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PubMed1976

Plasma levels and antidepressive effect of imipramine.

The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin-layer chromatography. Individual variations in plasma concentration were 20- to 30-fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (HRS post-treatment score less than 8) had plasma concentration of imipramine greater than or equal to 45 mug/L, and desipramine greater than 75 mug/L, whereas the 12 patients not responding satisfactorily (post-treatment score on HRS greater than or equal to 8) all had concentrations of imipramine or desipramine or both below these limits.

Adult↗
PubMed1989

The uptake and metabolism of 3H-catecholamines in rat cerebral cortex slices.

The accumulation and metabolism of 3H-catecholamines were studied in cerebral cortex slices obtained from rats pretreated with reserpine, during 30 min of incubation with 50 nmol/l of the 3H-amines. In some experiments neuronal uptake (uptake1) was inhibited by the presence of 0.3 mumol/l desipramine, in others COMT was inhibited by 30 mumol/l U-0521. When both MAO and COMT were intact, most of the metabolism of 3H-noradrenaline was neuronal (i.e., desipramine-sensitive). For 3H-adrenaline rates of neuronal metabolism were much lower than for 3H-noradrenaline, non-neuronal O-methylation accounting for about 50% of total metabolism. Rates of metabolism of 3H-dopamine were similar to those of 3H-noradrenaline, but with a predominance of non-neuronal metabolism, which involved O-methylation and deamination. - Under these conditions, very little 3H-catecholamine was recovered from the tissues; moreover, desipramine tended to increase tissue levels. Hence, tissue content then appears to partly reflect extracellularly distributed 3H-amines. After block of MAO rates of metabolism of 3H-noradrenaline and 3H-dopamine were greatly reduced, and tissue levels were increased. Desipramine now antagonized the accumulation of 3H-amines in the tissue, while U-0521 increased it. Rates of O-methylation (in the presence of desipramine) increased in the order 3H-noradrenaline less than 3H-dopamine. It is concluded that neuronal uptake is associated with MAO only, and rates of neuronal deamination increased in the order: 3H-adrenaline less than 3H-dopamine much less than 3H-noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Conclusive evidence for distinct transporters for 5-hydroxytryptamine and noradrenaline in pulmonary endothelial cells of the rat.

The aims of this study were to obtain conclusive evidence about the roles of a 5-hydroxytryptamine [5-HT] transporter and uptake1 in the dissipation of 5-HT in the lungs of the rat and to compare the properties of the 5-HT transporter in rat lungs with that in other tissues, including brain and platelets. In the first part of the study, the IC50 values of a range of selective inhibitors and substrates of the 5-HT transporter or uptake1 were determined for inhibition of uptake of 5-HT or noradrenaline in intact perfused lungs of rats. Monoamine oxidase was inhibited and, in experiments with noradrenaline, catechol-O-methyltransferase was also inhibited. Initial rates of uptake of 5-HT or noradrenaline were measured in lungs perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min, in the absence or presence of at least three concentrations of paroxetine, citalopram, fluoxetine, 7-methyltryptamine, tryptamine, nisoxetine, imipramine, 5-HT, desipramine, (+)-oxaprotiline, cocaine or tyramine. The results showed that pharmacologically distinct transporters are involved in the uptake of 5-HT and noradrenaline in rat lungs, since there was no significant correlation between the IC50 values for inhibition of 5-HT and noradrenaline uptake in the lungs. However, there were significant correlations between the IC50 values for (a) inhibition of 5-HT uptake in rat lungs and of uptake by the 5-HT transporter in rat brain and (b) inhibition of noradrenaline uptake in rat lungs and of uptake1 in rat phaeochromocytoma PC-12 cells. The results support the conclusion that 5-HT uptake in rat lungs occurs, at least predominantly, by a 5-HT transporter which is very similar to or the same as that in other tissues, such as the brain, and provide further evidence for transport of noradrenaline by uptake1. Further experiments were carried out to determine whether there is any transport of 5-HT by uptake1 or of noradrenaline by the 5-HT transporter in rat lungs. Lungs were perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min in the absence or presence of 1 mumol/l citalopram, desipramine, or citalopram and desipramine. The results showed that there was no evidence of any transport of 5-HT in the lungs by uptake1 or of noradrenaline by the 5-HT transporter, in that desipramine had no effect on 5-HT uptake (in the absence or presence of citalopram) and citalopram had no effect on noradrenaline uptake (in the absence or presence of desipramine). The final series of experiments was carried out to determine whether, at high concentrations of the amine, there is any interaction of 5-HT with uptake1 or of noradrenaline with the 5-HT transporter. Noradrenaline, at a concentration of 10 mumol/l, did not affect 5-HT uptake in lungs perfused with 2 nmol/l 3H-5-HT for 2 min (uptake1 inhibited), but 50 mumol/l 5-HT inhibited noradrenaline uptake by 56% in lungs perfused with 2 nmol/l 3H-noradrenaline for 2 min (5-HT transporter inhibited). These and the above results show that the 5-HT transporter appears to be exclusively responsible for 5-HT uptake in rat lungs, despite the possible interaction of 5-HT at high concentrations with the uptake1 transporter in the cells. On the other hand, noradrenaline is transported exclusively by uptake1 in the lungs, and there is no evidence that it interacts with the 5-HT transporter, even at high concentrations.

Adrenergic Uptake Inhibitors↗
PubMed1988

Plasma concentrations of noradrenaline and 3,4-dihydroxyphenylethyleneglycol under conditions of enhanced sympathetic activity.

Antecubital venous blood was sampled at rest and during orthostasis or supine bicycle exercise. The plasma was analyzed for noradrenaline and 3,4-dihydroxyphenylethyleneglycol (DOPEG) by HPLC. Orthostasis resulted in increases in plasma concentrations of both noradrenaline and DOPEG. The magnitude of changes in both was dependent on the degree of orthostasis. In conditions of supine rest, sitting, and standing the plot of the geometric mean values of plasma DOPEG (ordinate) against those of plasma noradrenaline was linear, had a slope of about unity, and intersected the ordinate at a finite value of plasma DOPEG. After administration of desipramine (to block uptake), plasma concentrations of DOPEG fell both at rest and during orthostasis. Moreover, desipramine abolished the plasma DOPEG response to orthostasis without affecting the plasma noradrenaline response. Hence, changes in plasma DOPEG brought about by changes in sympathetic tone are presynaptic in origin. The plasma concentration of DOPEG observed in the presence of desipramine was virtually identical with the ordinate intercept of the regression line relating plasma DOPEG to plasma noradrenaline in the absence of desipramine. This pool of plasma DOPEG (which amounted to about 75% of that observed at supine rest in the absence of desipramine) probably stems from intraneuronal noradrenaline leaking out of the storage vesicles of peripheral sympathetic neurones and may in part also be derived from the central nervous system. Supine bicycle exercise failed to increase plasma DOPEG. This may be due to the separation of the sampling site from the site of noradrenaline release (i.e. the exercising limbs) by organs involved in DOPEG extraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Cholinergic drug effects on antidepressant-induced behaviour in the forced swimming test.

The contribution of anticholinergic effects to the action of desipramine and nomifensine was investigated in the forced swimming test in rats. The immobility time was reduced by high doses of atropine (10-25 mg/kg i.p.) and scopolamine (1.5 mg/kg i.p., 1 and 0.5 h before the test, respectively) and was unaffected by physostigmine (0.25-0.5 mg/kg i.p., 1 h before the test). Unlike atropine (25 mg/kg), scopolamine (1.5 mg/kg) increased motor activity (open-field). The anti-immobility effect of i.p. desipramine (20 or 30 mg/kg) and nomifensine (2.5 or 5 mg/kg), administered 24, 5 and 1 h before the test, was potentiated by scopolamine (0.5-1.0 mg/kg) and antagonized by physostigmine (0.25-0.5 mg/kg). The brain levels of desipramine and nomifensine were unaffected by scopolamine or physostigmine. Motor performance was impaired in rats treated with physostigmine and desipramine whereas hypermotility was observed in rats treated with scopolamine and nomifensine. The anti-immobility effect of atropine (25 mg/kg) and scopolamine (1.5 mg/kg) was not antagonized by physostigmine (0.5 mg/kg). These results indicate that anticholinergic mechanisms alone are not sufficient to influence immobility time and suggest that the cholinergic system may control, the neural circuitry upon which desipramine and nomifensine act to reduce immobility time.

Animals↗
PubMed1994

Effect of long-term administration of antidepressant drugs on the 5-HT3 receptors that enhance the electrically evoked release of [3H]noradrenaline in the rat hippocampus.

The present study investigated the effects of various classes of antidepressant drugs (10 mg/kg per day, s.c. during 21 days) on the electrically evoked release of [3H]noradrenaline and on its modulation by the 5-HT3 receptor agonist 2-methyl-5-hydroxy-tryptamine (2-methyl-5-HT) using preloaded rat hippocampal slices. Treatments with either fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, or moclobemide, a reversible type A monoamine oxidase inhibitor, increased the evoked release of [3H]noradrenaline. These two antidepressant treatments did not change, however, the magnitude of the enhancing effect of 2-methyl-5-HT on the electrically evoked release of [3H]noradrenaline. Desipramine produced a much larger increase of the electrically evoked release of [3H]noradrenaline than fluoxetine or moclobemide, and desensitized the 5-HT3 receptors that modulate this release. Trimipramine, which like desipramine has a tricyclic structure but does not block the reuptake of noradrenaline or that of 5-HT, did not increase the evoked release of [3H]noradrenaline and did not desensitize the 5-HT3 receptors that enhance the release of [3H]noradrenaline. Maprotiline, a selective noradrenaline reuptake inhibitor, did not produce the same changes as desipramine, but maprotiline inhibited noradrenaline reuptake to a lesser extent (50%) than desipramine (80%). These results suggest that the high potency noradrenaline reuptake blocker desipramine desensitizes 5-HT3 receptors modulating [3H]noradrenaline release, but that this effect is not common to all antidepressant drugs.

Animals↗
PubMed1990

Effects of social isolation on brain catecholamines and forced swimming in rats: prevention by antidepressant treatment.

Post-weaning rats were housed alone or in groups for a period of 4 or 8 weeks. A portion of the animals received tricyclic antidepressant treatment, desipramine 20 mg/kg/day, during this period. Animals were then tested behaviorally by forced swimming. Isolation was associated with significantly longer durations of immobility during forced swimming. This was blocked by desipramine treatment. Desipramine treatment did not have a significant effect on the swimming durations of group-housed rats. Hindbrain and midbrain levels of catecholamines were subsequently measured and turnover rates estimated by administration of alpha-methyl-p-tyrosine or saline. Isolated rats had increased levels and decreased turnover of catecholamines. The increase in norepinephrine but not dopamine levels was blocked by desipramine, while antidepressant effects on turnover could not be tested with this method. Reduced social stimulation thus appears to be associated with reduced catecholamine release which may result in the accumulation of these transmitters in the central nervous system. Treatment with desipramine appeared essentially to compensate for reduced social stimulation, blocking isolation-induced noradrenergic neurochemical changes, while having few significant effects on control animals. This study may be helpful in furthering our understanding of how the interaction of organisms with their environment influence catecholamine systems and how antidepressants may act to restore function.

Animals↗
PubMed1985

Monovalent cation dependency for the inhibition of outward transport of [3H]norepinephrine.

Rat hearts were labelled with [3H]norepinephrine in vivo. Slices of ventricles were prepared, preincubated in Krebs-HCO3 medium (KRB), and then incubated in a Na+-deficient, choline+-Krebs HCO3 (Ch+-Ca2+). The choline+-Krebs HCO3 medium induced a delayed neurosecretion which could be inhibited by either one of the blockers of the uptake of NE, cocaine or desipramine, when included in both the Krebs and the Ch+-Ca2+. When either desipramine or cocaine was present in the Na+-rich preincubation medium only, the duration of action of desipramine was more prolonged than that of cocaine. When desipramine was first added to the Ch+-Ca2+ medium at various times after incubation, the inhibitory response became smaller as the duration of preliminary Na+-deprivation was increased. After incubation for 80 min neither desipramine nor cocaine inhibited secretion. Sodium (added to Ch+-Ca2+ medium or in a Krebs replacement medium) then slowed the rate of release stimulated by Ch+-Ca2+ and facilitated an inhibitory action for both inhibitors. The inhibition did not require the continued presence of Na+. Depolarizing concentrations of K+ in the Ch+-Ca2+ medium with Na+ and either one of the inhibitors, prevented the inhibition of neurosecretion. However, K+ which was added to the preincubation medium with either inhibitor did not prevent the prolonged inhibition of neurosecretion. By contrast with the secretory response to Ch+-Ca2+, the secretory response to K+ in Na+-enriched Ch+-Ca2+ medium was weakly inhibited by the inhibitors of transport.

Animals↗
PubMed1988

Effects of antidepressants on entrainment of circadian rhythms.

1. Anti-depressant drugs alter the period of circadian rhythms under free running conditions. We have examined whether treatment with anti-depressants alters such rhythms under conditions of entrainment to a lighting cycle or following a phase advance of the lighting. 2. In the first experiment, following entrainment to a 10L:14D lighting schedule, male Long Evans rats were injected daily for three weeks, with either saline, desipramine or clomipramine at a dose of 10 mg/kg. Under these conditions, the resting circadian patterns of serum corticosterone and melatonin were not affected. 3. In a second experiment, male Wistar rats, adapted to a 12L:12D lighting cycle, were implanted with transmitters, permitting continuous recording of temperature. Animals were given chow supplemented with clomipramine or desipramine so that plasma clomipramine levels were within the normal therapeutic range for humans and desipramine levels were at 4-6 times the therapeutic range. After three weeks of drug treatment, the mean 24 h pattern of temperature was decreased and phase advanced by 72 min in the desipramine group compared to clomipramine or controls. Following a 6 h phase advance in the lighting cycle, the three groups responded differently. The clomipramine group evidenced the most rapid advance in the acrophase, equivalent to 6.9 h, while the saline and desipramine treated groups re-entrained significantly more slowly. 4. Clomipramine, given to achieve clinically meaningful blood levels, does not alter the circadian temperature rhythm under constant conditions of alternating light and dark, but significantly accelerates the rate of re-entrainment to a 6 h phase advance of the lighting schedule.

Animals↗
PubMed1994

NMDA-GABA interactions in an animal model of behaviour: a gating mechanism from motivation toward psychotic-like symptoms.

We studied the effects of desipramine, alprazolam, muscimol and dizocilpine (MK-801) (alone or associated with desipramine) in the forced swimming test in rats after long-lasting termination of chronic exposure to vehicle and pentylenetetrazol. Sensitisation with pentylenetetrazol was ineffective in changing immobility time in the forced swimming test compared to vehicle treatment; pentylenetetrazol enhanced the anti-immobility effect of desipramine, abolished the anti-immobility effect of alprazolam and did not affect the anti-immobility effect of muscimol. MK-801 at the dose that did not modify immobility time in vehicle-treated rats and in pentylenetetrazol-treated animals strongly potentiated the anti-immobility effect of desipramine in pentylenetetrazol-treated rats. MK-801 in association with desipramine induced a marked hyperlocomotion and hyperexcitability, with swaying movements and oral stereotypies in pentylenetetrazol-sensitised rats. Results are considered the experimental representation of a 'gating mechanism' toward psychotic-like symptoms.

Alprazolam↗
PubMed2005

Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers.

OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study. METHODS: This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir. RESULTS: Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer. CONCLUSIONS: Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.

Adolescent↗
PubMed2004

Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test.

In the present study, we examined effects of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor citalopram, the 5-HT/noradrenaline reuptake inhibitor imipramine, the selective noradrenaline reuptake inhibitor desipramine or the monoamine oxidase-A inhibitor moclobemide, administered in combination with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635) or the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)1,1'-biphenyl-4-carboxamide (GR 127935) and the 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641) in the forced swimming test in rats. When given alone, citalopram (20 and 30 mg/kg), imipramine (20 mg/kg), desipramine (20 mg/kg), moclobemide (20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) did not shorten the immobility time of rats. Co-administration of WAY 100635 (0.1 and 1 mg/kg) and citalopram (20 mg/kg), or imipramine (20 mg/kg), or moclobemide (20 mg/kg) did not affect the immobility time of rats, whereas WAY 100635 given jointly with desipramine (20 mg/kg) induced a weak anti-immobility effect. GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) co-administered with imipramine, desipramine or moclobemide, but not citalopram, produced a significant anti-immobility action in the forced swimming test in rats. These results indicate that the blockade of 5-HT(1B) rather than 5-HT(1A) receptors may facilitate the anti-immobility effect of imipramine, desipramine or moclobemide in the forced swimming test. No interaction was observed between 5-HT(1A) or 5-HT(1B/1D) receptor antagonists and citalopram.

Adrenergic Uptake Inhibitors↗
PubMed2005

A comparison of neurokinin 1 receptor knock-out (NK1-/-) and wildtype mice: exploratory behaviour and extracellular noradrenaline concentration in the cerebral cortex of anaesthetised subjects.

In behavioural screens, mice lacking functional NK1 receptors (NK1-/-) resemble wildtypes (NK1+/+) that have been given an antianxiety/antidepressant drug. Most, if not all, antidepressants increase noradrenergic transmission in the brain. Here, we have used in vivo microdialysis to compare the concentrations of extracellular noradrenaline ('efflux') in the cerebral cortex of anaesthetised NK1-/- and NK1+/+ mice. The effects of systemic administration of the antidepressant, desipramine, with and without local infusion of the alpha(2)-adrenoceptor antagonist, RX821002, were also evaluated. Finally, we compared the effects of desipramine on behaviour of NK1+/+ and NK1-/- mice in an activity chamber and in a light/dark exploration box. Basal noradrenaline efflux was increased 2 to 4-fold in NK1-/- mice compared with NK1+/+ mice but there was no difference in the effects of desipramine. RX821002 increased noradrenaline efflux in all vehicle-injected mice but, in desipramine-pretreated mice, noradrenaline efflux was increased in NK1+/+ mice, only. All behaviours in the light/dark exploration box differed in the two genotypes. Furthermore, with the exception of 'grooming', the effects of desipramine on behaviour of NK1-/- mice could be explained by the effects of this antidepressant on locomotor activity. Finally, alpha(2)-adrenoceptors are possibly desensitised in NK1-/- mice. We have yet to establish whether this is a cause or a consequence of the increased noradrenaline efflux.

Adrenergic alpha-Antagonists↗
PubMed1986

Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype.

Eighteen healthy volunteers, selected according to their ability to oxidize sparteine, took single oral doses of 100 mg imipramine and desipramine. For imipramine the following clearances (L X min-1) were found in six rapid extensive metabolizers (EM), six slow EM, and six poor metabolizers (PM), respectively (mean and range): apparent oral clearance: 2.55 (1.39 to 3.47), 2.28 (1.18 to 4.26), and 1.35 (0.96 to 1.64). Clearance via demethylation was: 1.42 (0.61 to 2.01), 1.60 (0.78 to 3.81), and 1.09 (0.76 to 1.64); clearance via other pathways was: 1.13 (0.74 to 1.75), 0.69 (0.40 to 1.59), and 0.26 (0 to 0.46). For desipramine the apparent oral clearance (L X min-1) was 0.19 (0.12 to 0.24) in PM compared with 1.64 (1.46 to 1.80) and 1.03 (0.77 to 1.13) in rapid EM and slow EM. Extremely long elimination t1/2s of desipramine were seen in PM: 81 to 131 hours compared with 13 to 23 hours in EM. 2-OH-imipramine and 2-OH-desipramine were detectable in plasma of only the 12 EM, where the ratio-to-parent compound was higher in rapid EM than in slow EM. This study confirms that 2-hydroxylation of imipramine and desipramine depends almost exclusively on the sparteine oxygenase, whereas the demethylation of imipramine depends mainly on a different isozyme.

Adult↗
PubMed1999

Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones.

Since the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) in the hippocampus have been implicated in cortisol feedback of the hypothalamus-pituitary-adrenal (HPA) axis, abnormalities in those receptors might underlie the hyperactivity of the HPA axis described in patients with major depression. Animal studies have shown that long-term in-vivo treatment with antidepressants up-regulates hippocampal GR and/or MR, but it is not clear whether this up-regulation is evoked through a direct action of antidepressants on these receptors. We therefore examined the direct effects of long-term antidepressant treatment on GR binding and the levels of GR messenger RNA (mRNA) in primary cultures of rat hippocampal neurones. The time course of the effects of the tricyclic antidepressants desipramine and amitriptyline on GR binding, as assessed by [3H]dexamethasone binding using RU 28362, a specific agonist for GR, showed a biphasic mode of stimulation: desipramine significantly increased the GR binding with 2-day exposure by 36% over that in controls and by 99% and 60% with 10- and 14-day exposures, respectively. Amitriptyline also led to a significant increase in GR binding, with peaks at 2 (by 60%) and 14 days of exposure (by 60%). The effects of 14-day treatment with desipramine required at least the first 4-day exposure, and the first 10-day exposure was required for the full effect. Northern blot analysis demonstrated that the GR mRNA level was significantly increased by 14-day treatment with desipramine (+142% over control), amitriptyline (+108%), mianserin (+124%), paroxetine (+42%) and sulpiride (+92%), but not with haloperidol. Immunocytochemistry for GR revealed that 2- or 14-day treatment with desipramine significantly increased the number of GR-positive cells with dominant immunoreactivity in the nuclei of granule cell-like neurones or in perikarya of pyramidal cell- and granule cell-like neurones. These findings suggest that tricyclic antidepressants directly increase hippocampal GR by short-term (2-day) and long-term (14-day) exposure, and that the increase by long-term exposure is evoked commonly with different classes of antidepressants through transcriptional up-regulation of GR expression.

Amitriptyline↗
PubMed1995

Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex.

Noradrenergic and dopaminergic projections converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region. We have examined the influence of drugs known to alter extracellular NE on extracellular NE and DA in medial prefrontal cortex using in vivo microdialysis. Local application of the NE uptake inhibitor desipramine (1.0 microM) delivered through a microdialysis probe increased extracellular DA (+149%) as well as NE (+201%) in medial prefrontal cortex. Furthermore, desipramine potentiated the tail shock-induced increase in both extracellular DA (stress alone, +64%; stress + desipramine, +584%) and NE (stress alone, +55%; stress + desipramine, +443%). In contrast, local application of desipramine did not affect extracellular DA in striatum, indicating that this drug does not influence DA efflux directly. Local application of the alpha 2-adrenoceptor antagonist idazoxan (0.1 or 5.0 mM) increased extracellular NE and DA in medial prefrontal cortex. Conversely, the alpha 2-adrenoceptor agonist clonidine (0.2 mg/kg; i.p.) decreased extracellular NE and DA in medial prefrontal cortex. These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region. This regulation may be achieved by mechanisms involving an action of NE on receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation).

Adrenergic Uptake Inhibitors↗
PubMed2000

Dual effects of intravenous anesthetics on the function of norepinephrine transporters.

BACKGROUND: Norepinephrine transporters (NETs) terminate the neuronal transmission of norepinephrine, which is released from noradrenergic neurons. To investigate the interaction with NET, the authors examined the effects of short- and long-term treatment with anesthetics on the activity and mRNA level of NET. METHODS: To assay [3H]norepinephrine uptake, bovine adrenal medullary cells in culture were incubated with [3H]norepinephrine in the presence of intravenous anesthetics, including propofol, thiamylal, and diazepam. To study the direct interaction between the anesthetics and NET, the effect of propofol on the binding of [3H]desipramine to the plasma membrane was examined. To study the long-term effect of anesthetics, [3H]norepinephrine uptake by cells pretreated with propofol for 6-24 h and [3H]desipramine binding after pretreatment for 12 h were measured. Simultaneously, we examined the effect of anesthetics on the expression of NET mRNA using the reverse transcriptase-polymerase chain reaction. RESULTS: All of the intravenous anesthetics inhibited [3H]norepinephrine uptake in a concentration-dependent manner. The active concentrations of propofol (1-3 microm) and thiamylal (< or = 30 microm) were similar to those encountered clinically. The kinetic analysis revealed that all the anesthetics noncompetitively inhibited [3H]norepinephrine uptake. Propofol inhibited [3H]desipramine binding with a potency similar to that observed in [3H]norepinephrine uptake. Scatchard analysis showed that propofol competitively inhibited [3H]desipramine binding. On the other hand, long-term treatment of cells with propofol (10 microm) enhanced the NET functional activity and [3H]desipramine binding, and also increased the level of NET mRNA. CONCLUSIONS: These results suggest that intravenous anesthetics have a dual effect on NET; short-term treatment causes inhibition, whereas long-term treatment leads to up-regulation. The interaction of intravenous anesthetics with NET may modulate the neuronal transmission of norepinephrine during anesthesia.

Adrenal Medulla↗
PubMed2000

Prospective CYP2D6 genotyping as an exclusion criterion for enrollment of a phase III clinical trial.

A phase III study was performed to compare the efficacy and safety of lamotrigine (Lamictal), desipramine (Norpramin), and placebo in the treatment of unipolar depression. Desipramine is extensively metabolized by cytochrome P450 2D6 (CYP2D6), and kinetics of this compound are altered in poor metabolizers. Genotyping was utilized to exclude poor metabolizers in order to increase subject safety and to eliminate the need to continuously monitor plasma desipramine levels. As part of screening, subjects were genotyped for the *3(A), *4(B), and *5(D) alleles, which identify approximately 95% of poor metabolizers. Extensive metabolizers were eligible for randomization to the lamotrigine, desipramine, or placebo arm. Follow-up genotyping for the *6(T) and *7(E) alleles was performed after study enrollment and was used to identify poor metabolizers who may have been incorrectly identified as extensive metabolizers upon initial three-allele screening. Of 628 subjects screened for *3(A), *4(B), *5(D) alleles, 590 (93.9%) were classified as extensive metabolizers. The remaining 38 (6.1%) subjects were poor metabolizers and excluded. Subsequent *6(T) and *7(E) testing revealed that two poor metabolizers had been enrolled, and the follow-up genotyping provided an explanation for the high desipramine plasma concentrations in one subject. No differences in phenotypic or allelic frequencies were found between the study population and literature populations. However, the frequency of poor metabolizers varied among clinical sites (0-15%). For a compound that is extensively metabolized by CYP2D6, prescreening subjects for *3(A), *4(B), *5(D), *6(T) and *7(E) alleles can increase subject safety and eliminate the need to continuously monitor drug plasma concentrations.

Antidepressive Agents↗