Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers.

Smoking is a risk factor for non-small cell lung cancer (NSCLC). The most common subtypes of NSCLC are lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). The cigarette smoke contains aryl hydrocarbon receptor (AhR) ligands, such as benzo(a)pyrene (BaP). By activating the AhR, BaP can change the expression of many genes, including miRNA-encoding genes. In this study, we have evaluated the expression of few miRNAs potentially regulated by AhR (miR-21, -342, -93, -181a, -146a), as well as CYP1A1, a known AhR target gene, in lung tumor samples from smoking (n=40) and non-smoking (n=30) patients with LAC and from smoking patients with SCC (n=40). We have also collected macroscopically normal lung tissue >5 cm from the tumor margin. We compared the obtained data on the miRNA expression in tumors with data from The Cancer Genome Atlas (TCGA). We found that in 76.7% of non-smoking LAC patients, CYP1A1 mRNA was not detected in tumor and normal lung tissues, while in smoking patients, CYP1A1 expression was detected in tumors in almost half of the cases (47.5% for SCC and 42.5% for LAC). The expression profile of AhR-regulated miRNAs differed between LAC and SCC and depended on the smoking status. In LAC patients, the expression of oncogenic miRNA-21 and miRNA-93 in tumors was higher than in normal lung tissue from the same patients. However, in SCC patients from our sample, the levels of these miRNAs in tumor and non-transformed lung tissue did not differ significantly. The results of our studies and TCGA data indicate that the expression levels of miRNA-181a and miRNA-146a in LAC are associated with smoking: expression of these miRNAs was significantly lower in tumors of smokers. It is possible that their expression is regulated by AhR and AhRR (AhR repressor), and inhibition of AhR by AhRR leads to a decrease in miRNA expression in tumors of smoking patients. Overall, these results confirm that smoking has an effect on the miRNA expression profile. This should be taken into account when searching for new diagnostic and therapeutic targets for NSCLC.

Search for New Target Genes of MicroRNA for Differential Diagnosis of Benign and Malignant Neoplasms of the Thyroid Gland by In Silico Methods.

Differential diagnosis of thyroid gland neoplasms is an urgent problem in modern oncothyroidology. This is especially true for the diagnosis of follicular thyroid cancer and follicular thyroid adenoma at the preoperative stage. In this study, in silico methods were used to search for potential markers that are microRNA target genes. A list of 19 microRNAs was compiled, the expression of which varies depending on the type of thyroid neoplasms. For these microRNAs, the target genes were selected considering tissue specificity and association with thyroid diseases. We selected 9 target genes (MCM2, RASSF2, SPAG9, SSTR2, TP53BP1, INPP4B, CCDC80, GNAS, and PLK1), which can be considered as promising markers according to published data. Also, 6 new potential markers (CDK4, FGFR1, ERBB3, EGR1, MYLK, and SRC) were found, which make it possible to distinguish between follicular thyroid cancer and follicular thyroid adenoma. The proposed algorithm using various bioinformatics tools allows us to identify potential markers for the differential diagnosis of thyroid neoplasms.

[Oxytocin receptor expression is associated with estrogen receptor status in breast tumors]. / Ékspressiia oksitotsinovogo retseptora assotsiirovana so statusom éstrogenovogo retseptora v opukholiakh molochnoi zhelezy.

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.

Single neonatal dexamethasone administration has long-lasting outcome on depressive-like behaviour, Bdnf, Nt-3, p75ngfr and sorting receptors (SorCS1-3) stress reactive expression.

Elevated glucocorticoid level in the early postnatal period is associated with glucocorticoid therapy prescribed at preterm delivery most often has severe long-lasting neurodevelopmental and behavioural effects. Detailed molecular mechanisms of such programming action of antenatal glucocorticoids on behaviour are still poorly understood. To address this question we studied neurotrophins: Bdnf, Nt-3, Ngf and their receptors: p75ngfr, Sorcs3 expression changes after subcutaneous dexamethasone (DEX) 0.2 mg/kg injection to P2 rat pups. Neurotrophins expression level was studied in the hippocampus (HPC). Disturbances in these brain regions have been implicated in the emergence of multiple psychopathologies. p75ngfr and Sorcs3 expression was studied in the brainstem-region where monoamine neurons are located. Immunohistochemically P75NTR protein level changes after DEX were investigated in the brainstem Locus Coereleus norepinephrine neurons (NE). In the first hours after DEX administration elevation of neurotrophins expression in HPC and decline of receptor's expression in the NE brainstem neurons were observed. Another critical time point during maturation is adolescence. Impact of elevated glucocorticoid level in the neonatal period and unpredictable stress (CMUS) at the end of adolescence on depressive-like behaviour was studied. Single neonatal DEX injection leads to decrease in depressive-like behaviour, observed in FST, independently from chronic stress. Neonatal DEX administration decreased Ntf3 and SorCS1 expression in the brainstem. Also Bdnf mRNA level in the brainstem of these animals didn't decrease after FST. CMUS at the end of adolescence changed p75ngfr and SorCS3 expression in the brainstem in the animals that received single neonatal DEX administration.

The Behavioral and Neurochemical Aspects of the Interaction between Antidepressants and Unpredictable Chronic Mild Stress.

The behavioral and neurochemical effects of amitriptyline (10 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) after single and chronic administration in the setting of unpredictable mild stress in outbred ICR (CD-1) mice were studied. After a 28-day exposure to stress, we observed an increase in depressive reaction in a forced swim test in mice, as well as reduced hippocampal levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and an increased hypothalamic level of noradrenaline (NA). Single and chronic administration of amitriptyline and fluoxetine shortened the immobility period and increased the time corresponding to active swimming in the forced swim test. The antidepressant-like effect of fluoxetine - but not of amitriptyline - after a single injection coincided with an increase in the 5-HT turnover in the hippocampus. Chronic administration of the antidepressants increased the hypothalamic levels of NA. Thus, the antidepressant- like effect of amitriptyline and fluoxetine may result from an enhancement of the stress-dependent adaptive mechanisms depleted by chronic stress.

[Analysis of prolactin receptor expression in breast cancer subtypes]. / Analiz ékspressii retseptora prolaktina v podtipakh raka molochnoi zhelezy.

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

Antiexudative Effects of Finasteride and a New Pyrazolo[C]Pyridine Derivative GIZh-72 in Acetic Acid-Induced Experimental Peritonitis.

It was shown that finasteride, a 5α-reductase inhibitor (50 mg/kg, intraperitoneally) produced analgesic and antiexudative effects in experimental peritonitis induced by intraperitoneal injection of 1% acetic acid. These results agree with published data on its anti-inflammatory properties and ability to potentiate the analgesic effect of morphine in rodents. New pyrazolo[C] pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]pyridine-3-on, chloral hydrate) injected intraperitoneally in doses of 20-80 mg/kg produced dose-dependent antiexudative effects, but exhibited no analgesic properties.

Psychotropic Effects of a New Pyrazolo[C]Pyridine Derivate GIZh-72 are Related to Functional Activity of Atp-Sensitive Potassium Channels.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

Role of GABAA Receptors in the Mechanism of In Vivo Psychotropic Activity of Amitriptyline in Rats.

Standard water-reinforced drug discrimination model was employed to train Wistar rats to discriminate the intraperitoneal injections of tricyclic antidepressant amitriptyline (5.4 mg/kg) and physiological saline. To examine the role of GABAA receptors in psychotropic action of amitriptyline, the substitution tests were performed with muscimol (0.1-1.0 mg/kg) and pregnenolone (30-50 mg/kg). Similar tests were carried out with amitriptyline interoceptive antagonists bicuculline (1 mg/kg), flumazenil (15 mg/kg), finasteride (5 mg/kg), and indomethacin (7.5 mg/kg). The study showed that interoceptive effects of amitriptyline depend on functional activity of GABAA receptors but not on the neurosteroid site of GABAA receptor complex.

Effect of Benzo(a)pyrene on the Expression of miR-483-3p in Hepatocyte Primary Culture and Rat Liver.

Here, we suggested that the epigenetic mechanism of benzo(a)pyrene (BP) action might be based on the aryl hydrocarbon receptor (AhR)-mediated transcription of the target genes, including miRNAs, that have the dioxin response element (DRE) in their promoters. The effect of BP on the expression of the oncogenic miR-483-3p, its host gene IGF2, and target gene IGF1 in primary hepatocytes and in the liver of Wistar female rats was investigated. The activation of AhR was confirmed using selective AhR inhibitor CH-223191 and by evaluating expression of the target CYP1A1 gene. The lack of coordination between the expression of miR-483-3p and its host gene IGF2 was revealed, which may be due to the presence of the binding site for the estrogen receptor alpha (ERα), which is a negative expression regulator. Our results confirm the existence of the AhR-mediated pathway in the regulation of expression of miR-483-3p, IGF1, and IGF2 under BP exposure, which is of considerable interest for understanding the epigenetic mechanisms of the carcinogenic effect of BP.

Calcium Salt of N-(5-Hydroxynicotinoyl)-L-Glutamic Acid Weakens Depressive-Like Behavior and Parkinsonian Syndrome in Experiment on Rodents.

We studied antidepressant and antiparkinsonian properties of N-(5-hydroxynicotinoyl)-Lglutamic acid calcium salt (Ampasse) in rodents. It was found that Ampasse in a dose of 30 mg/kg exhibited antidepressant activity in the forced swimming test in mice and in a dose of 0.1 mg/kg maximally alleviates the symptoms of parkinsonian syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57Bl/6 mice, and haloperidol-induced catalepsy in rats.

[A randomized, double-blind, placebo-controlled study of the efficacy and safety of ampasse in the treatment of chronic cerebral ischemia]. / Randomizirovannoe dvoinoe slepoe platsebo-kontroliruemoe issledovanie éffektivnosti i bezopasnosti preparata ampasse v terapii khronicheskoi ishemii mozga.

AIM: To study the efficacy and safety of ampasse in the treatment of chronic cerebral ischemia. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled study of the efficacy and safety of the 5-hydroxy-3-carboxypyridine-L-glutamine acid monocalcium salt (ampasse) was performed in 80 patients, aged from 50 to 75 years, with chronic cerebrovascular accident due to arterial hypertension and/or atherosclerosis of the main arteries of the head. The drug was used in daily doses of 5, 10, or 25 mg intravenously once a day for 15 days. Sodium chloride 0.9% was used as a placebo. RESULTS AND CONCLUSION: It has been established that ampasse improves the state of patients with chronic cerebral ischemia in relation to depression, sleep quality and cognitive functions.

Translocation of Oligonucleotide-Oligosaccharide Complexes into Cells of the Brain.

Irradiation of a mixture of oligonucleotides with dextran resulted in the formation of a complex that is detected by a decelerated migration of an irradiated sample in electrophoretic gel compared to a non-irradiated one. When injected into the brain of neonatal rats, the formed complex penetrated into the cells 3 times easier compared to the original oligonucleotide, thus indicating that the use of radiation crosslinking of oligonucleotides with oligosaccharides is promising to enhance the efficiency of delivery of gene-targeted oligonucleotide drugs into cells.

N-(5-Hydroxynicotinoil)-L-Glutamic Acid Calcium Salt Modifies Responses of Rat Hippocampal CA1 Pyramidal Neurons during Orthodromic Stimulation.

The study examined the effect of calcium salt of N-(5-hydroxynicotinoil)-L-glutamic acid (Ampasse preparation) on neuronal activity in hippocampal CA1 area evoked by stimulation of Schaffer collaterals at a rate of 1 Hz (30 impulses during 30 sec) in the surviving hippocampal slices of Wistar rats. The records of 1st and 30th orthodromic population spikes showed that Ampasse in concentrations of 500 µM, 1, 2, and 10 mM facilitated the synaptic transmission in Schaffer collaterals - hippocampal CA1 pyramidal neurons axis; the maximum effect was observed at 2 mM Ampasse. When used in a concentration of 10 mM, Ampasse provoked epileptiform activity, which could be prevented by MK-801, a specific noncompetitive antagonist of the NMDA-receptor complex.

Doxycycline Used for Control of Transgene Expression has its Own Effects on Behaviors and Bcl-xL in the Rat Hippocampus.

Doxycycline (Dox)-inducible transgenic approach is used to examine the neural mechanisms of anxiety and depression; however, its own effects on related behaviors are not clear. To address this, in the present study, we tested the anxiety- and depression-like behaviors in rats treated with Dox in drinking water (2 mg/ml) in the elevated plus-maze (EPM; on day 5) and forced swim (FST; on day 8) tests, respectively. In addition, the levels of mRNAs and proteins of brain-derived neurotrophic factor (BDNF) and anti-apoptotic protein Bcl-xL in the hippocampus (HIPP) and frontal cortex (FC) were also analyzed. Consumption of Dox for 4 days induced an anxiogenic-like phenotype that was manifested by the decreased percentages of open arm entries and time spent on the open arms of the EPM. After Dox for 7 days, animals demonstrated more active behavior in the FST than control rats as evidenced by the increase in climbing time. When assessed after the FST, expression of Bcl-xL was increased in the hippocampus of Dox-treated animals. Furthermore, hippocampal Bcl-xL content correlated positively with the duration of climbing in the test. This study is the first to find that Dox in treatment regime used to control transgene expression can affect anxiety- and depression-like behaviors in rats. Dox-induced increase in Bcl-xL expression in the hippocampus may be involved in the moderate activation of FST behavior.

Expression of Hormonal Carcinogenesis Genes and Related Regulatory microRNAs in Uterus and Ovaries of DDT-Treated Female Rats.

The insecticide dichlorodiphenyltrichloroethane (DDT) is a nonmutagenic xenobiotic compound able to exert estrogen-like effects resulting in activation of estrogen receptor-α (ERα) followed by changed expression of its downstream target genes. In addition, studies performed over recent years suggest that DDT may also influence expression of microRNAs. However, an impact of DDT on expression of ER, microRNAs, and related target genes has not been fully elucidated. Here, using real-time PCR, we assessed changes in expression of key genes involved in hormonal carcinogenesis as well as potentially related regulatory oncogenic/tumor suppressor microRNAs and their target genes in the uterus and ovaries of female Wistar rats during single and chronic multiple-dose DDT exposure. We found that applying DDT results in altered expression of microRNAs-221, -222, -205, -126a, and -429, their target genes (Pten, Dicer1), as well as genes involved in hormonal carcinogenesis (Esr1, Pgr, Ccnd1, Cyp19a1). Notably, Cyp19a1 expression seems to be also regulated by microRNAs-221, -222, and -205. The data suggest that epigenetic effects induced by DDT as a potential carcinogen may be based on at least two mechanisms: (i) activation of ERα followed by altered expression of the target genes encoding receptor Pgr and Ccnd1 as well as impaired expression of Cyp19a1, affecting, thereby, cell hormone balance; and (ii) changed expression of microRNAs resulting in impaired expression of related target genes including reduced level of Cyp19a1 mRNA.

Effects of Short-Term Exposure to Lithium on Antiapoptotic Bcl-xL Protein Expression in Cortex and Hippocampus of Rats after Acute Stress.

The antiapoptotic protein Bcl-xL is involved in development of neurobiological resilience to stress; hence, the possibility of use of psychotropic drugs to increase its expression in brain in response to stress is of considerable interest. Lithium is a neurotropic drug widely used in psychiatry. In work, we studied effects of lithium administration (for 2 or 7 days) on the expression of Bcl-xL mRNA and protein in the hippocampi and cortices of rats subjected to stress that induced depression-like behavior in the animals. In contrast to the brain-derived neurotrophic factor (BDNF), whose expression decreased in the hippocampus in response to acute stress, stress increased the level of Bcl-xL mRNA in the hippocampus, but decreased it in the frontal cortex. Treatment of stressed animals with lithium for 2 or 7 days increased Bcl-xL protein levels 1.5-fold in the hippocampus, but it decreased them in the cortex. Therefore, Bcl-xL expression in the brain can be modulated by both stress and psychotropic drugs, and the effects of these factors are brain region-specific: both stress exposure and lithium administration activated Bcl-xL expression in the hippocampus and suppressed it in the frontal cortex. The activation of Bcl-xL expression in the hippocampus by lithium, demonstrated for the first time in this study, suggests an important role of this protein in the therapeutic effects of lithium in the treatment of stress-induced psychoemotional disorders.

Anticompulsive Activity of a New Pyrazolo[C]Pyridine Derivative GIZh-72 under Conditions of Unpredictable Chronic Mild Stress.

Anticompulsive activity of a novel compound GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]Pyridine-3-on, chloral hydrate) in a dose of 20 mg/kg (single, subchronic, and chronic administration) in comparison with fluvoxamine (25 mg/kg) was studied in the marble burying test in the model of unpredictable chronic mild stress on BALB/c mice. GIZh-72 produced an anticompulsive effect that increased with increasing treatment duration under stress conditions in contrast to fluvoxamine that induced inversion of this effect after long-term administration. Neuroleptic activity of GIZh-72 in doses of 20 and 40 mg/kg was studied on the model of apomorphine-induced climbing in C57Bl/6 mice. In contrast to haloperidol (0.5 mg/kg), GIZh-72 exhibited no neuroleptic properties. Our results indicate that GIZh-72 holds much promise for pharmacotherapy of obsessive-compulsive disorder.

[Influence of dexamethasone on the expression of immediate early genes c-fos and c-jun in different regions of the neonatal brain].

The ratio of the expression levels of the immediate early genes c-jun and c-fos that encode components of the AP-1 transcription complex determines the direction of changes in the expression of genes controlled by the complex, including changes induced by glucocorticoids. The aim of the present work was to assess the levels of mRNA encoded by genes c-jun and c-fos and the ratio of expression levels of these genes in various regions of the neonatal rat brain after the administration of dexamethasone, a selective ligand of the glucocorticoid receptor. The level of mRNA encoded by the immediate early gene c-fos in the hippocampus and prefrontal cortex of 3-day-old rat pups was elevated at 30, 60, and 120 min after dexamethasone administration. The basal level of c-fos gene expression in the brainstem was higher than in the cortex and hippocampus, and administration of the hormone was followed by a reduction in the amount of transcript detectable in the brainstem after 2 h. As a result, the ratio of c-jun to c-fos transcript levels in the brainstem of neonatal rats was doubled after dexamethasone administration. The dexamethasone-induced shift of the ratio of c-jun to c-fos transcript levels in the brainstem of neonatal rats towards a predominance of c-jun reported for the first time in the present work may induce the expression of genes that contain AP-1 response elements in the promoters, since the glucocorticoid receptor can be involved in protein-protein interactions with the Jun/Jun homodimer of the AP-1 complex.

ANXIOLYTIC EFFECTS OF DIAZEPAM AND AFOBAZOLE ON THE ANXIETY RESPONSE EVOKED BY GABA(A) RECEPTOR BLOCKADE IN WISTAR RATS AND INBRED MICE OF Balb/c AND C57BI/6 STRAINS.

The anxyolitic effects of diazepam and afobazole on the anxiety model caused by subconvulsive doses of pentylenetetrazole have been studied in the open field test and drug discrimination in rodents. It is found that diazepam (I and 5 mg/kg, i.p.) and afobazole (1 mg/kg, i.p.) reduced the pentylenetetrazole-induced (20 mg/kg, i.p.) anxiety in Wistar rats in the open field test. Only diazepam (1 mg/kg, i.p.) in Balb/c mice and only afobazole (1 mg/kg, i.p.) in C57B11/6 mice decreased anxiety caused by pentylenetetrazole (30 mg/kg, i.p.). Afobazole (20 mg/kg, i.p.) partially inhibited the effect of pentylenetetrazole (20 mg/kg, i.p.) in drug discrimination paradigm in Wistar rats learned in the Skinner box, in contrast to diazepam (5 mg/kg, i.p.) that fully blocked the stimulus properties of non-competitive GABA(A) receptor antagonist. The obtained results suggest that restorative effects of diazepam and afobazole on pentylenetetrazole-induced anxiety depend on the type of emotional stress reaction in rodent species and mice strains, though anxiogenic effects of pentylenetetrazole are not influenced by interstrain differences.