Selected neuroendocrine factors as potential molecular biomarkers of early non-affective psychosis course in relation to treatment outcome: A pilot study.

The aim of this pilot study was to find whether the dysregulation of neuroendocrine biomarker signaling pathways in the first episode of non-affective psychosis is a predictive factor of treatment outcome. Patients with the first episode of non-affective psychosis (N = 29) were examined at admission, at discharge, and at follow-up (N = 23). The biomarkers included serum aldosterone, cortisol, free thyroxine, thyroid stimulating hormone, and prolactin. We revealed lower baseline aldosterone and higher baseline cortisol concentrations in patients with very good outcome compared to those with good outcome after one year. We failed to reveal any significant association between treatment outcome and neurohumoral biomarkers in the whole sample at 1-year follow-up. However, baseline aldosterone concentrations negatively correlated with total PANSS scores at the discharge. Lower baseline aldosterone and higher baseline cortisol concentrations have the potential to predict a more favorable outcome for patients with the first episode of psychosis.

Bridging the mood and stress hormone levels between mothers and their babies: The study design and first preliminary results.

The neurobiological mechanisms involved in the influence of post-partum maternal mood fluctuations on child development are far from being understood. Here we present the design of an ongoing study aimed to test the hypothesis that the mental state of the mother has an impact on her neonate which is manifested by similarities in the neuroendocrine function of the mother and the child. The hypothesis is being tested under both stress and non-stress conditions in mothers and babies aged 3-4 days and 7-9 months. The focus will be given to correlations with maternal postpartum mood. To confirm the correctness of methodological approaches and the feasibility of the study several preliminary analyses were performed. Salivary alpha-amylase activity as a marker of sympathetic activation and cortisol as the effective hormone of the hypothalamic-pituitary-adrenocortical axis were measured. The obtained results showed the feasibility of saliva sampling in neonates using a sampling time of 120 s. The analysis of cortisol in hair revealed increased concentrations during the third trimester of pregnancy, which is consistent with the knowledge of high cortisol concentrations during pregnancy. A positive correlation was observed between salivary cortisol values before and after the stress test in mother-infant dyads at both the post-partum period and 7-9 months thereafter. Understanding the mechanisms involved in "the bridge" between the mother and her baby will help to develop necessary interventions directed to help mothers in the early postpartum period.

Altered responsiveness to glutamatergic modulation by MK-801 and to repeated stress of immune challenge in female dopamine transporter knockout rats.

Chronic stress is a key factor in psychiatric and neurological disorders often worsening disease symptoms. In this study, a unique animal model, the dopamine transporter knockout (DAT-KO) rat exhibiting behavioral signs resembling those occurring in mania, schizophrenia, attention deficit hyperactivity disorder, and obsessive-compulsive disorder was used. We have tested the hypothesis that the hyperdopaminergic state in DAT-KO rats (i) modulates behavioral response to the NMDA antagonist MK-801 (dizocilpine) and (ii) leads to abnormal endocrine and immune activation under subchronic stress induced by an immune challenge. Glutamatergic modulation with MK-801 induced a different behavioral pattern. While the WT rats responded to MK-801 injection with a robust rise in their locomotor activity, the hyperactive DAT-KO rats exhibited reduced locomotion. Signs of chronic stress including increased basal corticosterone and aldosterone but blunted anxiety were demonstrated in rats lacking the DAT. Repeated injections of increasing doses of lipopolysaccharide (LPS, 5 days) did not modify plasma prolactin concentrations which were however significantly lower in DAT-KO than in WT rats. Concentrations of plasma high mobility group box 1 (HMGB1) protein were significantly higher in LPS-treated DAT-KO than in WT rats. The gene expression of interleukin-6 in the anterior pituitary increased under the stress induced by the immune challenge in the WT but not the DAT-KO rats. The most evident differences between the genotypes were revealed in the spleen. The splenic gene expression of interleukin-1ß, interleukin-6, and HMGB1 was lower and that of ferritin was higher in DAT-KO compared to WT rats. Obtained results emphasize the functional interaction of the endocrine and immune systems with monoamine and glutamatergic neurotransmission in the mechanisms leading to behavioral alterations and psychiatric disorders associated with dopamine dysfunction.

Role of miR-124-3p in regulatory mechanisms of Gpm6a expression in the hippocampus of chronically stressed rats.

The neuronal membrane glycoprotein M6a (GPM6A) belongs to the family of myelin proteolipid protein and plays a role in neuronal remodeling and plasticity. Decreased expression of GPM6A mRNA is observed in the hippocampal tissue of suicide victims who suffered from depression and after chronic stress exposure in animals. The regulatory mechanisms that impact expression of GPM6A under chronic stress or in pathological conditions are not well understood. Previously, miRNAs miR-133b, miR-124-3p, and miR-9-5p have been shown to regulate the expression of Gpm6a mRNA under normal conditions. Here, we employed the paradigm of chronic-restraint stress in rats and using quantitative polymerase chain reaction (qPCR) showed down-regulation of expression of Gpm6a and the brain-derived neurotrophic factor (Bdnf) genes at mRNA level as well as miR-133b, and miR-124-3p, but not miR-9-5p in the hippocampus of chronically stressed rats. Furthermore, we observed alterations in the expression of histone deacetylase (Hdac5) and myocyte enhancer factor 2C (Mef2c) mRNAs. Our data suggest that chronic stress influences Gpm6a expression by miR-124-mediated impact on the expression of Hdac5 and Mef2c. Upon miR-124 over-expression in hippocampal neurons cultured in vitro, we observed enhanced neuronal arborization as evaluated by Sholl analysis, increased Gpm6a and Mef2c expression, and decreased Hdac5 expression. Moreover, treatment of hippocampal neurons cultured in vitro with BDNF resulted in an elevation in the miR-124-3p expression, a decrease in the miR-9-5p expression but did not affect miR-133b. This was accompanied by augmented expression of Gpm6a and Mef2c mRNAs and significantly lower levels of Hdac5 mRNA. Altogether, these results indicate that the regulatory mechanism that influence expression of Gpm6a under chronic stress involves miR-124-mediated impact on the expression of Hdac5 and Mef2c and a role of BDNF in the activation of Gpm6a expression.

Association of HTTLPR, BDNF, and FTO Genetic Variants with Completed Suicide in Slovakia.

Since suicide and suicidal behavior are considered highly heritable phenotypes, the identification of genetic markers that can predict suicide risk is a clinically important topic. Several genes studied for possible associations between genetic polymorphisms and suicidal behaviors had mostly inconsistent and contradictory findings. The aim of this case-control study was to evaluate the associations between completed suicide and polymorphisms in genes BDNF (rs6265, rs962369), SLC6A4 (5-HTTLPR), and FTO (rs9939609) in relation to sex and BMI. We genotyped 119 completed suicide victims and 137 control subjects that were age, sex, and ethnicity matched. A significant association with completed suicide was found for BDNF rs962369. This variant could play a role in completed suicide, as individuals with the CC genotype were more often found among suicides than in control subjects. After sex stratification, the association remained significant only in males. A nominally significant association between the gene variant and BMI was observed for BDNF rs962369 under the overdominant model. Heterozygotes with the TC genotype showed a lower average BMI than homozygotes with TT or CC genotypes. FTO polymorphism (rs9939609) did not affect BMI in the group of Slovak suicide completers, but our findings follow an inverse association between BMI and completed suicide.

Analysis of Motives and Factors Connected to Suicidal Behavior in Patients Hospitalized in a Psychiatric Department.

(1) Background: This study aimed to investigate the motives and factors connected to suicidal behavior in 121 hospitalized patients with intentional self-harm (diagnosis X 60-81 according to the ICD-10); (2) Methods: Suicidal behavior of the patient was assessed from data obtained by psychiatric examinations and by the Columbia Suicide Severity Rating Scale. Analysis of data to identify the patients' reason and motives behind suicidal behavior in a group of patients with a suicide attempt (SA, n = 80) and patients with Non-Suicidal Self-Injurious Behavior (NSSIB, n = 41) was carried out; (3) Results: Results showed that patients with affective disorder have a 19-times higher rate of SA against other diagnoses. Patients with personality disorders have a 32-times higher rate of NSSIB than patients with other diagnoses. Living alone and the absence of social support increased the likelihood of SA. Qualitative data analysis of patients' statements showed different themes in the justification of motives for suicidal behavior between SA and NSSIB cases. Significant differences were shown for non-communicated reasons, loneliness, social problems, extortion, and distress; (4) Conclusions: The evaluation of patients' verbal statements by qualitative analysis during the psychiatric examination should be considered in clinical practice. It should be considered to include self-poisoning in the criteria of the Non-suicidal Self-Injury diagnostic categories.

Psychotropic Drug Effects on Steroid Stress Hormone Release and Possible Mechanisms Involved.

There is no doubt that chronic stress accompanied by adrenocortical stress hormone release affects the development and treatment outcome of several mental disorders. Less attention has been paid to the effects of psychotropic drugs on adrenocortical steroids, particularly in clinical studies. This review focuses on the knowledge related to the possible modulation of cortisol and aldosterone secretion under non-stress and stress conditions by antipsychotic drugs, which are being used in the treatment of several psychotic and affective disorders. The molecular mechanisms by which antipsychotic drugs may influence steroid stress hormones include the modulation of central and/or adrenocortical dopamine and serotonin receptors, modulation of inflammatory cytokines, influence on regulatory mechanisms in the central part of the hypothalamic-pituitary axis, inhibition of corticotropin-releasing hormone gene promoters, influencing glucocorticoid receptor-mediated gene transcription, indirect effects via prolactin release, alteration of signaling pathways of glucocorticoid and mineralocorticoid actions. Clinical studies performed in healthy subjects, patients with psychosis, and patients with bipolar disorder suggest that single and repeated antipsychotic treatments either reduce cortisol concentrations or do not affect its secretion. A single and potentially long-term treatment with dopamine receptor antagonists, including antipsychotics, has a stimulatory action on aldosterone release.

Steroid stress hormone changes throughout the menstrual cycle: A rise in evening aldosterone concentration in early luteal phase precedes the symptoms of premenstrual syndrome.

There is still a lack of consistent evidence on dysregulation of steroid stress hormones cortisol and aldosterone in premenstrual syndrome (PMS). We aimed to test the hypothesis that, in healthy women, salivary aldosterone concentrations are higher in those with PMS compared to controls, particularly during the luteal phase of the menstrual cycle. In total, 99 female subjects (49 women with and 50 women without PMS) participated in a prospective non-interventional case-control study. Saliva sampling was performed in the follicular (day 8), early luteal (day 20) and late luteal phase (2 days before expected onset of bleeding) of the menstrual cycle in the morning and the evening. The results confirmed the hypothesis that salivary aldosterone concentrations are higher in women with PMS during the early luteal phase compared to controls (p < .01) in the evening. Early luteal phase aldosterone concentrations positively correlated with the frequency of premenstrual symptoms. Women with PMS exhibited a flatter morning to evening aldosterone slope compared to controls (p < .05). Morning and evening salivary cortisol concentrations were unchanged throughout the menstrual cycle in both groups of women. In conclusion, evening salivary aldosterone, but not cortisol concentrations, are increased in women with PMS during the early luteal phase compared to controls. Cortisol does not appear to be involved in the mechanisms contributing to the course of PMS. High evening salivary aldosterone in the early luteal phase may represent an important risk factor and could be of predictive value for the occurrence of premenstrual symptoms.

Tight junction proteins in the small intestine and prefrontal cortex of female rats exposed to stress of chronic isolation starting early in life.

BACKGROUND: Simultaneous evaluation of barrier protein expression in the gut and the brain and their modulation under stress conditions have not been studied before now. As the permeability and function of the gut and blood-brain barrier are different and both express the MRs, we hypothesized that stress of post-weaning social isolation induces changes in tight junction protein expression in the gut which are (1) independent of changes in the brain and (2) are mediated via the mineralocorticoid receptor (MR). METHODS: First, using UPLC-MS/MS we have successfully validated and selected a dose (1.2 mg/rat/day) of the MR antagonist spironolactone to treat female rats exposed to stress of chronic isolation or control conditions from postnatal day 21 for 9 weeks. KEY RESULTS: Isolation stress caused an enhancement of gene expression of occludin and ZO-1 and a decrease in claudin-5 and MR expression in both the small intestine and prefrontal cortex. Isolation stress failed to decrease claudin-5 (small intestine) and MR (prefrontal cortex) gene expression in spironolactone-treated rats. MR blockade resulted in a decrease in claudin-15 expression in the small intestine. Anxiogenic effect of chronic stress, measured in elevated plus-maze test, was partly prevented by spironolactone treatment. CONCLUSIONS & INFERENCES: Claudins, the main regulators of intestinal barrier permeability responded to chronic stress of social isolation and/or simultaneous blockade of MR in female rats by alterations independent of changes in the brain cortex. The results suggest a physiological role of MR in the control of claudin expression in the small intestine, but not in the brain cortex.

Lipid Profile, Lipoprotein Subfractions, and Fluidity of Membranes in Children and Adolescents with Depressive Disorder: Effect of Omega-3 Fatty Acids in a Double-Blind Randomized Controlled Study.

Depressive disorder (DD) is a psychiatric disorder whose molecular basis is not fully understood. It is assumed that reduced consumption of fish and omega-3 fatty acids (FA) is associated with DD. Other lipids such as total cholesterol (TCH), LDL-, and HDL-cholesterols (LDL-CH, HDL-CH) also play a role in depression. The primary endpoint of the study was the effect of omega-3 FA on the severity of depression in children and adolescents. This study aimed to investigate the secondary endpoint, relationship between depressive disorder symptoms and lipid profile, LDL- and HDL-cholesterol subfractions, Paraoxonase 1 (PON1) activities, and erythrocyte membrane fluidity in 58 depressed children and adolescents (calculated by the statistical program on the effect size), as well as the effect of omega-3 FA on the monitored parameters. Depressive symptoms were assessed by the Children's Depression Inventory (CDI), lipid profile by standard biochemical procedures, and LDL- and HDL-subfractions by the Lipoprint system. Basic biochemical parameters including lipid profile were compared with levels in 20 healthy children and were in the physiological range. Improvement of symptoms in the group supplemented with a fish oil emulsion rich in omega-3 FA in contrast to omega-6 FA (emulsion of sunflower oil) has been observed. We are the first to report that omega-3 FAs, but not omega-6 FA, increase large HDL subfractions (anti-atherogenic) after 12 weeks of supplementation and decrease small HDL subfractions (proatherogenic) in depressed children. We found a negative correlation between CDI score and HDL-CH and the large HDL subfraction, but not LDL-CH subfractions. CDI score was not associated with erythrocyte membrane fluidity. Our results suggest that HDL-CH and its subfractions, but not LDL-CH may play a role in the pathophysiology of depressive disorder. The study was registered under ISRCTN81655012.

Dopamine concentrations and dopamine receptor gene expression in emotion-related brain structures of female adult rats exposed to stress of chronic isolation from weaning.

It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral tegmental area (VTA), which contains neuron cell bodies of the mesolimbic dopaminergic system. The aim of this study is to test the hypothesis that stress induced by long-term social isolation from weaning in female rats is associated with alterations in amygdalar dopamine receptor gene expression and VTA dopamine concentrations. Rats were weaned on postnatal day 21 and then exposed to stress of chronic isolation for 9 weeks. Control animals were housed socially. Amygdalar dopamine D1 but not D2 receptor gene expression was decreased in isolated rats compared to controls. Dopamine concentrations in the VTA were enhanced following chronic isolation. A negative correlation was observed between amygdalar D1 gene expression and dopamine concentrations in the VTA. In conclusion, a reduction of dopamine D1 receptor gene expression in the amygdala in response to stress induced by chronic isolation in female rats was accompanied by an increase in dopamine concentration in the VTA. Further studies are needed to understand the physiological significance, if any, of negative association of amygdalar dopamine receptor D1 gene expression and dopamine concentrations in the VTA.

Relationships between antenatal corticosteroids and catecholamine blood pressure support in neonates: considering of maternal stress-related diseases.

Healthy child development is under the influence of prenatal and perinatal exposure to stress stimuli. The aim of this study is to test the hypotheses that (1) neonates requiring catecholamine blood pressure support are more often born to mothers with stress-related cardiometabolic diseases, (2) maternal stress-related diseases are associated with more frequent requirement of maternal corticosteroid treatment and (3) antenatal steroid exposure of neonates reduces the need of postnatal catecholamine support. A retrospective cohort study was performed on a sample of 427 mature (13%), preterm (64%) and extremely preterm (23%) neonates of both sexes. Mothers at risk of preterm delivery were treated with dexamethasone. The blood pressure support in neonates was performed by intravenous treatment via umbilical or epicutaneous venous catheter with dopamine (5 ug/kg/min) or dobutamine (5 ug/kg/min) or a combination of both. The results showed a lack of association between maternal stress-related diseases and the complicated outcome of their neonates. Maternal treatment with corticosteroid dexamethasone was associated with lower frequency of catecholamine blood pressure support requirement. Catecholamine support was more needed in male infants. Thus, the occurrence of maternal cardiometabolic stress-related diseases does not appear to be related to the need of catecholamine support in the neonate. In agreement with the second hypothesis, a more frequent maternal corticosteroid treatment was associated with the presence of maternal stress-related diseases. Most importantly, the obtained results support the hypothesis on positive influence of maternal glucocorticoid administration on cardiovascular outcome of the neonate, representing an additional beneficial effect of antenatal corticosteroids. LAY SUMMARY Maternal hypertension, diabetes and obesity, which belong to cardiometabolic stress-related diseases, failed to show a negative influence on neonatal health as was determined by the need of catecholamine blood pressure support in a large sample of 427 immature and mature newborns. Since glucocorticoids are often viewed as negative agents that should be avoided, the important finding of the present study is the beneficial effect of maternal corticosteroid treatment on blood pressure stability of the neonate.

Lower activity of salivary alpha-amylase in youths with depression.

Measurement of basal and stress-induced salivary alpha-amylase activity may help to understand autonomic nervous system disturbance in mental disorders. The potential sympathetic nervous system dysregulation in children and adolescent psychopathologies is mostly unknown. The present study was aimed to test the hypothesis that salivary alpha-amylase activity is higher in youths diagnosed with depression than in healthy subjects considering a part of the daily rhythm of enzyme activity and its morning to midday slope. A total of 30 children aged 15 ± 0.46 years (15 patients with depression, 4 boys, 11 girls, and 15 sex- and age-matched healthy controls) participated in the study. Two saliva samples were collected from each subject to measure activity of alpha-amylase in the morning and midday. The results of the present study revealed that the midday but not morning alpha-amylase activity was lower in patients with depression than in healthy controls. The diurnal increase in enzyme activity present in healthy subjects was absent in patients. The children and adolescents with depression exhibited flatter morning to midday slopes of alpha-amylase activity. In conclusion, the present results indicate a disturbance of alpha-amylase daily rhythm in youths with depression and motivate further studies on the relationship between sympathetic activation and mood disorders.

Salivary Aldosterone, Cortisol, and Their Morning to Evening Slopes in Patients with Depressive Disorder and Healthy Subjects: Acute Episode and Follow-Up 6 Months after Reaching Remission.

BACKGROUND/OBJECTIVE: Cortisol is thought to be involved in the pathophysiology of affective disorders. Less attention has been given to other neuroendocrine factors. The aim of the present study was to test the hypothesis that adrenocortical steroids aldosterone and cortisol show different dynamic changes in the course of clinical depression with the assumption that aldosterone is a state marker of depression. METHODS: A total of 78 adult subjects (39 patients with depressive disorder and 39 healthy controls) participated in a prospective non-interventional clinical study. Patients were investigated at the time of an acute episode and 6 months after reaching remission. The clinical and personal characteristics, and morning and evening salivary concentrations of aldosterone and cortisol were evaluated. RESULTS: Patients with an acute depressive episode exhibited higher evening aldosterone and lower morning cortisol concentrations compared to healthy subjects. In these patients, both hormone concentrations showed flatter morning to evening slopes. Salivary aldosterone, but not cortisol concentrations, were lower in patients 6 months after reaching remission compared to those in the acute state. Similarly, 6 months of remission resulted in a steeper morning to evening slope of salivary aldosterone compared to the acute state. The cortisol rhythm remained dysregulated. A significant negative correlation between trait anxiety scores and morning cortisol concentrations in patients at 6 months of clinical remission was observed. CONCLUSION: Diurnal changes in salivary aldosterone concentrations appear to be a state marker, whilst those of cortisol a trait marker of depression.

Classical Steroids in a New Fashion: Focus on Testosterone and Aldosterone.

Several endocrine glands produce steroid hormones. Thanks to the work of chemists and biochemists, the main synthetic as well as metabolic pathways of steroid hormones were included in the textbooks more than 50 years ago and the classical endocrine gland functions were identified. Later on, evidence of steroid hormone effects beyond the classical endocrine gland function has been accumulating. Testosterone was shown to participate in the stress response and may influence coping with stressors. We have shown a decrease in testosterone concentrations in saliva in children undergoing a school exam compared to values on a non-exam school day. Testosterone has been associated with different cognitive functions in both adults and children. Circulating testosterone has been linked to negative symptoms of schizophrenia. Aldosterone is acting via mineralocorticoid receptors, which are thought to be fully occupied by glucocorticoids in the brain. Until now, an action of aldosterone in the brain has not been considered at all, because the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, which would enable aldosterone to bind to receptors is absent in most of the brain areas. We have brought evidence that aldosterone can act in the brain and produce anxiogenic and depressogenic effects. To facilitate the translation of animal findings into clinical research, we have developed methodology for measurement of salivary aldosterone and obtained first data on a relationship between salivary aldosterone and trait anxiety. We have shown that salivary aldosterone concentrations reflect treatment outcome in patients with major depressive disorder.

Post-weaning social isolation of rats induces reduction in the gene expression of vascular endothelial growth factor (VEGF) in the hippocampus.

The role of vascular endothelial growth factor (VEGF) in chronic stress and neurodevelopmental disorders is of growing research interest. Here we show that post-weaning isolation rearing of rats decreased gene expression of VEGF in the hippocampus. Gene expression of VEGF upstream regulator fibroblast growth factor-2 (FGF-2) or its downstream mediator endothelial nitric oxide synthase (eNOS) was unchanged. Other signaling pathways appear to be involved in isolation-induced reduction in VEGF gene expression. Sex differences in VEGF and eNOS gene expression with significantly higher mRNA levels in females than males were revealed.

Brain derived neurotrophic factor expression and DNA methylation in response to subchronic valproic acid and/or aldosterone treatment.

AIM: To test the hypothesis that valproic acid treatment positively affects brain-derived neurotrophic factor (BDNF) expression and DNA methylation in the hippocampus and brain cortex of rats simultaneously treated with aldosterone. METHODS: Male Sprague-Dawley rats (N=40) were treated for two weeks with valproic acid (100 mg/1 kg body weight/d) in drinking water and aldosterone (2 µg/100 g body weight/d) or placebo via subcutaneous osmotic minipumps. RESULTS: Treatment with valproic acid did not modify BDNF gene expression in the hippocampus but reduced BDNF mRNA levels in the brain cortex. Valproic acid treatment marginally enhanced global DNA methylation in the frontal cortex. BDNF expression negatively correlated with DNA methylation in the hippocampus of valproic acid-treated rats. An unexpected finding was that aldosterone treatment significantly decreased global DNA methylation in the hippocampus. CONCLUSION: The effect of valproic acid on BDNF expression in the brain may depend on the extent of pathological changes present at the time of treatment onset. The observed negative correlation between BDNF expression and DNA methylation in the hippocampus of valproic acid-treated rats encourages further studies.

Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models.

The endocannabinoid system is important for many physiologic and pathologic processes, but its role in the regulation of liver cytochromes P450 (P450s) remains unknown. We studied the influence of the endocannabinoid oleamide on rat and human liver P450s. Oleamide was administered intraperitoneally to rats at doses of 0.1, 1, and 10 mg/kg per day for 7 days. The content and activity of key P450s were evaluated in rat liver microsomes. Moreover, interactions with nuclear receptors regulating P450 genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in in vitro P450 inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11, along with a drop in metabolic activity of CYP2D2, were observed in animals treated with oleamide (10 mg/kg per day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat CYP2A, CYP2B, CYP2C11, and CYP3A and human CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were not altered. Oleamide did not interact with human pregnane X, constitutive androstane, or aryl hydrocarbon receptors in reporter gene experiments and did not regulate their target P450 genes in primary human hepatocytes. Our results indicate that oleamide caused the downregulation of some rat liver P450s, and hormones are not mediators of this effect. In vitro oleamide inhibits mainly rat CYP2C6 and is neither an agonist nor antagonist of major human nuclear receptors involved in the regulation of xenobiotic metabolism.

The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review.

There is evidence that development and maintenance of neural connections are disrupted in major mental disorders, which indicates that neurotrophic factors could play a critical role in their pathogenesis. Stress is a well-established risk factor for psychopathology and recent research suggests that disrupted signaling via brain-derived neurotrophic factor (BDNF) may be involved in mediating the negative effects of stress on the brain. Social isolation of rats elicits chronic stress and is widely used as an animal model of mental disorders such as schizophrenia and depression. We carried out a systematic search of published studies to review current evidence for an altered expression of BDNF in the brain of rats reared or housed in social isolation. Across all age groups (post-weaning, adolescent, adult), majority of the identified studies (16/21) reported a decreased expression of BDNF in the hippocampus. There are far less published data on BDNF expression in other brain regions. Data are also scarce to assess the behavioral changes as a function of BDNF expression, but the downregulation of BDNF seems to be associated with increased anxiety-like symptoms. The reviewed data generally support the putative involvement of BDNF in the pathogenesis of stress-related mental illness. However, the mechanisms linking chronic social isolation, BDNF expression and the elicited behavioral alterations are currently unknown.

ß3-Adrenergic receptors, adipokines and neuroendocrine activation during stress induced by repeated immune challenge in male and female rats.

The main hypothesis of the study is that stress associated with repeated immune challenge has an impact on ß3-adrenergic receptor gene expression in the brain. Sprague-Dawley rats were intraperitoneally injected with increasing doses of lipopolysaccharide (LPS) for five consecutive days. LPS treatment was associated with body weight loss and increased anxiety-like behavior. In LPS-treated animals of both sexes, ß3-receptor gene expression was increased in the prefrontal cortex but not the hippocampus. LPS treatment decreased ß3-receptor gene expression in white adipose tissue with higher values in males compared to females. In the adipose tissue, LPS reduced peroxisome proliferator-activated receptor-gamma, leptin and adiponectin gene expression, but increased interleukin-6 expression, irrespective of sex. Repeated immune challenge resulted in increased concentrations of plasma aldosterone and corticosterone with higher values of corticosterone in females compared to males. Concentrations of dehydroepiandrosterone (DHEA) in plasma were unaffected by LPS, while DHEA levels in the frontal cortex were lower in the LPS-treated animals compared to the controls. Thus, changes of DHEA levels in the brain take place irrespective of the changes of this neurosteroid in plasma. We have provided the first evidence on stress-induced increase in ß3-adrenergic receptor gene expression in the brain. Greater reduction of ß3-adrenergic receptor expression in the adipose tissue and of the body weight gain by repeated immune challenge in male than in female rats suggests sex differences in the role of ß3-adrenergic receptors in the metabolic functions. LPS-induced changes in adipose tissue regulatory factors and hormone concentrations might be important for coping with chronic infections.