The effects of new sigma (σ) receptor ligands, PB190 and PB212, in the models predictive of antidepressant activity.

Background: A number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress).

Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma1 receptor ligands.

Clinical evidence has indicated a high degree of comorbidity of alcoholism and depression. Manifestation of the depression symptoms during abstinence increases the likelihood of relapse and indicates a worse prognosis in terms of treatment outcome. The depressive symptoms may be alcohol independent or alcohol induced.

Effects of PB190 and PB212, new σ receptor ligands, on glucocorticoid receptor-mediated gene transcription in LMCAT cells.

The hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often observed in patients with major depression. It has even been implicated in the pathophysiology of this disease. Some antidepressant drugs (ADs) inhibit glucocorticoid receptor (GR) function under in vitro conditions.

Anxiolytic-like effects of olanzapine, risperidone and fluoxetine in the elevated plus-maze test in rats.

In the present study was examined the effect of treatment with olanzapine or risperidone, given separately or in combination with fluoxetine, in the elevated plus-maze test (an animal model of anxiety) in male Wistar rats. The obtained results showed that treatment with olanzapine (1 mg/kg), risperidone (0.1 and 0.

Pharmacology of sigma (σ) receptor ligands from a behavioral perspective.

The σ receptors are regarded as unique binding sites, distinct from opiate and PCP receptors and implicated in higher brain function. They were classified into σl and σ2 subtypes, the former was cloned from rodent and human tissues while the latter has not yet been fully characterized. Although the precise mechanism of the functional response of σ receptors is still uncertain, it has been accepted that they can modulate a number of central neurotransmitter systems, including glutamate/NMDA, serotonergic, dopaminergic, noradrenergic routes, as well as some other signaling pathways (e.

Antidepressant-like effect of PRE-084, a selective sigma1 receptor agonist, in Albino Swiss and C57BL/6J mice.

PRE-084, a selective sigma receptor agonist, exhibited an antidepressant-like effect in the forced swim test (FST) in Albino Swiss and C57BL/6J mice. This effect was counteracted by BD 1047 (5 and 10 mg/kg) but not by SM-21 (3 and 10 mg/kg), which are sigma(1)- and sigma(2)-receptor antagonists, respectively. The results indicated that PRE-084 has an antidepressant-like effect in C57BL/6J and, to a lesser extent, in Albino Swiss mice.

Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats.

In the present study we found that repeated co-treatment with fluoxetine and amantadine for 14 days (but not for 7 days) enhanced the hyperactivity induced by amphetamine or quinpirole (a dopamine D(2/3) agonist), compared to treatment with either drug alone. Whereas repeated co-treatment with fluoxetine and amantadine for 7 days more potently inhibited the behavioral syndrome evoked by the 5-hydroxytryptamine (5-HT)(1A) receptor agonist (+/-)-8-hydroxy-2(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT), it did not change the action of the 5-HT(2) receptor agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (/+/-/-DOI). The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone.

Effects of selective sigma receptor ligands on glucocorticoid receptor-mediated gene transcription in LMCAT cells.

It has been shown previously that sigma receptor agonists reveal potential antidepressant activity in experimental models. Moreover, some data indicate sigma receptor contribution to stress-induced responses (e.g.

Effects of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in rats subjected to the forced swim test.

Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in male Wistar rats subjected to the forced swim test. Metyrapone alone (50 mg/kg, but not 25 mg/kg) reduced the immobility time of rats in the forced swim test; moreover, both doses tested (25 and 50 mg/kg), dose-dependently decreased the stress-induced plasma corticosterone concentration.

Repeated co-treatment with fluoxetine and amantadine induces brain-derived neurotrophic factor gene expression in rats.

In the present study, we investigated the influence of repeated treatment with fluoxetine (FLU, 5 or 10 mg/kg) and amantadine (AMA, 10 mg/kg), given separately or jointly (twice daily for 14 day), at the mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was dissected 24 h after the last dose of drug.

Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression.

The paper describes the effect of amantadine addition to imipramine therapy in patients suffering from treatment-resistant unipolar depression who fulfilled DSM IV criteria for major (unipolar) depression. Fifty patients were enrolled in the study on the basis of their histories of illness and therapy. After a 2-week drug-free period, 25 subjects belonging to the first group were treated only with imipramine twice daily (100 mg/day) for 12 weeks, and 25 subjects belonging to the second group were treated with imipramine twice daily (100 mg/day) for 6 weeks and then amantadine was introduced (150 mg/day, twice daily) and administered jointly with imipramine for the successive 6 weeks.

Antidepressant-like effect of combined treatment with selective sigma receptor agonists and a 5-HT1A receptor agonist in the forced swimming test in rats.

The interaction between the selective sigma (sigma) receptor agonists and 8-OH-DPAT, a serotonin (5-HT)(1A) receptor agonist, was examined in the forced swimming test in rats. The results indicate that joint administration of DTG (5 mg/kg) or SA4503 (3 mg/kg), the selective sigma(1)/sigma(2)- or sigma(1)-receptor agonists, respectively, and 8-OH-DPAT (0.1 or 0.

Effect of acute and repeated treatment with mirtazapine on the immunity of noradrenaline transporter knockout C57BL/6J mice.

Pathological immunoactivation is thought to play an important role in the etiology of depression; however, the effect of novel antidepressant drugs on immunity has been poorly recognized. Mirtazapine, an antidepressant drug, enhances noradrenergic and serotonergic neurotransmissions, which are crucially involved in the regulation of immune system activity. In the present study we examined the effect of acute and seven-day repeated administration of mirtazapine (20 mg/kg, i.

Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity.

The sigma receptors were first classified as a subtype of opioid receptors but later they were found to be a distinct pharmacological entity. Many preclinical and clinical data have indicated that sigma receptor ligands have to be involved in neuropsychiatric disorders, including schizophrenia. Numerous data have suggested that potential antipsychotic activity of sigma ligands results from their "antagonistic" activity.

Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats.

The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test.

Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test.

The activation of cell-mediated immunity and the hypothalamic-pituitary-adrenal axis may play a role in the pathophysiology of depression, especially a treatment-resistant one, and antidepressant treatments may exert their effect by suppressing this activation. In our previous studies we described synergistic, antidepressant-like effects of a combination of amantadine (10 mg/kg) and imipramine (5 mg/kg) - drugs otherwise ineffective when given separately in such doses - in the forced swimming test (FST), an animal model of depression. Moreover, preliminary clinical data show that the above-described combination has beneficial effects on treatment-resistant patients.

Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression.

The paper describes the effect of metyrapone supplementation on imipramine therapy in patients (with treatment-resistant unipolar depression) who fulfilled DSM IV criteria for major depression. Nine patients were enrolled to the study on the basis of history of their illness and therapy. Following 2 weeks of washout period, the patients were treated with imipramine twice daily (100 mg/day) for 6 weeks, and then metyrapone was introduced (twice daily, 500 mg/day), and administered jointly with imipramine for further 6 weeks.

Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioral and pharmacokinetic studies.

Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptor, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either of drugs given alone. Since it has been suggested that, in addition to their other functions, dopamine and alpha(1)-adrenergic receptors may play a role in behavioral response in the forced swimming test, in the present study we examined the effect of sulpiride (dopamine D(2/3) receptor antagonist) and prazosin (alpha(1)-adrenergic receptor antagonist) on the effect of AMA given alone or in combination with IMI in the forced swimming test in rats. We also measured the level of IMI and its metabolite, desipramine, in the rat plasma and brain, 1 h after the forced swimming test.

Sigma1 receptor antagonists attenuate antidepressant-like effect induced by co-administration of 1,3 di-o-tolylguanidine (DTG) and memantine in the forced swimming test in rats.

The obtained results show that DTG, the sigma1/sigma2 receptor agonist, exerts a synergistic effect with memantine, an uncompetitive NMDA receptor antagonist, in the forced swimming test in rats, and that progesterone and BD 1047, the sigma1 receptor antagonists, counteract this effect. The results suggest that the sigma1 receptor subtype may contribute to the behavioral response induced by combined administration of DTG and memantine in Porsolt's test in rats.

Effects of combined treatment with imipramine and metyrapone in the forced swimming test in rats. Behavioral and pharmacokinetic studies.

In the present study, we examined the effects of imipramine (IMI) and metyrapone (MET) given alone or in combination of IMI and MET in the forced swimming test in rats. We also measured pharmacokinetic parameters: the level of IMI and its metabolite, desipramine (DMI), in the rat plasma and brain (1 h after the forced swimming test). The present studies indicate that MET (50 mg/kg) reduced immobility time.

Potential antidepressant activity of sigma ligands.

Despite many years' studies of antidepressant drugs (ADs), their mechanism of action still remains unclear. Recently, it has been postulated that substances capable of reducing neurotransmission at the NMDA complex may represent a new class of ADs. Since several ADs have a high affinity for sigma receptors, the sigma binding site may be a relevant mechanism in antidepressant action.

Anxiolytic-like effects of preferential dopamine D3 receptor agonists in an animal model.

The aim of the present study was to examine a potential anxiolytic-like action of (+)-7-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (7-OH-DPAT), a preferential dopamine D(3) receptor agonist, and (N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide (BP 897), partial dopamine D(3) receptor agonist. Diazepam was used as a reference compound. The anxiolytic-like effect of those drugs was tested in the conflict drinking test (Vogel test) in male Wistar rats.

Effect of combined treatment with selective sigma ligands and amantadine in the forced swimming test in rats.

The obtained results showed that the selective sigma, receptor agonist, SA4503 (but not siramesine, the sigma2 receptor agonist), given alone, exerted an antidepressant-like activity in the forced swimming test in rats. Amantadine (an uncompetitive NMDA receptor antagonist) potentiated or revealed the effect of SA4503 or siramesine, respectively, in this model.

Effect of repeated treatment with reboxetine on the central alpha 1-adrenergic and dopaminergic receptors.

Reboxetine (REB) is a member of a new class of antidepressant drugs, which selectively inhibit the neuronal reuptake of noradrenaline. It is devoid of any affinity for neurotransmitter receptors nor does it inhibit monoamine oxidases A or B. Since our earlier studies have shown that antidepressant drugs administered repeatedly increase the responsiveness of alpha1-adrenergic receptors and induce the up-regulation of postsynaptic dopamine D2/D3 receptors in the rat brain, we designed the present experiments to determine whether repeated administration of REB evokes similar effects.

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats.

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane).