Acute Stress Affects the Relaxin/Insulin-Like Family Peptide Receptor 3 mRNA Expression in Brain of Pubertal Male Wistar Rats.

The current literature suggests that relaxin-3/relaxin/insulin-like family peptide receptor 3 (RLN-3/RXFP-3) system is involved in the pathophysiology of affective disorders because the results of anatomical and pharmacological studies have shown that the RLN-3 signaling pathway plays a role in modulating the stress response, anxiety, arousal, depression-like behavior, and neuroendocrine homeostasis. The risk of developing mental illnesses in adulthood is increased by exposure to stress in early periods of life. The available data indicate that puberty is especially characterized by the development of the neural system and emotionality and is a "stress-sensitive" period. The presented study assessed the short-term changes in the expression of RLN-3 and RXFP-3 mRNA in the stress-dependent brain regions in male pubertal Wistar rats that had been subjected to acute stress. Three stressors were applied from 42 to 44 postnatal days (first day: a single forced swim; second day: stress on an elevated platform that was repeated three times; third day: restraint stress three times). Anxiety (open field, elevated plus maze test) and anhedonic-like behavior (sucrose preference test) were estimated during these tests. The corticosterone (CORT) levels and blood morphology were estimated. We found that the RXFP-3 mRNA expression decreased in the brainstem, whereas it increased in the hypothalamus 72 h after acute stress. These molecular changes were accompanied by the increased levels of CORT and anxiety-like behavior detected in the open field test that had been conducted earlier, that is, 24 h after the stress procedure. These findings shed new light on the neurochemical changes that are involved in the compensatory response to adverse events in pubertal male rats and support other data that suggest a regulatory interplay between the RLN-3 pathway and the hypothalamus-pituitary-adrenal axis activity in the mechanisms of anxiety-like behavior.

Tricyclic Antidepressants Modulate Stressed Mitochondria in Glioblastoma Multiforme Cells.

A common feature of solid tumors, including glioblastoma multiforme (GBM), is mitochondrial dysfunction. However, it is reported that the current standard of anti-GBM therapies may potentiate mitochondrial damage and, in effect, support the aggressive character of cancer. As mitochondria are implicated in the modulation of cellular drug sensitivity and chemoresistance mechanisms, activation-stressed mitochondria in GBM cells may represent a new target for anti-GBM therapy that is nontoxic for normal cells. METHODS: As mitochondria are possible targets for antidepressant drugs used as adjuvant therapy in patients with GBM, we examined their influence on mitochondrial volume and activity, reactive oxygen species level, extracellular lactate concentration, and p65 NF-κB gene expression in GBM cells. RESULTS: Our investigation showed, for the first time, that tricyclic antidepressants, imipramine and amitriptyline, partially reverse GBM abnormalities. CONCLUSION: In the light of reported studies, the mitochondrial disturbance observed in glioma cells is a dynamic process that can be reversed or silenced. Moreover, imipramine and amitriptyline are attractive cellular metabolic modulators and can potentially be used to restoring a proper function of mitochondria in GBM cells.

Medicinal Plant Materials in the Treatment of Anxiety Disorders: Neurobiological Aspects.

Context: Pathological anxiety, which affects approximately one-third of the world population, is an inadequate, irrational reaction of an organism to the environment and to a potential threat. Despite advancements in pharmacotherapy for anxiety disorders, further studies are still necessary to search for new substances possessing the desired anxiolytic effects, with as few unwanted effects as possible. Objective: This study intended to examine the characteristics of medicinal plant materials that exhibit anxiolytic properties, with a special emphasis on the mechanisms of action of their active ingredients on the systems involved in the pathophysiology of anxiety. Design: The research team performed a review of the literature, searching well-known online scientific databases, including PubMed, Google Scholar, Medline, ScienceDirect, and SpringerLink. The team searched for the newest research from various regions of the world. Setting: The study was done in the Medical University of Silesia (Katowice, Poland). Results: The medicinal plant materials presented in the current article undoubtedly influence the central nervous system. Our analysis showed that their mechanism of action is very complicated and appropriately still enigmatic. Among them, V officinalis represents the most thoroughly investigated medicinal plant material that produces anxiolytic, sedative effects. However, extracts of other medicinal plants may also emerge as helpful in the treatment of fear and anxiety and in the prophylaxis of those disorders. Conclusions: The current review discusses the most recent data on medicinal plant materials that are effective as anxiolytic treatments, with special emphasis on the neurobiological mechanisms of action of their active ingredients. The research team hopes that the information may open up new directions in the search for drugs capable of enhancing the existing therapy.

Long-term treatment with haloperidol affects neuropeptide S and NPSR mRNA levels in the rat brain.

OBJECTIVE: The brainstem-derived neuropeptide S (NPS) has a multidirectional regulatory activity, especially as a potent anxiolytic factor. Accumulating data suggests that neuroleptics affect peptidergic signalling in various brain structures. However, there is no information regarding the influence of haloperidol on NPS and NPS receptor (NPSR) expression. METHODS: We assessed NPS and NPSR mRNA levels in brains of rats treated with haloperidol using quantitative real-time polymerase chain reaction. RESULTS: Chronic haloperidol treatment (4 weeks) led to a striking upregulation of NPS and NPSR expression in the rat brainstem. Conversely, the NPSR mRNA expression was decreased in the hippocampus and striatum. CONCLUSIONS: This stark increase of NPS in response to haloperidol treatment supports the hypothesis that this neuropeptide is involved in the dopamine-dependent anxiolytic actions of neuroleptics and possibly also in the pathophysiology of mental disorders. Furthermore, our findings underline the complex nature of potential interactions between dopamine receptors and brain peptidergic pathways, which has potential clinical applications.

Neuropeptides as regulators of the hypothalamus-pituitary-gonadal (HPG) axis activity and their putative roles in stress-induced fertility disorders.

Neuropeptides being regulators of the hypothalamus-pituitary-adrenal (HPA) axis activity, also affect the function of the hypothalamus-pituitary-gonadal (HPG) axis by regulating gonadotrophin-releasing hormone (GnRH) secretion from hypothalamic neurons. Here, we review the available data on how neuropeptides affect HPG axis activity directly or indirectly via their influence on the HPA axis. The putative role of neuropeptides in stress-induced infertility, such as polycystic ovary syndrome, is also described. This review discusses both well-known neuropeptides (i.e., kisspeptin, Kp; oxytocin, OT; arginine-vasopressin, AVP) and more recently discovered peptides (i.e., relaxin-3, RLN-3; nesfatin-1, NEFA; phoenixin, PNX; spexin, SPX). For the first time, we present an up-to-date review of all published data regarding interactions between the aforementioned neuropeptide systems. The reviewed literature suggest new pathophysiological mechanisms leading to fertility disturbances that are induced by stress.

Chronic treatment with escitalopram and venlafaxine affects the neuropeptide S pathway differently in adult Wistar rats exposed to maternal separation.

Neuropeptide S (NPS), which is a peptide that is involved in the regulation of the stress response, seems to be relevant to the mechanism of action of antidepressants that have anxiolytic properties. However, to date, there have been no reports regarding the effect of long-term treatment with escitalopram or venlafaxine on the NPS system under stress conditions. This study aimed to investigate the effects of the above-mentioned antidepressants on the NPS system in adult male Wistar rats that were exposed to neonatal maternal separation (MS). Animals were exposed to MS for 360 min. on postnatal days (PNDs) 2-15. MS causes long-lasting behavioral, endocrine and neurochemical consequences that mimic anxiety- and depression-related features. MS and non-stressed rats were given escitalopram or venlafaxine (10mg/kg) IP from PND 69 to 89. The NPS system was analyzed in the brainstem, hypothalamus, amygdala and anterior olfactory nucleus using quantitative RT-PCR and immunohistochemical methods. The NPS system was vulnerable to MS in the brainstem and amygdala. In the brainstem, escitalopram down-regulated NPS and NPS mRNA in the MS rats and induced a tendency to reduce the number of NPS-positive cells in the peri-locus coeruleus. In the MS rats, venlafaxine insignificantly decreased the NPSR mRNA levels in the amygdala and a number of NPSR cells in the basolateral amygdala, and increased the NPS mRNA levels in the hypothalamus. Our data show that the studied antidepressants affect the NPS system differently and preliminarily suggest that the NPS system might partially mediate the pharmacological effects that are induced by these drugs.

Escitalopram alters the hypothalamic OX system but does not affect its up-regulation induced by early-life stress in adult rats.

We hypothesized that there is a relationship between the orexinergic system (OX) alterations and changes elicited by escitalopram or venlafaxine in adult rats subjected to maternal separation (MS). This animal model of childhood adversity induces long-lasting consequences in adult physiology and behavior. Male Wistar rats from the control and MS groups were injected with escitalopram or venlafaxine (10 mg/kg) IP from postnatal day (PND) 69-89. Adult rats were subjected to behavioral assessment, estimation of hypothalamic-pituitary-adrenal (HPA) axis activity and analysis of the OX system (quantitative PCR and immunohistochemistry) in the hypothalamus and amygdala. MS caused anxiety- and depressive-like behavior, endocrine stress-related response, and up-regulation of the OX system in the hypothalamus. Escitalopram, but not venlafaxine, increased the activity of hypothalamic OX system in the control rats and both drugs had no effect on OXs in the MS group. The disturbed signaling of the OX pathway may be significant for harmful long-term consequences of early-life stress. Our data show that the normal brain and brain altered by MS respond differently to escitalopram. Presumably, anti-anxiety and antidepressant effects of this drug do not depend on the activity of hypothalamic OX system.

Are neuropeptides relevant for the mechanism of action of SSRIs?

Selective serotonin reuptake inhibitors (SSRIs) are drugs of first choice in the therapy of moderate to severe depression and anxiety disorders. Their primary mechanism of action is via influence of the serotonergic (5-HT) system, but a growing amount of data provides evidence for other non-monoaminergic players in SSRI effects. It is assumed that neuropeptides, which play a role as neuromodulators in the CNS, are involved in their mechanism of action. In this review we focus on six neuropeptides: corticotropin-releasing factor - CRF, galanin - GAL, oxytocin - OT, vasopressin - AVP, neuropeptide Y - NPY, and orexins - OXs. First, information about their roles in depression and anxiety disorders are presented. Then, findings describing their interactions with the 5-HT system are summarized. These data provide background for analysis of the results of published preclinical and clinical studies related to SSRI effects on the neuropeptide systems. We also report findings showing how modulation of neuropeptide transmission influences behavioral and neurochemical effects of SSRIs. Finally, future research necessary for enriching our knowledge of SSRI mechanisms of action is proposed. Recognition of new molecular targets for antidepressants will have a significant effect on the development of novel therapeutic strategies for mood-related disorders.

Imipramine and Venlafaxine Differentially Affect Primary Glial Cultures of Prenatally Stressed Rats.

Here, we examine the effects of prenatal administration of two antidepressants-imipramine (IMI) and venlafaxine (VEN)-on morphology and activity of a primary glial culture. Microglia are targeted by antidepressants used for antenatal depression and are important regulators of central nervous system development. In this study, female Wistar rats were assigned to one of four groups: a control group that received water ad libitum (1), and groups that received additionally once daily either water (2), IMI (10 mg/kg) (3), or VEN (20 mg/kg) (4) by oral gavage from gestation day 7 to 22. Oral gavage administration induced prenatal stress. Cell cultures were obtained from the brains of 1-day-old pups. Prenatal stress caused a disturbance of sensorimotor function in pups. Prenatal stress also produced alterations in the glial cultures, specifically, an increased percentage of microglia in the mixed glial cultures and an increased percentage of dead cells. Moreover, increased levels of IL1-ß, TNF-α, NO, and an increased expression of CX3CR1 mRNA were found in microglia. However, the ratio of Bax/Bcl2 mRNA was reduced. Prenatal stress increased the vulnerability of microglia to lipopolysaccharide (LPS). The mixed glial culture derived from pups exposed to IMI showed greater morphological changes and the highest percentage of microglia. Microglia were characterized by the largest increase in the production of pro-inflammatory cytokines and NO, and the greatest reduction in the expression of CX3CR1 mRNA. Exposure to IMI reduced the effects of LPS on IL-1ß production and Bax/Bcl2 mRNA, and exacerbated the effects of LPS on CX3CR1 mRNA expression. Prenatal administration of VEN induced protective effects on microglia, as measured by all studied parameters. Taken together, our data suggest that, by disturbing microglia function, exposure to even mild forms of chronic prenatal stress may predispose individuals to psychiatric or neurodevelopmental disorders. These data also indicate that chronic mild stress sensitizes microglia to immune challenges, which may lead to enhanced neuronal damage in the embryonic brain. The observed detrimental effects of IMI on microglial activity under conditions of prenatal stress may help to explain the teratogenic effects of IMI reported in the literature.