Repeated co-treatment with mirtazapine and aripiprazole reversed the schizophrenia-like behaviors and increased the brain-derived neurotrophic factor mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal brain development.

Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.

The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats.

Several clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors (SSRI), in the treatment of drug-resistant depression and treatment-resistant anxiety disorders. In the present study, we investigated the effect of treatment with the antidepressant escitalopram (SSRI) given separately or jointly with a low dose of risperidone (an atypical antipsychotic) in the forced swim test and in the elevated plus-maze test in rats. The obtained results showed that escitalopram at doses of 2.5 or 5 mg/kg evoked antidepressant-like effect in the forced swim test. Moreover, risperidone at low doses (0.05 or 0.1 mg/kg) enhanced the antidepressant-like activity of escitalopram (1 mg/kg) in this test by increasing the swimming time and decreasing the immobility time in those animals. WAY 100635 (a serotonin 5-HT1A receptor antagonist) at a dose of 0.1 mg/kg abolished the antidepressant-like effect induced by co-administration of escitalopram and risperidone. The active behavior in that test did not reflect an increase in general activity, since the combined treatment with escitalopram and risperidone failed to enhance the exploratory activity of rats. In the following experiment, we showed that escitalopram (5 mg/kg) and mirtazapine (5 or 10 mg/kg) or risperidone (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze test, and the combined treatment with an ineffective dose of risperidone (0.05 mg/kg) enhanced the anxiolytic-like effects of escitalopram (2.5 mg/kg) or mirtazapine (1 and 2.5 mg/kg) in this test. The obtained results suggest that risperidone applied at a low dose enhances the antidepressant-like activity of escitalopram in the forced swim test, and that 5-HT1A receptors may play some role in these effects. Moreover, a low dose of risperidone may also enhance the anxiolytic-like action of the studied antidepressants.

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

The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. In our earlier papers we described synergistic, antidepressant-like effects of a combination of imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats, an animal model of depression. Moreover, preliminary clinical data showed that the above-mentioned combination had beneficial effects in treatment-resistant patients. In addition, a number of studies predicted a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and AMA (10 mg/kg), given separately or jointly (twice daily for 14 day), on 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 IMI and AMA. We also studied the effect of repeated treatment with IMI and AMA on the action of 5-HT(1A)- and 5-HT(2A) receptor agonists (8-OH-DPAT and (+/-)DOI, respectively) in behavioral tests. The obtained results showed that in the hippocampus IMI (10 mg/kg), and in the cerebral cortex IMI (5 and 10 mg/kg) and AMA (10 mg/kg) significantly elevated BDNF mRNA level. Joint administration of IMI (5 or 10 mg/kg) and AMA (10 mg/kg) induced a more potent increase BDNF gene expression in the hippocampus (but not in cerebral cortex) and either inhibited the behavioral syndrome induced by (+/-)DOI or did not change the action of 8-OH-DPAT (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 co-administration of IMI and AMA to drug-resistant depressed patients, and that among other mechanisms, 5-HT(2A) receptors possibly play some role in this effect.

The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats.

Data acquired to date show that some sigma receptor ligands reveal "antidepressant-like" activity in the forced swim test in mice and rats. Moreover, our preliminary results suggested that joint administration of sigma receptor ligands and amantadine (AMA, a glutamatergic/NMDA receptor antagonist) caused a positive interaction in the Porsolt test in rats, as had already been observed in the case of co-treatment with clinically active antidepressants and AMA. The aim of the present study was to examine the effect of combined administration of sigma1 or sigma2 receptor agonists, SA4503 or siramesine, respectively, and AMA or memantine (MEM) (uncompetitive NMDA receptor antagonist). SA4503 or siramesine given jointly with MEM (as well as with AMA) decreased the immobility time in rats. The effect of SA4503 and AMA co-administration was antagonized by progesterone, a sigma1 receptor antagonistic neurosteroid. Combined treatment with siramesine and AMA was modified by neither progesterone nor BD1047 (a novel sigma antagonist with preferential affinity for sigma1 sites); but it was counteracted by sulpiride and prazosin (a dopamine D2- and an alpha1-adrenergic receptor antagonist, respectively). The "antidepressant-like" effect induced by siramesine and MEM was not antagonized by progesterone, but was attenuated by BD1047, sulpiride and prazosin. The obtained results give support to the hypothesis that sigma (particularly sigma1) receptors may be one of the possible mechanisms by which drugs induce antidepressant-like activity in the forced swim test, and that this effect may be enhanced by NMDA receptor antagonists. Combined treatment with sigma ligands and AMA or MEM (applied in the clinic) may be an alternative to the treatment of antidepressant-resistant depressive patients in the future.

Norepinephrine transporter knockout-induced up-regulation of brain alpha2A/C-adrenergic receptors.

The norepinephrine transporter (NET) is responsible for the rapid removal of norepinephrine released from sympathetic neurons; this release is controlled by inhibitory alpha(2)-adrenergic receptors (alpha(2)ARs). Long-term inhibition of the NET by antidepressants has been reported to change the density and function of pre- and postsynaptic ARs, which may contribute to the antidepressant effects of NET inhibitors such as desipramine. NET-deficient (NET-KO) mice have been described to behave like antidepressant-treated mice. By means of quantitative real-time PCR we show that mRNAs encoding the alpha(2A)-adrenergic receptor (alpha(2A)AR) and the alpha(2C)-adrenergic receptor (alpha(2C)AR) are up-regulated in the brainstem, and that alpha(2C)AR mRNA is also elevated in the hippocampus and striatum of NET-KO mice. These results were confirmed at the protein level by quantitative autoradiography. The NET-KO mice showed enhanced binding of the selective alpha(2)AR antagonist [(3)H]RX821002 in several brain regions. Most robust increases (20-25%) in alpha(2)AR expression were observed in the hippocampus and in the striatum. Significant increases (16%) were also seen in the extended amygdala and thalamic structures. In an 'in vivo' test, the alpha(2)AR agonist clonidine (0.1 mg/kg) caused a significantly greater reduction of locomotor activity in NET-KO mice than in wild-type mice, showing the relevance of our findings at the functional level.

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the 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 joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.

Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats.

Recent studies indicate a role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs). It has been shown that serum BDNF levels are decreased in depressed patients. Moreover, antidepressant treatment increases serum BDNF levels and it is positively correlated with medication response. In addition, repeated administration of ADs induces an increase in rat hippocampal or cortical BDNF gene expression. Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment (twice daily for 14 days) of the new AD mirtazapine (5 or 10 mg/kg) on BDNF mRNA level (the Northern blot) in rat hippocampus and cerebral cortex. Imipramine was used as a reference compound. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last doses of mirtazapine and imipramine. We also studied the effect of repeated mirtazapine on the action of the 5-HT2A receptor agonist (+/-)DOI in the behavioral test (head twitches induced by (+/-)DOI) in rats. The obtained results showed that, like imipramine (10 mg/kg), mirtazapine (10 mg/kg) increased BDNF gene expression in both the examined brain regions: in the hippocampus by 24.0 and 26.5%, in the cerebral cortex by 29.9 and 41.5%, respectively, compared with the vehicle-treated control. Neither mirtazapine nor imipramine administered repeatedly at a lower dose (5 mg/kg) significantly changed BDNF mRNA levels in the hippocampus and cerebral cortex. Repeated treatment with mirtazapine (10, but not 5 mg/kg) inhibited the behavioral syndrome induced by (+/-)DOI. This study provides first conclusive evidence that repeated mirtazapine administration increases BDNF mRNA levels; moreover, it indicates that the enhancement of BDNF gene expression may be essential for the clinical effect of mirtazapine.

Anxiolytic- and antidepressant-like effects of 7-OH-DPAT, preferential dopamine D3 receptor agonist, in rats.

The aim of the present study was to examine a potential anxiolytic- and antidepressant-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), a partial dopamine D(3) receptor agonist, in male Wistar rats. Diazepam or imipramine were used as reference compounds. The anxiolytic-like effect of those drugs was tested in the elevated plus-maze test. The antidepressant-like effect was estimated using the forced swimming test. The obtained results showed that 7-OH-DPAT at low doses and BP 897 (like diazepam) induced anxiolytic-like effects in the elevated plus-maze test. 7-OH-DPAT, BP 897 and diazepam, tested at the doses effective in the model of anxiolytic-like actions, did not affect motor coordination. Moreover, 7-OH-DPAT at higher doses, like imipramine, showed antidepressant-like effect, significantly reducing immobility time in the forced swimming test. Combined treatment with 7-OH-DPAT and imipramine induced a stronger effect in Porsolt's test than administration of either drug alone, but did not increase the locomotor activity. In contrast, BP 897 was inactive in the forced swimming test when given alone but it potentiated the antidepressant-like effect of imipramine. These data suggest that preferential D(3) receptor agonists may play a role in the therapy of anxiety and/or depression, however, further studies are necessary to elucidate the mechanism of these actions.

Opposite influence of MPEP, an mGluR5 antagonist, on the locomotor hyperactivity induced by PCP and amphetamine.

Potential antipsychotic effects of a selective non-competitive antagonist of metabotropic glutamate receptor 5 (mGluR5), 2-methyl-6-phenylethynylpyridine (MPEP), was examined in two commonly used screening tests: (1) the hyperactivity induced by an NMDA receptor antagonist phencyclidine (PCP), and (2) the hyperactivity induced by an indirect dopamine agonist, D-amphetamine. PCP was administered at a dose of 2.5 mg/kg s.c. and D-amphetamine was given at a dose of 1 mg/kg s.c. MPEP (5 mg/kg i.p.) significantly enhanced the locomotor activity increased by PCP, but inhibited amphetamine-induced hyperactivity. The opposite effect of MPEP in the two above-mentioned models questions significance of the blockade of mGluR5 receptors to antipsychotic effects.

The effect of combined treatment with imipramine and amantadine on the behavioral reactivity of central alpha1-adrenergic system in rats.

The problem of drug-resistant depression implies a strong need for alternative antidepressant therapies. Recently, it has been shown that joint administration of a tricyclic antidepressant, imipramine (IMI), with amantadine (AMA), a drug already approved for clinical use in the treatment of other diseases, induces a stronger 'antidepressant' effect in the forced swimming test in rats than treatment with either drug given separately. Combined treatment with IMI and AMA also induces up-regulation of dopamine D2 and D3 receptors in the rat brain, and appears to be effective in the treatment of patients with drug-resistant unipolar depression. In the present study, we examined the effect of IMI (5 or 10 mg/kg p.o.) and AMA (10 mg/kg p.o.) given separately or jointly, either as a single dose or repeatedly (twice daily for 14 days) on the development of adaptive changes in the behavioral reactivity of the central alpha1-adrenergic system. Following repeated administration of the higher dose of IMI together with AMA, we observed an increase in clonidine-induced aggression in mice, and significant enhancement of D-amphetamine-induced locomotor hyperactivity, as well as phenylephrine-induced exploratory behavior, in rats. In binding studies using [3H]prazosin, no changes in the density (Bmax) or affinity (Kd) of alpha1-adrenergic receptors were observed in rat brain cortex. However, competition analysis allowed us to observe an increase in the affinity of alpha1-adrenergic receptors (Ki) for an agonist (phenylephrine) upon repeated treatment with IMI, given alone or in combination with AMA. AMA appears to act through several pharmacological mechanisms, none of which has been identified as the chief mode of action. In the light of data obtained in the present study, one can supplement the postulated mechanisms of antidepressant action of AMA by adaptive changes in the reactivity of alpha1-adrenergic receptors, which develop upon repeated combined treatment with IMI.

Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, we can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain, and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.

A potential antidepressant activity of SA4503, a selective sigma 1 receptor agonist.

The aim of the present study was to examine SA4503 [1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a novel selective receptor agonist, in respect of its potential antidepressant action. To this end we used a forced swimming test in rats to study SA4503 alone, as well as its interaction with imipramine, a classic tricyclic antidepressant. SA4503 decreased the immobility time in the forced swimming test in rats (although only at one of the three doses used); at the same time it did not change the locomotor activity recorded under the same experimental conditions. Moreover, SA4503 showed a synergistic effect with imipramine in the forced swimming test (both those compounds given jointly decreased the immobility time, but were ineffective when administered separately). It had previously been shown that repeated administration of antidepressants with different pharmacological profiles enhanced the action of D-amphetamine, quinpirole and other dopamine stimulants. SA4503 administered repeatedly increased the locomotor hyperactivity induced by D-amphetamine and quinpirole (a dopamine D /D receptor agonist), but not by (+/-)-7-hydroxy-dipropyloamino-tetralin hydrobromide [(+/-)-7-OH-DPAT; a dopamine D receptor agonist]. The results presented in this paper support the suggestion that SA4503 may have potential antidepressive properties.

Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2) /D(3) receptors.

Tianeptine (TIA) is an antidepressant drug that has been shown to decrease extracellular serotonin level and reveals no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced any adaptive changes in the central dopamine D(2)/D(3) system (behavioural and biochemical) similar to those reported earlier for tricyclic antidepressants. Experiments were carried out on male Wistar rats. TIA was administered at a dose of 5 and 10 mg/kg once or repeatedly (twice daily for 14 days). Fluoxetine (FLU), used as a reference compound, was also administered at a dose of 10 mg/kg. The results obtained showed that TIA or FLU administered repeatedly increased the hyperlocomotion induced by D-amphetamine and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). Biochemical study revealed a decrease in the [(3)H]7-OH-DPAT binding sites after acute and repeated treatment with TIA or FLU in the islands of Calleja minor, as well as in the shell part of nucleus accumbens septi. On the other hand, both TIA and FLU administered repeatedly increased the binding of [(3)H]quinpirole (a D(2)/D(3) receptor agonist) in the nucleus caudatus as well as in the core part of the nucleus accumbens septi. Similar effects have been observed when dopamine D(2)/D(3) receptors were visualized with the use of [3H]raclopride, a dopamine D(2)/D(3) receptor antagonist. However, TIA and FLU induced a decrease in the level of mRNA encoding for dopamine D(2) receptors, not only after repeated but also after acute treatment. These results indicate that repeated TIA and FLU administration induces adaptive changes in the dopaminergic D(2)/D(3) system and especially enhances the functional responsiveness of dopamine D(2) and D(3) receptors. However, the question of whether this increased responsiveness is important for clinical antidepressant efficacy remains open.

Effect of repeated treatment with mirtazapine on the central alpha1-adrenergic receptors.

Mirtazapine (MIR) is an antidepressant which enhances noradrenergic and serotonergic 5-HT1A neurotransmission via antagomism of central alpha2-adrenergic autoreceptors and heteroreceptors. The drugs does not inhibit noradrenaline and serotonin reuptake but blocks the 5-HT, and 5-HT3 receptors and has high affinity only for central and peripheral histamine H1 receptors. The present study was aimed at determining whether repeated MIR treatment induced adaptive changes in the alpha1-adrenergic receptors, similar to those reported by us early for tricyclic antidepressants, The experiments were carried out on male mice and rats. MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days). The obtained results showed that MIR administrated repeatedly potentiated the methoxamine- induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, those effects being mediated by alpha1-adrenergic receptors. MIR given repeatedly (but not acutely) increased the binding (Bmax ) of [3H]prazosin to alpha1-adrenergic receptors in cerebral cortex, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for the these sites was not significantly changed. The above results indicate that repeated MIR administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes), as tricyclics do. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.

Effect of tianeptine and fluoxetine on the levels of Met-enkephalin and mRNA encoding proenkephalin in the rat.

The purpose of the present study was to evaluate the effects of acute and repeated treatment with two antidepressant drugs (ADs) of opposite pharmacological profile, i.e. tianpetine (TIA, serotonin reuptake enhancer) and fluoxetine (FLU, serotonin reuptake inhibitor) on the levels of Met-Enkephalin, (Met-Enk, a member ofopioid peptide family, which has been suggested to play a role in the mechanism of action ADs) as well as on mRNA coding for proenkephalin (mRNA PENK) in various regions of the rat brain, pituitary, adrenal glands and plasma. Male Wistar rats were treated acutely or repeatedly (10 mg/kg p.o., twice daily for 14 days) with TIA or FLU. Tissue for biochemical experiments was taken 2 h after last dose of appropriate drug. The levels of Met-Enk were estimated by radioimmunoassay, mRNA PENK was measured using in situ hybridization. From the results obtained in the present study it may be concluded that repeated administration of TIA or FLU induced similar changes in the levels of Met-Enk in the rat hippocampus, striatum, hypothalamus and neurointermediate lobe of pituitary. Such an effect is interesting, especially if one takes into account the differences in pharmacological profile between these two antidepressant drugs. It may be suggested that serotonin level might not be crucial for inducing the alterations in the content of Met-Enk. Since we did not observe any changes in the levels of PENK mRNA in the studied rat brain regions after repeated administration of TIA or FLU, it seems that the observed changes in the levels of Met-Enk do not result from effects of these antidepressants on biosynthesis of PENK, but rather from alterations in the peptide release. Another interesting finding of the present study was that in the anterior lobe of pituitary, adrenal glands and plasma, repeated administration of TIA induced alterations in the contents of Met-Enk, while repeated administration of FLU remained without any effect. It is tempting to speculate that such a differentiation between the effects of these two antidepressants might be linked to the well known feature of TIA (but not FLU) which has been shown to reduce both basal and stress-evoked activity of the hypothalamic-pituitary-adrenal (HPA) axis.

Effect of repeated treatment with tianeptine and fluoxetine on the central alpha(1)-adrenergic system.

Tianeptine (TIA) is an antidepressant drug which enhances the reuptake of serotonin but, in contrast to tricyclics, shows no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated TIA treatment induced adaptive changes in the alpha(1)-adrenergic system, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. TIA was administered at a dose of 5 or 10mg/kg once or repeatedly (twice daily for 14 days) and fluoxetine (FLU), used as a reference compound, at a dose of 10mg/kg. The obtained results showed that TIA administered repeatedly potentiated the methoxamine- and phenylephrine (PHEN)-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, the effects mediated by alpha(1)-adrenoceptors. TIA given repeatedly (but not acutely) increased the binding (B(max)) of alpha(1)-adrenergic receptors in cerebral cortex for [(3)H]prazosin. However, the ability of the alpha(1)-adrenoceptor agonist PHEN to compete for these sites was not significantly changed. The above results indicate that repeated TIA administration increases the responsiveness of the alpha(1)-adrenergic system (behavioural and biochemical changes). On the other hand, FLU did not affect any behavioural and biochemical changes in this system.

Some behavioural effects of antidepressant drugs are time-dependent.

1. The effects of repeated administration of antidepressant drugs (imipramine, IMI and citalopram, CIT) on the beta- and alpha2-adrenergic as well as dopaminergic D3 receptors were compared with time-dependent changes in the receptor responsiveness after acute treatment. 2. Repeated treatment with IMI or CIT (administered at a dose of 10 mg/kg p.o. twice a day for 14 days) induced down-regulation of beta-adrenergic receptors, demonstrated by behavioural experiment using salbutamol-induced hypoactivity and by binding studies using [3H]CGP12177. The changes in alpha2-adrenergic receptors were studied using clonidine-induced hypoactivity, which was attenuated by repeated treatment with IMI or CIT. Behavioural responsiveness of dopamine D3 receptors was investigated using two doses of 7-OH-DPAT. This drug at a dose of 0.05 mg/kg s.c. induced locomotor hypoactivity (interpreted as a result of stimulation of presynaptic dopamine D3 receptors), which was reversed by repeated administration of IMI or CIT, while 7-OH-DPAT at a dose of 3 mg/kg s.c. (which stimulated postsynaptic dopamine D3 receptors) induced significant hyperactivity, which was markedly enhanced by repeated administration of antidepressant drugs. 3. The effect of acute administration of IMI or CIT measured 14 days after drug treatment were similar to the described above alterations at the level of alpha2 adrenoreceptors and presynaptic dopamine D3 receptors, i.e. the drugs attenuated clonidine-induced hypoactivity and reversed locomotor hypoactivity evoked by low dose of 7-OH-DPAT. To induce the down-regulation of beta-adrenergic receptors or up-regulation of the behavioural responsiveness of dopaminergic D3 postsynaptic receptors, the repeated administration of IMI or CIT was necessary. 4. Therefore it has been concluded that presynaptic dopaminergic D3 and alpha2-adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 and beta-adrenergic receptors.

Repeated imipramine treatment enhances the 7-OH-DPAT-induced hyperactivity in rats: the role of dopamine D2 and D3 receptors.

Previous studies have shown that antidepressant drugs with different pharmacological profiles, administered repeatedly, increase the locomotor hyperactivity induced by various dopaminomimetics, among others by (+/-)7-hydroxydipropylaminotetralin (7-OH-DPAT). Since, according to a recent study, this drug shows a high affinity for not only dopamine D3 but also dopamine D2 receptors, a question arises whether dopamine D3 receptors are involved in the increase in 7-OH-DPAT-elicited locomotor hyperactivity induced by repeated treatment with antidepressant drugs. The aim of the present study was to investigate the effect of imipramine (IMI), administered repeatedly, on the hyperactivity induced by 7-OH-DPAT, a dopamine D3 receptor-preferring agonist. Male Wistar rats were treated with IMI (10 mg/kg po) either acutely (single dose) or repeatedly (twice daily for 14 days). The locomotor hyperactivity induced by 7-OH-DPAT (3 mg/kg sc) was measured in photoresistor actometers. The influence of nafadotride (0.2 and 0.4 mg/kg ip), a dopamine D3-preferring antagonist or sulpiride (10 and 25 mg/kg ip), a dopamine D2/D3 antagonist, on the 7-OH-DPAT-induced locomotor hyperactivity was studied. Nafadotride (in both doses used) or sulpiride (in the higher dose only) reduced (by about 50%) the hyperactivity induced by 7-OH-DPAT. Combined treatment with nafadotride (0.2 mg/kg) and sulpiride (25 mg/kg) completely abolished the effect of 7-OH-DPAT. IMI administered repeatedly (but not acutely) enhanced the 7-OH-DPAT-induced hyperactivity. Neither nafadotride, 0.2 mg/kg (or sulpiride, 10 mg/kg), given alone nor combined treatment with both these substances changed the hyperactivity induced by repeated treatment with IMI and 7-OH-DPAT (given 2 h after the last dose of IMI). Joint treatment with nafadotride, 0.2 mg/kg, and sulpiride, 25 mg/kg, completely abolished the enhancing effect of repeated treatment with IMI and 7-OH-DPAT. The above results indicate that both types of dopamine receptors, D3 and D2, may play a substantial role in the mechanism of the 7-OH-DPAT-induced hyperactivity, as well as in the increase evoked by repeated treatment with IMI in rats.

Effect of repeated treatment with reboxetine on the central alpha1-adrenergic system.

The obtained results indicate that repeated administration of reboxetine (selective noradrenaline reuptake inhibitor, without any affinity for neurotransmitter receptors) increased the responsiveness of alpha1-adrenergic system (potentiating the methoxamine-induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice), as tricyclic antidepressants did. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.