NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine.

RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. OBJECTIVES: The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. METHODS: Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. RESULTS: Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. CONCLUSIONS: NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.

Biphasic effects of losartan potassium on immobility in mice.

The effects of losartan potassium, an angiotensin AT(1) receptor blocker on immobility in forced swim test have been studied. Effect of losartan potassium, nortriptyline HCl, fluoxetine HCl and reserpine per se and in combination on forced swimming-induced immobility in mice have also been studied. In mice, losartan potassium elicits biphasic responses i.e. positive responses at lower doses (0.1, 1.0 and 5 mg/kg, i.p.) in the forced swim test, a test of potential antidepressant activity and vice versa at higher dose (20 and 100 mg/kg, i.p.). In chronic studies, enhancement in immobility was observed for losartan potassium (3 and 30 mg/kg, p.o., 21 days). In acute combination studies, losartan potassium (1 and 5 mg/kg) significantly reversed the reserpine-induced immobility, but vice versa at 100 mg/kg. Losartan potassium (0.1 and 5 mg/kg) potentiate antidepressant activity of nortriptyline (30 mg/kg, i.p.) in mice, but vice versa at 100 mg/kg. Likewise, Losartan potassium (100 mg/kg), significantly reversed antidepressant activity of fluoxetine HCl, but at 0.1 and 5 mg/kg, failed to modify fluoxetine HCl induced immobility. The obtained biphasic effect of losartan potassium on immobility in mice might be due to inhibitory effect on AT(1) receptor at lower dose and pronounced effect on AT(2) receptor at higher dose (large concentrations of losartan potassium can displace Angiotensin II (Ang II) from its AT(1) receptor to AT(2) receptor.

Selective effect of nortriptyline on smooth muscle as an anticholinergic drug: a pharmacological and clinical study.

The anticholinergic potency of nortriptyline was studied on muscle strips from human bladder and ileum. Concurrently the effect of nortriptyline low dosage therapy was studied in 21 women suffering from motor or sensory urgency and urge incontinence. Analysis of the results by the dose ratio method showed a significant difference in the affinity of the anticholinergic receptors to the antagonist. The Ki values were 0.298 microM for the bladder and 0.938 microM for the ileum. In the clinical study, the condition of 15 (71.4%) women treated with notriptyline improved considerably. The higher affinity of the drug to the receptors in the bladder than to those in the ileum may explain the positive therapeutic effect of a relatively low dose of nortriptyline in over 70% of the patients treated.

Effect of activated charcoal on absorption of nortriptyline.

The ability of 'Medicoal', a new effervescent, activated charcoal preparation, to adsorb nortriptyline, has been investigated both in vitro and in vivo. A single dose of the effervescent charcoal 30 min after a dose of 75 mg nortriptyline produced a 60% mean reduction in both peak plasma levels and nortriptyline availability in healthy volunteers. Multiple doses of the effervescent charcoal produced 70% mean reduction in peak nortriptyline levels and availabiltiy. Activated charcoal is recommended for the treatment of tricyclic antidepressant poisoning. In in-vitro tests, a 10 g packet of the effervescent preparation containing 5 g activated charcoal) had an adsorptive capacity of approximately 3000 mg nortriptyline, a dose not usually exceeded in most cases of trycyclic antidepressant overdose.

Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man.

Total urinary excretion of radioactivity after oral or intravenous administration of a test dose of (14)C-imipramine was measured in eight patients. They were tested before, during, and after treatment with neuroleptics. Excretion diminished while the patients were being treated with perphenazine, haloperidol, or chlorpromazine, though not during flupenthixol treatment.Total urinary excretion of radioactivity and plasma levels of metabolites and unchanged drug were measured in five patients after a test dose of (14)C-nortriptyline. Each patient was tested before and again during perphenazine treatment. In all patients perphenazine treatment caused: (1) decrease of total urinary excretion, (2) decreased plasma level of metabolites, and (3) increased plasma level of unchanged nortriptyline.These results indicate that neuroleptics inhibit the metabolism of tricyclic antidepressants in man.

Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy.

Nineteen identical (monozygotic) and 20 fraternal (dizygotic) sets of twins between 45 and 51 years of age were given nortriptyline orally in doses of 0.2 mg./kg. body weight three times daily for eight days. The steady-state plasma concentrations of nortriptyline were calculated from the mean of the determinations for days 6, 7, and 8. Identical twins, not treated with other drugs, achieved similar steady-state plasma concentrations of nortriptyline in contrast to fraternal twins who were not given other drugs. The intrapair similarity in steady-state plasma concentrations was not found in identical twins simultaneously treated with various drugs during the experiment. Identical and fraternal twins treated with drugs containing barbiturates had considerably lower steady-state plasma concentrations of nortriptyline compared with untreated twins.It is concluded that most of the variability in nor-triptyline steady-state plasma concentration between persons who have not received drugs is genetically determined. Exposure to other drugs also influences the steady-state plasma concentration of nortriptyline, which in a given patient may therefore be determined by a resultant of genetic and environmental factors.