Exposure to chronic stress impairs the ability to cope with an acute challenge: Modulation by lurasidone treatment.

Chronic stress represents a major contributor for the development of mental illness. This study aimed to investigate how animals exposed to chronic mild stress (CMS) responded to an acute stress (AS), as a vulnerability's challenge, and to establish the potential effects of the antipsychotic drug lurasidone on such mechanisms. Adult male Wistar rats were exposed or not (controls) to a CMS paradigm for 7 weeks. Starting from the end of week 2, animals were randomized to receive vehicle or lurasidone for 5 weeks. Sucrose intake was used to measure anhedonia. At the end, half of the animals were exposed to an acute stress before sacrifice. Exposure to CMS produced a significant reduction in sucrose consumption, whereas lurasidone progressively normalized such alteration. We found that exposure to AS produced an upregulation of Brain derived neurotrophic factor (Bdnf) in the prefrontal cortex of controls animals. This response was impaired in CMS rats and restored by lurasidone treatment. While in control animals, AS-induced increase of Bdnf mRNA levels was specific for Parvalbumin cells, CMS rats treated with lurasidone show a significant upregulation of Bdnf in pyramidal cells. Furthermore, when investigating the activation of different brain regions, CMS rats showed an impairment in the global response to the acute stressor, that was largely restored by lurasidone treatment. Our results suggest that lurasidone treatment in CMS rats may regulate specific circuits and mechanisms, which will ultimately contribute to boost resilience under stressful challenges.

Basal prolactin levels in rat plasma correlates with response to antidepressant treatment in animal model of depression.

Prolactin (PRL) has been shown to be altered by psychotropic drugs, including antidepressant drugs (ADs). Many studies have focused on the response to antidepressant treatment (especially related to the serotonergic system) using the fenfluramine test (PRF), however some data suggest lack of correlation between PRF and prediction of clinical response to ADs. In our study we have investigated the hypothesis that basal plasma level of prolactin is a better predictor of antidepressant treatment. We have used Chronic Mild Stress (CMS) - the animal model of depression. Rats are exposed to CMS in combination with imipramine (IMI) treatment for 5 consecutive weeks. Blood samples were collected from the rat tail vein three times: before the CMS procedure, after 2 weeks of stress and after the complete CMS procedure (after 5 weeks of stress and IMI treatment). The PRL level in plasma was determined using the commercially available ELISA kit. In CMS, anhedonia in rats is manifested by reduced consumption of sucrose solution while administration of antidepressant drugs reverses anhedonia. Some animals (ca.30%) did not respond to antidepressant therapy and were considered treatment-resistant. There was no correlation between basal PRL levels and stress response, however, from the results obtained by Spearman Rank Correlation analysis we have observed a significant negative correlation between basal PRL levels before the CMS procedure and behavioral response to IMI administration. The obtained results indicate that the basal PRL level in rat plasma correlates with a good response to treatment in the animal model of depression.

Qualitative and quantitative changes in phospholipids and proteins investigated by spectroscopic techniques in animal depression model.

Depression becomes nowadays a high mortality civilization disease with one of the major causes being chronic stress. Raman, Fourier Transform Infra Red (FTIR) and Ultraviolet-Visible (UV-vis) spectroscopies were used to determine the changes in the quantity and structure of phospholipids and proteins in the blood serum of rats subjected to chronic mild stress, which is a common animal depression model. Moreover, the efficiency of the imipramine treatment was evaluated. It was found that chronic mild stress not only damages the structure of the phospholipids and proteins, but also decreases their level in the blood serum. A 5weeks imipramine treatment did increase slightly the quantity of proteins, leaving the damaged phospholipids unchanged. Structural information from phospholipids and proteins was obtained by UV-vis spectroscopy combined with the second derivative of the FTIR spectra. Indeed, the structure of proteins in blood serum of stressed rats was normalized after imipramine therapy, while the impaired structure of phospholipids remained unaffected. These findings strongly suggest that the depression factor, which is chronic mild stress, may induce permanent (irreversible) damages into the phospholipid structure identified as shortened carbon chains. This study shows a possible new application of spectroscopic techniques in the diagnosis and therapy monitoring of depression.

Chronic mild stress alters the somatostatin receptors in the rat brain.

RATIONALE: The involvement of somatostatin (SST) and its receptors in the pathophysiology of depression and stress has been evidenced by numerous studies. OBJECTIVES: The purpose of the present study was to find whether chronic mild stress (CMS), an animal model of depression, affects the SST receptors in the rat brain and pituitary, as well as the level of SST in plasma. METHODS: In CMS model, rats were subjected to 2 weeks of stress and behaviorally characterized using the sucrose consumption test into differently reacting groups based on their response to stress, i.e., stress-reactive (anhedonic), stress-non-reactive (resilient), and invert-reactive rats (characterized by excessive sucrose intake). We measured specific binding of [125I]Tyr3-Octreotide, expression of mRNA encoding sst2R receptors in the rat brains, expression of SST and its receptors in rat pituitary, and the level of SST in the plasma. RESULTS: The obtained results show decreases in binding of [125I]Tyr3-Octreotide in most of rat brain regions upon CMS and no significant differences between three stressed groups of animals, except for significant up-regulation of sst2 receptor in medial habenula (MHb) in the stress-reactive group. In the same group of animals, significant increase in plasma SST level was observed. CONCLUSIONS: There are two particularly sensitive sites distinguishing the response to stress in CMS model. In the brain, it is MHb, while on the periphery this predictor is SST level in plasma. These changes may broaden an understanding of the mechanisms involved in the stress response and point to the intriguing role of MHb.

Prolactin and its receptors in the chronic mild stress rat model of depression.

Prolactin (PRL) exhibits many physiological functions with wide effects on the central nervous system including stress responses. Our study aimed to investigate the effect of chronic unpredictable mild stress (CMS) - which is a good animal model of depression - on PRL receptor (PRLR) expression in the rat brain. Rats were exposed to CMS for two weeks and subsequently to CMS in combination with imipramine (IMI) treatment for five consecutive weeks. Behavioral deficit measured in anhedonic animals is a reduced intake of sucrose solution. Two weeks of CMS procedure allowed the selection of animals reactive to stress and displaying anhedonia, and the group which is considered as stress-non-reactive as far as behavioral measures are concerned. In this group the elevated level of PRL in plasma was observed, decrease in dopamine release in the hypothalamus, increase in [(125)I]PRL binding to PRLR in the choroid plexus, increase of mRNA encoding the long form of PRLR in the arcuate nucleus and the decrease of mRNA encoding its short form, and decrease in the mRNA encoding dopamine D2 receptor. All these alterations indicate these parameters as involved in the phenomenon of stress-resilience. The prolongation of the CMS procedure for additional five weeks shows the form of habituation to the stressful conditions. The most interesting result, however, was the up-regulation of PRLR in the choroid plexus of rats subjected to full CMS procedure combined with treatment with IMI, which may speak in favor of the role of this receptor in the mechanisms of antidepressant action.

The reversal of cognitive, but not negative or positive symptoms of schizophrenia, by the mGlu2/3 receptor agonist, LY379268, is 5-HT1A dependent.

mGlu(2/3) receptor agonists were shown to possess an antipsychotic-like potential in animal studies. Recent clinical investigations revealed that their antipsychotic potential might also manifest in humans. LY379268, the group II mGlu receptor orthosteric agonist, was previously shown to exhibit antipsychotic-like action in animal models of schizophrenia. However, the mechanism of its action is not fully recognized. Here, we decided to investigate the involvement of 5-HT1A receptors in the LY379268-induced antipsychotic effects. We used models of positive, negative and cognitive symptoms of schizophrenia, such as MK-801- and amphetamine-induced hyperactivity tests, DOI-induced head twitches, social interaction and novel object recognition. LY379268 was active in a wide range of doses (0.5-5 mg/kg), depending on the paradigm. The effects of the drug were not antagonized by 5-HT(1A) antagonist, WAY100635 (0.1 mg/kg) in the models of positive and negative symptoms. Conversely, in the novel object recognition test, which exerts cognitive disturbances, the action of LY379268 was antagonized by WAY100635. Concomitantly, the action of a sub-effective dose of the drug was enhanced by the administration of a sub-effective dose of 5-HT(1A) agonist, (R)-(+)-8-Hydroxy-DPAT. Altogether, we propose that the antipsychotic-like action of group II mGlu receptors' agonist is 5-HT(1A) independent in context of positive and negative symptoms, while the action toward cognitive disturbances seems to be 5-HT(1A) dependent.

R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model.

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-(+)-citalopram (escitalopram) and R-(-)-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day), R-citalopram (7.8 mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day). R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).

Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression.

The aim of our study was to investigate the level of metabotropic glutamate receptors (mGluRs) in the brains of rats after chronic mild stress. Using Western blotting procedure we showed that the level of mGluR5 receptor protein was increased in CA1 and decreased in CA3 region of the hippocampus. Our results indicate that mGluR5 can possibly be engaged in the mechanism of depression.

Luminol-chemiluminescence in free peritoneal cells in hemorrhagic shock in rats treated with PAF-receptor-antagonist BN 52021.

The activity of rat peritoneal cells were assessed by the phorbol mirystinian acetate (PMA)-induced luminol chemiluminescence (LCL). Results in control groups (0 - no manipulation, and I - carotid artery cannulation) were compared with those in the untreated hemorrhagic shock (group II), in the shock treated with the standard polyelectrolyte solution (PES) (group III), and in shock treated with PAF receptor-antagonist BN 52021 + PES (group IV). The maximal and the most rapid LCL was observed in the group treated with BN 52021 (group IV), while chemiluminescent response in the the untreated shock (group II) and in shock treated with PES was minimally expressed and late. The findings indicate for a rapid activation of peritoneal cells during ca 1 hour of hemorrhagic shock. This leads to exhausting their ability to the superoxide anion generation 15 minutes later. Peritoneal cells obtained from the group treated with the BN 52021 revealed a preserved ability to the respiratory burst. It can be concluded that BN 52021 effectively inhibits activation of the PC during hemorrhagic shock.