BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

• MeSH
• Antipsychotic Agents pharmacology   MeSH
• Haloperidol pharmacology   MeSH
• Cognitive Dysfunction metabolism   drug therapy   MeSH
• Rats MeSH
• Kynurenic Acid * metabolism   MeSH
• Methylazoxymethanol Acetate * analogs & derivatives   MeSH
• Disease Models, Animal MeSH
• Piperidines pharmacology   MeSH
• Rats, Sprague-Dawley * MeSH
• Prefrontal Cortex * metabolism   drug effects   MeSH
• Pyrazoles pharmacology   MeSH
• Receptor, Cannabinoid, CB1 metabolism   MeSH
• Schizophrenia * metabolism   drug therapy   MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects * metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

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
• Antipsychotic Agents * therapeutic use   MeSH
• Haloperidol * toxicity   MeSH
• Rats MeSH
• Lipids MeSH
• Methylazoxymethanol Acetate toxicity   analogs & derivatives   MeSH
• Disease Models, Animal MeSH
• Olanzapine toxicity   MeSH
• Rats, Sprague-Dawley MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article 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.

• MeSH
• Electric Fish * MeSH
• Haloperidol pharmacology   MeSH
• Ketamine * pharmacology   MeSH
• Locomotion MeSH
• Schizophrenia * chemically induced   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

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
• Aggression MeSH
• Adult MeSH
• Brain Edema etiology   MeSH
• Haloperidol administration & dosage   adverse effects   MeSH
• Communication MeSH
• Humans MeSH
• Schizophrenia, Paranoid * complications   MeSH
• Autopsy MeSH
• Resuscitation MeSH
• Death MeSH
• Emergency Medical Services * MeSH
• Treatment Outcome MeSH
• Physician-Patient Relations MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports 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
• Antipsychotic Agents therapeutic use   MeSH
• Haloperidol pharmacology   therapeutic use   MeSH
• Rats MeSH
• Methylazoxymethanol Acetate pharmacology   MeSH
• Disease Models, Animal MeSH
• Intra-Abdominal Fat drug effects   embryology   metabolism   MeSH
• Olanzapine pharmacology   therapeutic use   MeSH
• Rats, Sprague-Dawley MeSH
• Proteomics MeSH
• Risperidone pharmacology   therapeutic use   MeSH
• Schizophrenia drug therapy   MeSH
• Signal Transduction drug effects   MeSH
• Pregnancy MeSH
• TOR Serine-Threonine Kinases metabolism   MeSH
• Adipose Tissue drug effects   metabolism   MeSH
• Prenatal Exposure Delayed Effects chemically induced   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Antipsychotic Agents * pharmacokinetics   therapeutic use   MeSH
• Aripiprazole pharmacokinetics   therapeutic use   MeSH
• Haloperidol pharmacokinetics   therapeutic use   MeSH
• Hippocampus drug effects   MeSH
• Clinical Trials as Topic MeSH
• Rats MeSH
• Brain-Derived Neurotrophic Factor drug effects   MeSH
• Prefrontal Cortex drug effects   MeSH
• Stress, Psychological drug therapy   MeSH
• Receptors, Glucocorticoid drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't 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
• Antipsychotic Agents * pharmacology   MeSH
• Aripiprazole pharmacology   MeSH
• Haloperidol * MeSH
• Hippocampus MeSH
• Rats MeSH
• Brain-Derived Neurotrophic Factor genetics   MeSH
• Prefrontal Cortex MeSH
• Receptors, Glucocorticoid genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article 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
• Antipsychotic Agents pharmacology   therapeutic use   MeSH
• Haloperidol pharmacology   therapeutic use   MeSH
• Lipid Metabolism drug effects   MeSH
• Metabolome drug effects   MeSH
• Methylazoxymethanol Acetate analogs & derivatives   MeSH
• Disease Models, Animal * MeSH
• Olanzapine pharmacology   therapeutic use   MeSH
• Rats, Sprague-Dawley MeSH
• Risperidone pharmacology   therapeutic use   MeSH
• Schizophrenia chemically induced   drug therapy   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Antipsychotic Agents pharmacology   MeSH
• Haloperidol chemistry   pharmacology   MeSH
• Cannabidiol chemistry   pharmacology   MeSH
• Magnetic Resonance Imaging MeSH
• Methylazoxymethanol Acetate toxicity   MeSH
• Disease Models, Animal MeSH
• Models, Molecular MeSH
• Brain diagnostic imaging   drug effects   MeSH
• Cerebrovascular Circulation MeSH
• Rats, Sprague-Dawley MeSH
• Puberty MeSH
• Receptors, Dopamine D2 chemistry   genetics   metabolism   MeSH
• Receptors, Dopamine D3 chemistry   genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• Schizophrenia chemically induced   diagnostic imaging   drug therapy   genetics   MeSH
• Molecular Dynamics Simulation MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Citalopram pharmacology   MeSH
• Drug Therapy MeSH
• Pharmacovigilance MeSH
• Haloperidol pharmacology   MeSH
• Humans MeSH
• Arrhythmias, Cardiac drug therapy   MeSH
• Long QT Syndrome * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH