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
The present study aimed to examine a weakly electric fish Gnathonemus petersii (G. petersii) as a candidate model organism of glutamatergic theory of schizophrenia. The idea of G. petersii elevating the modeling of schizophrenia symptoms is based on the fish's electrolocation and electrocommunication abilities. Fish were exposed to the NMDA antagonist ketamine in two distinct series differing in the dose of ketamine. The main finding revealed ketamine-induced disruption of the relationship between electric signaling and behavior indicating impairment of fish navigation. Moreover, lower doses of ketamine significantly increased locomotion and erratic movement and higher doses of ketamine reduced the number of electric organ discharges indicating successful induction of positive schizophrenia-like symptoms and disruption of fish navigation. Additionally, a low dose of haloperidol was used to test the normalization of the positive symptoms to suggest a predictive validity of the model. However, although successfully induced, positive symptoms were not normalized using the low dose of haloperidol; hence, more doses of the typical antipsychotic haloperidol and probably also of a representative of atypical antipsychotic drugs need to be examined to confirm the predictive validity of the model.
Tu referujeme letálne sa končiaci bezpečnostný zásah proti 26-ročnému mužovi s paranoidnou schizofréniou, ktorý ignoroval ambulantným psychiatrom nariadenú terapiu. V priebehu 14-dní dochádza k nápadnému stupňovaniu nepokoja, opakovaným verbálnym útokom, vyhrážaniu a agresívnemu správaniu. Privolaný lekár nedokázal nadviazať kontakt s mužom, a tak si zavolal na pomoc policajnú hliadku, ktorá muža spacifikovala. Lekár pritom injekčnou formou aplikoval mužovi do svalu Haloperidol, ktorý však nezabral, a tak v krátkom časovom intervale aplikoval ďalšiu dávku Haloperidolu. Po prvotnom utlmení dochádza k náhlej zástave dýchania, pričom muž je opakovane resuscitovaný a transportovaný do nemocnice, kde na šiesty deň umiera. Nariadenou súdnou pitvou bolo zistené, že príčinou smrti muža bol malígny edém mozgu. Práca na podklade prípadu z praxe upozorňuje lekárov prvého kontaktu, lekárov pracujúcich v teréne, zdravotné sestry, iných pomocných zdravotníkov, sociálnych pracovníkov, ale aj príslušníkov bezpečnostných síl na možné nebezpečenstvá pri komunikácii a práci s klientmi, ktorí sa verbálne vyhrážajú, alebo aj správajú agresívne. Tu odporúčame racionálne vyhodnotiť riziká potencionálnych zákrokov a až následne na základe konkrétnej situácie a výpovedí svedkov zvážiť alternatívy postupov, včítane možnosti privolania iných odborníkov. Zákroky by mali prebehnúť koordinovane s prioritným akcentom na ochranu vlastných životov, životov klientov, na ochranu vlastného zdravia, zdravia klientov a nakoniec na elimináciu škôd na majetku.
This is a case report of a fatal intervention against a 26-year-old man with paranoid schizophrenia who ignored therapy prescribed by a psychiatrist. Over a 14-day period, there was a striking escalation of restlessness, repeated verbal attacks, threats and aggressive behaviour. The doctor who was called was not able to establish a valid contact with the man, so he called the police to help him pacify the man. During this time, the doctor applied Haloperidol as an injection to the muscle, but without an effect, thus the doctor applied another shot of Haloperidol within a very short time. After an initial sedation, there was a sudden respiratory arrest, the man was repeatedly resuscitated and transported to a hospital, where he died on the sixth day. A requested forensic autopsy revealed that the cause of the man?s death was a malignant cerebral oedema. This case report draws the attention of primary care physicians, doctors working in the field, nurses, other health care professionals, social workers, as well as members of the security forces to the possible dangers of communicating and working with clients who are verbally or physically aggressive. Here, we recommend a rational assessment of the risks of potential interventions and only then, based on the specific situation and witness statements, to consider alternatives to next steps, including the possibility of calling in other professionals. Interventions should be conducted in a coordinated manner with a priority emphasis on protecting one ́s own life, the clients ́ lives, and ultimately the prevention of property damage.
- MeSH
- agrese MeSH
- dospělí MeSH
- edém mozku etiologie MeSH
- haloperidol aplikace a dávkování škodlivé účinky MeSH
- komunikace MeSH
- lidé MeSH
- paranoidní schizofrenie * komplikace MeSH
- pitva MeSH
- resuscitace MeSH
- smrt MeSH
- urgentní zdravotnické služby * MeSH
- výsledek terapie MeSH
- vztahy mezi lékařem a pacientem MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky 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
- MeSH
- antipsychotika * farmakokinetika terapeutické užití MeSH
- aripiprazol farmakokinetika terapeutické užití MeSH
- haloperidol farmakokinetika terapeutické užití MeSH
- hipokampus účinky léků MeSH
- klinické zkoušky jako téma MeSH
- krysa rodu rattus MeSH
- mozkový neurotrofický faktor účinky léků MeSH
- prefrontální mozková kůra účinky léků MeSH
- psychický stres farmakoterapie MeSH
- receptory glukokortikoidů účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Objective. Changes in the brain derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC) and hippocampus (HIP) are associated with psychiatric diseases and stress response. Chronic mild stress (CMS) may alter BDNF as well as GR levels in both the PFC and the HIP. The aim of the present study was to find out whether chronic treatment with a typical antipsychotic haloperidol (HAL) and an atypical antipsychotic aripiprazole (ARI) may modify the CMS effect on the BDNF and GR expression in the above-mentioned structures. Methods. The rats were exposed to CMS for 3 weeks and from the 7th day of CMS injected with vehicle (VEH), HAL (1 mg/kg) or ARI (10 mg/kg) for 4 weeks. BDNF and GR mRNA levels were established in the PFC and the HIP by Real Time PCR, whereas, PFC and HIP samples were obtained by punching them from 500 μm thick frozen sections. C-Fos immunoreactivity was analyzed in the PFC and the HIP on 30 μm thick paraformaldehyde fixed sections. Weight gain and corticosterone (CORT) levels were also measured. Results. The CMS and HAL suppressed the BDNF and GR mRNA levels in the PFC. In the HIP, CMS elevated BDNF mRNA levels that were suppressed by HAL and ARI treatments. The CMS decreased the c-Fos immunoreactivity in the PFC in both HAL- and ARI-treated animals. In the HIP, HAL increased the c-Fos immunoreactivity that was again diminished in animals exposed to CMS. Stressed animals gained markedly less weight until the 7th day of CMS, however, later their weight gain did not differ from the unstressed ones or was even higher in CMS+HAL group. Un-stressed HAL and ARI animals gained less weight than the VEH ones. Neither CMS nor HAL/ARI affected the plasma CORT levels. Conclusion. The present data indicate that HAL and ARI in the doses 1 mg/kg or 10 mg/kg, respectively, does not modify the effect of the CMS preconditioning on the BDNF and GR mRNA levels in the PFC or the HIP. However, HAL seems to modify the CMS effect on the HIP activation.
- MeSH
- antipsychotika * farmakologie MeSH
- aripiprazol farmakologie MeSH
- haloperidol * MeSH
- hipokampus MeSH
- krysa rodu rattus MeSH
- mozkový neurotrofický faktor genetika MeSH
- prefrontální mozková kůra MeSH
- receptory glukokortikoidů genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
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
- MeSH
- citalopram farmakologie MeSH
- farmakoterapie MeSH
- farmakovigilance MeSH
- haloperidol farmakologie MeSH
- lidé MeSH
- srdeční arytmie farmakoterapie MeSH
- syndrom dlouhého QT * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
