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). The objective of the present study was to find out whether PB190 and PB212, new σ1 receptor ligands, show the effects in some models predictive of antidepressant activity. METHODS: The impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP3 pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2. RESULTS: In the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ1-receptor antagonist. The in vitro studies indicated that Ca(2+)-response was increased by 1µM PB190, like by the σ1-agonist (+)-pentazocine, while 1 µM PB212 behaved line σ1-antagonist, BD1063. On the other hand, 100 µM PB190 negatively affected the Ca(2+)-response after bradykinin. CONCLUSIONS: The obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ1-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ1-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.

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. In this paper, only the ethanol-related depression is the focus of interest. In preclinical studies, some models of depressive-like symptoms induced by chronic alcohol treatment and withdrawal were proposed. In this minireview, the results concerning the depression-like behavior and some accompanying biochemical changes induced by prolonged ethanol exposure and its cessation in rats and mice were summarized. Moreover, the therapeutic potential of sigma1 receptor ligands for the treatment of depression disorder induced by ethanol abuse and withdrawal is discussed.

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.g. neurotrophin and growth factor signaling) which are seemingly important for the brain function. In accordance with their modulatory role, σ receptor ligands have been proposed to be useful in several therapeutic areas such as schizophrenia, depression and anxiety, amnesic and cognitive deficits, drugs of abuse. The present review summarizes the findings related to the pharmacological effects and potential activity of σ receptor ligands from behavioral models predictive of some neuropsychiatric disorders.

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 0.3 mg/kg) or fluoxetine (5 and 10 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze test. Olanzapine, risperidone and fluoxetine, tested in doses effective in the model of anxiolytic-like actions, did not affect motor coordination, while olanzapine (3 mg/kg) and risperidone (0.3 mg/kg) produced a significant reduction of exploratory activity in the open field test. In a combination study, the anxiolytic-like effect of olanzapine or risperidone was significantly antagonized by co-treatment with fluoxetine. Additionally, co-treatment with olanzapine or risperidone and fluoxetine disturbed the motor coordination of rats in a rota-rod test. These findings indicate that olanzapine, risperidone and fluoxetine per se may be clinically effective in treating anxiety disorders, but their effects may be attenuated when they are used in combination with other medications.

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. The σ(1) receptor agonists reveal potential antidepressant activity in animals, moreover, igmesine is promising as an AD in humans. As already shown, σ receptors are involved in stress-induced responses (e.g., conditioned fear stress in mice). The aim of the present study was to find out whether the new selective σ receptor ligands, PB190 and PB212, are able to affect directly the endocrine system activity. To this end, we evaluated their influence on GR function in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). Fluvoxamine, a selective serotonin reuptake inhibitor, recognized as a σ(1) receptor agonist was used for comparison. The obtained results showed that both PB190 and PB212 (potential σ(1) receptor agonist and antagonist, respectively) like fluvoxamine, decreased the corticosterone-induced CAT activity in a concentration-dependent manner. The significance of this fact remains ambiguous and requires further studies.

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. Moreover, our results suggest that 5-HT(1A) receptors are useful targets for the development of more rapidly acting and more effective medication.

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. These results support the idea that sigma(1)-receptors, but not sigma(2)-receptors, contribute to the mechanism of antidepressant activity of sigma agonists in FST.

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. Joint administration of fluoxetine or tianeptine (10 mg/kg) and metyrapone (25 mg/kg - a dose inactive per se) exhibited antidepressant-like activity in the forced swim test in rats. WAY 100636 (a 5-HT(1A) antagonist), but not prazosin (an alpha(1)-adrenergic antagonist), used in doses ineffective in the forced swim test, inhibited the antidepressant-like effect induced by co-administration of fluoxetine or tianeptine with metyrapone (25 mg/kg). Combined treatment of fluoxetine or tianeptine and metyrapone inhibited stress-induced corticosterone secretion to a similar extent as metyrapone alone. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of fluoxetine or tianeptine and that, among other mechanisms, 5-HT(1A) receptors may play some role in this effect. Moreover, metyrapone exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration. These findings suggest that the co-administration of metyrapone and an antidepressant drug may be useful for the treatment of drug-resistant depression and/or depression associated with a high cortisol level.

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. We also studied the effect of repeated treatment with FLU and AMA on the action of 5-hydroksytryptamine (5-HT)(1A)- and 5-HT(2) receptor agonists (+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (+/-)-1-(4-iodo-2,5-dimethoxy-phenyl)-2-aminopropane ((+/-)DOI), respectively, in behavioral tests. The obtained results showed that FLU (10 mg/kg) in the hippocampus, and FLU (5 and 10 mg/kg) and AMA(10 mg/kg) in the cerebral cortex, significantly elevated BDNF mRNA levels. Joint administration of FLU (5 or 10 mg/kg) and AMA(10 mg/kg) induced a more substantial increase in BDNF gene expression in the cerebral cortex (but not in the hippocampus), and inhibited the behavioral syndrome induced by 8-OH-DPAT or (+/-)DOI (compared to treatment with either drug alone). The obtained results suggest that the enhancement of BDNF gene expression may be essential for the therapeutic effect of the co-administration of FLU and AMA in drug-resistant depressed patients, and that among other mechanisms, 5-HT(1A) and 5-HT(2) receptors may play some role in this effect.

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., conditioned fear stress in mice), though the mechanism by which sigma ligands can exert their effects, remains unclear. Recent studies have indicated that antidepressant drugs (ADs) inhibit glucocorticoid receptor (GR) function in vitro. The aim of the present study was to find out whether sigma receptor ligands are able to directly affect GR action. To this end, we evaluated the effect of sigma receptor agonists and antagonists on GR function in mouse fibroblast cells (L929) stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). For this study, we chose SA4503, PRE 084, DTG (selective sigma(1) or sigma(1/2) receptor agonists) and BD 1047, SM 21, rimcazole (sigma receptor antagonists). Fluvoxamine, the selective serotonin reuptake inhibitor with sigma(1/2) receptor affinity, was used for comparison. It was found that SM 21 (at 1, 3, 10 and 30 microM), BD 1047 (3, 10 and 30 microM) rimcazole (10 microM), and fluvoxamine (at 3, 10 and 30 microM) significantly inhibited corticosterone-induced gene transcription, while DTG, SA 4503 and PRE 084 remained ineffective. Thus, the sigma receptor agonists that predominantly showed antidepressant-like activity in behavioral models, were without effect in this in vitro model. These results suggest that antidepressant-like activity of sigma receptor agonists is independent of corticosterone-induced gene transcription. Therefore, the attenuation of GR function induced by sigma receptor antagonists remains ambiguous and requires further study.

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 0.3 mg/kg) induces an antidepressant-like effect. The doses of sigma agonists and 8-OH-DPAT used in the study were inactive per se in this model. The effect of DTG and 8-OH-DPAT co-administration was partly counteracted by WAY 100635 (0.1 mg/kg) as well as by BD 1047 (3 mg/kg), a 5-HT(1A) and sigma(1) receptor antagonists, respectively, suggesting the involvement of both receptor types in the anti-immobility effect in rats.

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. Hamilton Depression Rating Scale (HDRS) was used to assess the efficacy of antidepressant therapy. Imipramine did not change the HDRS score after 3, 6 or 12 weeks of treatment when compared with the washout (before treatment). The addition of amantadine to the classic antidepressant reduced HDRS scores after 6-week joint treatment. Moreover, the obtained pharmacokinetic data indicated that amantadine did not significantly influence the plasma concentration of imipramine and its metabolite desipramine in patients treated jointly with imipramine and amantadine, which suggests lack of a pharmacokinetic interaction. The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.

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. However, the subcellular mechanisms by which sigma ligands exert their effects have not been elucidated in detail, therefore, the terms "agonist" or "antagonist" and their functional implications are not entirely unequivocal. The aim of the present study was to find out if BD 1047, described recently as a selective functional antagonist of sigma receptors, shows antipsychotic activity in animal models predictive of efficacy in schizophrenia. In contrast to rimcazole and panamesine, two selective sigma ligands whose antipsychotic activity was confirmed clinically, BD 1047 did not decrease amphetamine-induced hyperactivity in mice in a statistically significant manner. Likewise, it did not modify the hyperactivity induced by NMDA receptor antagonists, phencyclidine, memantine or dizocilpine. On the other hand, BD 1047 attenuated apomorphine-induced climbing in mice and phencyclidine-induced head twitches in rats, like rimcazole and panamesine did. Summing up, BD 1047 shows a moderate activity in models used in this study suggesting that its usefulness as an antipsychtic drug is doubtful. However, more detailed studies are required for definitive confirmation of this conclusion.

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. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD 1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Moreover, sigma(1) receptors may constitute one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in that 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. However, it is still unknown whether these positive effects of combined treatment with amantadine and imipramine on behavioural depressive changes are accompanied with normalization of immunoendocrine parameters. Therefore, the present study was aimed at ascertaining whether the antidepressive effect of a combination of amantadine and imipramine was accompanied with a decrease in some immunoendocrine parameters. The antidepressant activity was accompanied with a reversal of the stress-induced increase in the proliferation of splenocytes in response to concanavalin A (ConA). Imipramine, amantadine and a combination of amantadine and imipramine enhanced the production of the negative immunoregulator IL-10 in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with imipramine or amantadine (a combination of imipramine and amantadine causes reduction within the margin of error). In summary, the antidepressive efficacy of a combination of amantadine and imipramine given in suboptimal doses may be related to their negative immunoendocrine effects.

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.p.) on immunoreactivity in noradrenaline transporter knockout (NET-KO) and wild-type male C57BL/6J mice subjected to the forced swimming test (FST). Mirtazapine decreased immobility time in the FST after acute, but not seven-day repeated, administration to C57BL/6J mice. Lack of the antidepressant effect of mirtazapine was observed, after acute and repeated administration to NET-KO mice, although those mice showed a significantly shorter immobility time in the FST than did wild-type animals. Seven-day repeated mirtazapine administration to wild-type mice suppressed the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines, whereas production of IL-4 was stimulated. Acute mirtazapine administration did not change immune parameters in C57BL/6J mice. In NET-KO mice, acute and seven-day repeated mirtazapine administration reduced the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines. This study indicates that, in comparison with wild-type C57BL/6J mice, NET-KO mice show enhanced mobility, which is not further potentiated by mirtazapine treatment. Furthermore, the NET-KO mice display higher susceptibility to the immunosuppressive effects of mirtazapine than do the wild-type animals. The present paper postulates an essential role of noradrenergic system in the immunological and behavioral effects of mirtazapine.

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. Joint treatment with IMI (5 or 10 mg/kg) and AMA (20 mg/kg) produced stronger antidepressant-like effect than either of agents given alone. Sulpiride (10 mg/kg) or prazosin (1 mg/kg) (ineffective in the forced swimming test) inhibited an antidepressant-like effect induced by co-administration of IMI and AMA. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and AMA failed to enhance the locomotor activity of rats, measured in the open field test. Also sulpiride and prazosin did not decrease the exploratory activity induced by co-administration of IMI and AMA. The above result suggests that the dopamine D(2/3) and alpha(1)-adrenergic receptors may contribute to the mechanism of synergistic action of IMI and AMA in the forced swimming test in rats. The pharmacokinetic interaction can be excluded, since AMA did not change significantly the antidepressant level in the rat plasma and brain, measured 1 h after exposure to the forced swimming test.

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. Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were used to assess efficacy of antidepressant therapy. Imipramine changed neither HDRS nor BDI score after 6 weeks of treatment when compared with baseline (before treatment). Metyrapone supplementation significantly reduced both HDRS and BDI scores after 6-week supplementation. Moreover, pharmacokinetic data indicate that metyrapone did not influence significantly the plasma concentration of imipramine and its metabolite, desipramine in the patients during joint treatment with metyrapone and imipramine, what suggests the lack of pharmacokinetic interaction. This preliminary study is the first demonstration of the benefit of metyrapone supplementation in imipramine therapy of treatment-resistant unipolar depression and suggests that a change in the level of neurotransmitters, hormones and immunological parameters, which are disturbed in depression, may contribute to the mechanism of the action of this drug.

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. The obtained results showed that 7-OH-DPAT and BP 897 (like diazepam) induced anxiolytic-like effects in the conflict drinking test. 7-OH-DPAT (0.05 and 0.1 mg/kg), BP 897 (0.5 mg/kg) and diazepam (5 and 10 mg/kg), tested at the effective doses in an animal model, did not affect motor coordination but produced significant reduction in exploratory activity in the open field test. These data suggest that preferential dopamine D(3) agonists may play a role in the therapy of anxiety, however, further studies are necessary to elucidate the mechanism of these actions.

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. Moreover, sigma ligands are able to modulate the activity of the central neurotransmitter systems, including noradrenergic, serotonergic, dopaminergic and glutamatergic (NMDA) ones, which are seemingly important for the mechanism of action of known ADs. The existence of at least two different subtypes of sigma receptors, denoted sigma1 and sigma2 is now widely accepted. The selective agonists of both sigma receptor subtypes are available at present. In particular, a potential antidepressant activity of sigma1 receptor agonists has been postulated, since the antidepressive-like actions of these compounds have been shown in animal models. This article reviews the findings related to potential antidepressant activity of new, selective sigma ligands.