AIM: Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders. METHODS: In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats. RESULTS: Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM. CONCLUSION: Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.
- MeSH
- antipsychotika * terapeutické užití MeSH
- haloperidol * toxicita MeSH
- krysa rodu rattus MeSH
- lipidy MeSH
- methylazoxymethanolacetát toxicita analogy a deriváty MeSH
- modely nemocí na zvířatech MeSH
- olanzapin toxicita MeSH
- potkani Sprague-Dawley MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.
- MeSH
- krysa rodu rattus MeSH
- methylazoxymethanolacetát * MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- receptor kanabinoidní CB1 MeSH
- schizofrenie * chemicky indukované farmakoterapie genetika MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.
- MeSH
- antipsychotika terapeutické užití MeSH
- haloperidol farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- methylazoxymethanolacetát farmakologie MeSH
- modely nemocí na zvířatech MeSH
- nitrobřišní tuk účinky léků embryologie metabolismus MeSH
- olanzapin farmakologie terapeutické užití MeSH
- potkani Sprague-Dawley MeSH
- proteomika MeSH
- risperidon farmakologie terapeutické užití MeSH
- schizofrenie farmakoterapie MeSH
- signální transdukce účinky léků MeSH
- těhotenství MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zpožděný efekt prenatální expozice chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mortality in psychiatric patients with severe mental illnesses reaches a 2-3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.
- MeSH
- antipsychotika farmakologie terapeutické užití MeSH
- haloperidol farmakologie terapeutické užití MeSH
- metabolismus lipidů účinky léků MeSH
- metabolom účinky léků MeSH
- methylazoxymethanolacetát analogy a deriváty MeSH
- modely nemocí na zvířatech * MeSH
- olanzapin farmakologie terapeutické užití MeSH
- potkani Sprague-Dawley MeSH
- risperidon farmakologie terapeutické užití MeSH
- schizofrenie chemicky indukované farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
- MeSH
- aurora kinasa B metabolismus MeSH
- azoxymethan toxicita MeSH
- chemorezistence genetika MeSH
- chromozomální nestabilita * MeSH
- cytogenetické vyšetření MeSH
- dextrany toxicita MeSH
- experimentální nádory chemicky indukované genetika patologie MeSH
- genový knockdown MeSH
- karcinogeneze genetika MeSH
- kolon cytologie patologie MeSH
- kolorektální nádory chemicky indukované genetika patologie MeSH
- lidé MeSH
- myši transgenní MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- organoidy MeSH
- primární buněčná kultura MeSH
- proteiny vázající RNA genetika metabolismus MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-myc metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- RNA dlouhá nekódující genetika metabolismus MeSH
- signální transdukce genetika MeSH
- střevní sliznice cytologie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol chemie farmakologie MeSH
- kanabidiol chemie farmakologie MeSH
- magnetická rezonanční tomografie MeSH
- methylazoxymethanolacetát toxicita MeSH
- modely nemocí na zvířatech MeSH
- molekulární modely MeSH
- mozek diagnostické zobrazování účinky léků MeSH
- mozkový krevní oběh MeSH
- potkani Sprague-Dawley MeSH
- puberta MeSH
- receptory dopaminu D2 chemie genetika metabolismus MeSH
- receptory dopaminu D3 chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- schizofrenie chemicky indukované diagnostické zobrazování farmakoterapie genetika MeSH
- simulace molekulární dynamiky MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.
- MeSH
- endokanabinoidy metabolismus MeSH
- ethanolaminy metabolismus MeSH
- glyceridy metabolismus MeSH
- hipokampus metabolismus MeSH
- interpersonální vztahy MeSH
- kanabidiol farmakologie MeSH
- krysa rodu rattus MeSH
- kyseliny arachidonové metabolismus MeSH
- kyseliny olejové metabolismus MeSH
- kyseliny palmitové metabolismus MeSH
- messenger RNA metabolismus MeSH
- methylazoxymethanolacetát farmakologie MeSH
- modely nemocí na zvířatech MeSH
- piperidiny farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- polynenasycené alkamidy metabolismus MeSH
- prefrontální mozková kůra metabolismus MeSH
- puberta MeSH
- pyrazoly farmakologie MeSH
- receptor kanabinoidní CB1 metabolismus MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- schizofrenie chemicky indukované farmakoterapie metabolismus MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Clinical studies consistently report structural impairments (i.e.: ventricular enlargement, decreased volume of anterior cingulate cortex or hippocampus) and functional abnormalities including changes in regional cerebral blood flow in individuals suffering from schizophrenia, which can be evaluated by magnetic resonance imaging (MRI) techniques. The aim of this study was to assess cerebral blood perfusion in several schizophrenia-related brain regions using Arterial Spin Labelling MRI (ASL MRI, 9.4 T Bruker BioSpec 94/30USR scanner) in rats. In this study, prenatal exposure to methylazoxymethanol acetate (MAM, 22 mg/kg) at gestational day (GD) 17 and the perinatal treatment with Δ-9-tetrahydrocannabinol (THC, 5 mg/kg) from GD15 to postnatal day 9 elicited behavioral deficits consistent with schizophrenia-like phenotype, which is in agreement with the neurodevelopmental hypothesis of schizophrenia. In MAM exposed rats a significant enlargement of lateral ventricles and perfusion changes (i.e.: increased blood perfusion in the circle of Willis and sensorimotor cortex and decreased perfusion in hippocampus) were detected. On the other hand, the THC perinatally exposed rats did not show differences in the cerebral blood perfusion in any region of interest. These results suggest that although both pre/perinatal insults showed some of the schizophrenia-like deficits, these are not strictly related to distinct hemodynamic features.
- MeSH
- circulus arteriosus Willisi diagnostické zobrazování účinky léků embryologie MeSH
- hipokampus krevní zásobení diagnostické zobrazování účinky léků embryologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- magnetická rezonanční angiografie metody MeSH
- methylazoxymethanolacetát toxicita MeSH
- modely nemocí na zvířatech MeSH
- mozkový krevní oběh účinky léků MeSH
- neurogeneze účinky léků MeSH
- schizofrenie chemicky indukované diagnóza MeSH
- senzorimotorický kortex krevní zásobení diagnostické zobrazování účinky léků embryologie MeSH
- techniky pozorování chování MeSH
- těhotenství MeSH
- tetrahydrokanabinol toxicita MeSH
- zpožděný efekt prenatální expozice chemicky indukované diagnostické zobrazování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype.
- MeSH
- acetylace MeSH
- antagonisté kanabinoidních receptorů farmakologie MeSH
- antipsychotika farmakologie MeSH
- časové faktory MeSH
- epigeneze genetická MeSH
- gestační stáří MeSH
- histondeacetylasa 1 antagonisté a inhibitory genetika metabolismus MeSH
- histondeacetylasy genetika metabolismus MeSH
- histony metabolismus MeSH
- inhibitory histondeacetylas farmakologie MeSH
- methylazoxymethanolacetát MeSH
- modely nemocí na zvířatech MeSH
- molekuly buněčné adheze nervové genetika metabolismus MeSH
- mozek účinky léků embryologie enzymologie patologie MeSH
- myši inbrední C57BL MeSH
- neurogeneze * účinky léků MeSH
- neurony účinky léků enzymologie patologie MeSH
- posttranslační úpravy proteinů MeSH
- potkani Sprague-Dawley MeSH
- receptor kanabinoidní CB1 antagonisté a inhibitory metabolismus MeSH
- schizofrenie chemicky indukované farmakoterapie enzymologie genetika MeSH
- signální transdukce MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Patients with schizophrenia often suffer comorbid substance abuse regardless of gender. However, the vast majority of studies are only conducted in male subjects. Therefore, the aim of these experiments is to assess addictive behaviors of both sexes in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) acetate exposure. METHODS: MAM (22 mg/kg) was administered intraperitoneally on gestational day 17. Two studies were performed in the offspring: (1) an alcohol-drinking procedure to assess daily intake of 20% alcohol and relapse-like behavior after a period of forced abstinence; (2) Methamphetamine (METH) intravenous self administration (IVSA) followed by forced abstinence and reinstatement phases. RESULTS: MAM exposure during the prenatal period did not change alcohol drinking regardless of sex. However, MAM females showed higher alcohol consumption in comparison to MAM males. The METH IVSA study revealed only a modest increase of drug consumption in MAM males, while there was no difference between the female groups. Reinstatement data showed no effect of the MAM model in either sex, but suggested increased responding in female rats. CONCLUSIONS: This study suggests that female sex and schizophrenia-like phenotype may work synergistically to enhance alcohol consumption. However, future research is needed to establish paradigms in which these findings would be readily assessed to test anti-addiction treatments.
- MeSH
- chování zvířat účinky léků MeSH
- krysa rodu rattus MeSH
- methamfetamin aplikace a dávkování MeSH
- methylazoxymethanolacetát analogy a deriváty MeSH
- modely nemocí na zvířatech MeSH
- pití alkoholu patofyziologie MeSH
- pohlavní dimorfismus MeSH
- potkani Sprague-Dawley MeSH
- schizofrenie chemicky indukované komplikace MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH