rat brain monoaminergic neurons was studied and compared with that of other antidepressants, particularly with that of imipramine and desipramine. Lofepramine inhibited both 5-HT and noradrenaline uptake into synaptosomal fractions in vitro but was 4 times more potent in inhibiting noradrenaline than 5-HT uptake, indicating the effect resembles that of desipramine. Noradrenaline uptake was also preferentially inhibited in synaptosomes from brain of rats treated previously with lofepramine or desipramine (i.p.). Pretreatment with SKF 525A (i.p.) did not diminish the effect of lofepramine, but rather potentiated it. Therefore it is suggested that the formation of desipramine is not necessary for lofepramine to exhibit, the effect on amine uptake in vivo. Both lofepramine and desipramine inhibited intraventricular noradrenaline uptake into synaptosomes without any effect on 5-HT uptake. These results suggest that lofepramine is qualitatively similar to desipramine with respect to preferential inhibition of noradrenaline uptake into central noradrenergic neurons.

Animals↗
PubMed1999

Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial.

BACKGROUND: Studies show that selective serotonin reuptake inhibitors are effective for severe premenstrual syndrome and premenstrual dysphoric disorder. This study compares the efficacy of a selective serotonin reuptake inhibitor with that of a tricyclic antidepressant to determine whether efficacy for premenstrual syndrome/premenstrual dysphoric disorder is a general or more serotonergic effect of antidepressants. METHODS: After 3 screening months, 189 subjects were randomized to sertraline hydrochloride, desipramine hydrochloride, or placebo for 3 months of double-blind treatment. The flexible dosage range was 50 to 150 mg/d. The outcome measures included the Penn Daily Symptom Report (DSR), the Hamilton Depression Rating Scale, the Clinical Global Impressions-Severity Scale, the Quality of Life Scale, and Patient Global Ratings of Functioning and Improvement. Analyses included all subjects with treatment data, with the last observation carried forward. RESULTS: Sertraline was significantly more effective than placebo or desipramine; desipramine was not better than placebo (F2,163 = 12.47, P<.001). All DSR factors were more improved with sertraline compared with desipramine and placebo; the factors for mood (P<.001) and pain (P = .05) were significant, and the results of all outcome measures were consistent. A history of depression, postmenstrual symptom levels, and other diagnostic variables added individually as covariates did not alter the treatment results. At end point analysis, DSR symptoms had decreased by more than 50% in 40 subjects (65%) in the sertraline group, 18 subjects (36%) in the desipramine group, and 16 subjects (29%) in the placebo group (P<.001). CONCLUSIONS: The comparison of 2 classes of antidepressants strongly favored the serotonergic drug, which effectively reduced symptoms and improved functioning and was well tolerated by women with severe premenstrual syndrome. A history of depression did not alter the treatment results.

Antidepressive Agents, Second-Generation↗