Neuroleptic Activity Research Articles

Synergistic Effect, and Therapeutic Potential of Aqueous Prickly Pear Extract. In vivo Neuroleptic, Catatonic, and Hypoglycemic Activity

Background: Prickly pear "Opuntia ficus indica (L.) Mill. "otherwise known as the Indian fig tree, belongs to the family Cactaceae, and was known as a medicinal plant for its rich source of bioactive substances. Objective: The present work aims to promote prickly pear seeds for traditional therapy by phenolic profiling and pharmacological tests of aqueous extract. Method: An analytical quantification was performed by UV-Visible, and the identification of different bioactive compounds was done by HPLC-DAD. For pharmacological screening, an in vivo evaluation of the various tests, neuroleptic activity which consists of testing the recovery reflex; catatonic activity which is a test to detect catalepsy that can be characterized in animals by the administration of neuroleptic drugs; and for hypoglycemic activity a test was performed to assess glucose tolerance. Results: The administration of aqueous extract of the prickly pear seeds at a dose (400 mg/kg) allows a reduction in blood sugar with a maximum decrease of one and a half hours compared to the control group. Conclusion: This work makes it possible to postulate that the extract of prickly pear seeds is associated with a very interesting antihyperglycemic activity given its high content of phenolic compounds.

Drug-induced hyperprolactinemia: mechanism of development, features of diagnosis and treatment

One of the causes of non-tumor related hyperprolactinemia is taking a medications. Physicians of various specialties, such as cardiologists, gastroenterologists, endocrinologists, and neurologists, encounter hyperprolactinemia as a side effect of drug therapy in their practice, but it is most often observed in the practice of a psychiatrist when treating patients with psychotropic medications. Over the past few years, there has been an increase in the frequency of prescriptions of antidepressants and neuroleptics due to post-COVID-19 syndrome, anxiety and stress caused by the pandemic of a new coronavirus infection. There is also a predisposition to the development of hyperprolactinemia on the background of taking neuroleptics due to genetic features of patients. Currently, there is no established common algorithm for diagnosis and treatment of drug-induced hyperprolactinemia in the world. Based on a review of foreign and domestic literature, the article discusses in detail the mechanisms of development and various approaches to the correction of iatrogenic (drug-induced) hyperprolactinemia, assesses the prolactogenic activity of neuroleptics, and proposes algorithms for prolactin monitoring and correction of hyperprolactinemia using dopamine agonists. Often the tactics of management of such patients need to be discussed by a team of specialized physicians.

EVALUATION OF PHYTOCHEMICALS AND NEUROLEPTIC POTENTIAL OF LEAVES EXTRACT OF ADENIUM OBESUM

The term psychosis refers to illnesses that impair the mind and cause a loss of touch with reality. The present research focuses on screening of phytochemicals and neuroleptic potential of leaves extract of Adenium Obesum in animal models. Leaves of Adenium obesum were obtained from the Saharanpur, UP region and these were identified and authenticated by a botanist at BSI, (Prayagraj) Allahabad. The leaves were washed making dust-free and dried at room temperature or shade. The dried leaves were rendered into coarse powders and then finally into fine ones. The powder was weighed and soaked into hydroalcoholic solution consisting ethanol+ distilled water (1:1) for fifteen days with gradual stirrings. A rotating evaporator is used to dry the brownish until a semisolid extract was obtained. Animal House, Department of Pharmacy, Glocal University Saharanpur (UP) was provided Wistar rats of either sex weighing 130–160g. Animals were divided in 4 groups (n=6) i.e., group1 administered only normal saline daily for 21 days, group 2 administered pregabalin (10mg/kg) orally, for 21 days, group 3 administered hydroalcoholic leaves extract of Adenium obesum (HLAO) at dose of 200mg/kg orally, for 21 days and group 4 administered hydroalcoholic leaves extract of Adenium obesum (HLAO) at dose of 400mg/kg orally up to 21 days. Screening of phytochemicals and then neuroleptic activity of Adenium Obesum by screening models i.e., Apomorphine-induced stereotypy, Haloperidol-induced catalepsy and Climbing behavior test was evaluated. In results, Adenium obesum has prominent neuroprotective effect at lower and higher doses (200mg/kg & 400mg/kg). But response was based on dose levels. It exhibited a significant neuroprotective behavior it might be due to better release of constituents from the leaves of Adenium obesum plant. In conclusion, Adenium obesum has potential neuroprotective behaviour at the all the doses used but highest was observed at higher dose of ethanolic extract that might be due to better solubility and constituents release from the A. obesum leaves in extraction. Future research suggests, to identify and isolate the responsible element for the pharmacological potential and make the suitable dosage form.

Effect of Clozapine and 5-NT2A-Antagonist RU-31 on electroencephalography and Motor Activity of Rats in a Model of Schizophrenia with Neonatal Destruction of the Ventral Hippocampus

Background. Schizophrenia is a socially signifi cant disease that takes a variety of forms. The form of the course determines prescribing antipsychotic drugs with a different range of clinical effects. The study of the pharmacological activity of neuroleptics involves an experimental model using animals which makes it possible to reproduce some aspects of schizophrenia.Objectives. The study is aimed at evaluating the antipsychotic activity of 5-HT2A— RU-31 antagonist and atypical neuroleptic clozapine in behavioral tests and electroencephalography (EEG).Methods. The research methodology involved a dysontogenetic model of schizophrenia, implemented via aspiration destruction of the ventral hippocampus of rats on day 7 of postnatal development. The study was carried out on white outbred male rats selected from the offspring of females, represented by a simple random sample, provided by Rappolovo animal breeding facility of the National Research Center “Kurchatov Institute”. Injection of the studied substances was initiated on day 35 of postnatal development. Motor activity was assessed on day 54 of postnatal development in the Open Field unit and included assessing vertical motor activity, measured as the number of acts of verticalization in 5 minutes, and horizontal motor activity of rats, recorded as the number of crossed squares in 5 minutes. EEG signals were recorded on day 55 of postnatal development; thereafter the spectral density was calculated in the delta- (д) (0.4–4 Hz), theta- (и) (4.8–8 Hz), alpha- (б) (8–12 Hz) and beta- (в) (12–30 Hz) frequency ranges and the effect of the “operation” and “substance” factors on spectral density was evaluated in comparison with control groups. Statistical data processing was performed using GraphPad Prism 9 (Insight Partners, USA).Results. The antipsychotic activity of 1-(2-diethylaminoethyl)-2-(4-methoxyphenyl)-imidazo[1,2-a] benzimidazole — RU-31 compound with 5-HT2A-antagonistic mechanism of action was evaluated. RU-31 compound (10 mg/kg, intraperitoneally (i.p.)) statistically signifi cantly reduced vertical and horizontal spontaneous locomotor activity in rats with psychotic disorder by 18.8% and 20.9%, while the atypical neuroleptic clozapine (2 mg/kg, i.p.) signifi cantly reduced these values by 41.15% and 27.67%, respectively. The 5-HT2A-receptor antagonist RU-31 increased EEG signal power in the delta range by 123.33% and decreased it in the alpha range by 41.86% in surgically operated animals (p < 0.05). Clozapine increased the EEG signal power in all studied frequency ranges: in delta — by 107.99%, theta — by 97.16%, alpha — by 41.86% and in beta — by 49.16% in animals with neonatal destruction of the ventral hippocampus (p < 0.05).Conclusion. The studied substances contributed to the correction of behavioural disturbances associated with hypermobility as well as electrophysiological changes induced by a surgical operation, while similar activity was not observed (or was observed to a lesser extent) in healthy animals.

Molecular mechanisms of antipsychotics - their influence on intracellular signaling pathways, and epigenetic and post-transcription processes.

The purpose of this paper is to describe some aspects of the intra-cellular mechanism of action of neuroleptics, drugs widely used in psychiatry in treatment of psychotic and affective disorders. The ability of neuroleptics to influence and modify the metabolic, energetic and structural processes of neurons, as well as their apoptosis, probably influence their therapeutic potential. The direct and indirect mechanisms of antipsychotics are discussed on the basis of epigenetic, intra-cellular and post-transcription processes. Antipsychotic drugs facilitate chromatin remodeling, decreasing or increasing histone acetylation, and affect DNA methylation differently. Antipsychotics modulate the intracellular signaling cascades like the cyclic adenosine monophosphate (cAMP), AKT/glycogen synthase kinase-3 (GSK-3) pathway and mitogen-activated protein kinase (MAPK) in a variety of ways that contribute to their different clinical and side-effect profiles. Among the cellular processes involved in the activity of antipsychotics are energy and metabolism, protein synthesis and processing, cytoskeleton functions like microtubule dynamics, dendritic branching, and spine dynamics, as well as cell adhesion and synaptic activity. Finally, antipsychotics have the ability to modulate the expression of a large number of miRNAs, which is related to oxidative stress and metabolism. Despite the efficacy of antipsychotics in treating schizophrenia and bipolar disorders over the last several decades, their molecular mechanisms of action turn out to be very complex and have not yet been fully elucidated. Recent thinking about a more personalized and endophenotype-specific diagnosing and treatment requires a more advanced genomic and proteomic approach and seems to be the next step in the treatment of mental disorders.

3D-ALMOND-QSAR Models to Predict the Antidepressant Effect of Some Natural Compounds.

The current treatment of depression involves antidepressant synthetic drugs that have a variety of side effects. In searching for alternatives, natural compounds could represent a solution, as many studies reported that such compounds modulate the nervous system and exhibit antidepressant effects. We used bioinformatics methods to predict the antidepressant effect of ten natural compounds with neuroleptic activity, reported in the literature. For all compounds we computed their drug-likeness, absorption, distribution, metabolism, excretion (ADME), and toxicity profiles. Their antidepressant and neuroleptic activities were predicted by 3D-ALMOND-QSAR models built by considering three important targets, namely serotonin transporter (SERT), 5-hydroxytryptamine receptor 1A (5-HT1A), and dopamine D2 receptor. For our QSAR models we have used the following molecular descriptors: hydrophobicity, electrostatic, and hydrogen bond donor/acceptor. Our results showed that all compounds present drug-likeness features as well as promising ADME features and no toxicity. Most compounds appear to modulate SERT, and fewer appear as ligands for 5-HT1A and D2 receptors. From our prediction, linalyl acetate appears as the only ligand for all three targets, neryl acetate appears as a ligand for SERT and D2 receptors, while 1,8-cineole appears as a ligand for 5-HT1A and D2 receptors.

Pharmaco-Magnetic Resonance as a Tool for Monitoring the Medication-Related Effects in the Brain May Provide Potential Biomarkers for Psychotic Disorders.

The neurodegenerative and neurodevelopmental hypotheses represent the basic etiological framework for the origin of schizophrenia. Additionally, the dopamine hypothesis, adopted more than two decades ago, has repeatedly asserted the position of dopamine as a pathobiochemical substrate through the action of psychostimulants and neuroleptics on the mesolimbic and mesocortical systems, giving insight into the origin of positive and negative schizophrenic symptoms. Meanwhile, cognitive impairments in schizophrenia remain incompletely understood but are thought to be present during all stages of the disease, as well as in the prodromal, interictal and residual phases. On the other hand, observations on the effects of NMDA antagonists, such as ketamine and phencyclidine, reveal that hypoglutamatergic neurotransmission causes not only positive and negative but also cognitive schizophrenic symptoms. This review aims to summarize the different hypotheses about the origin of psychoses and to identify the optimal neuroimaging method that can serve to unite them in an integral etiological framework. We systematically searched Google scholar (with no concern to the date published) to identify studies investigating the etiology of schizophrenia, with a focus on impaired central neurotransmission. The complex interaction between the dopamine and glutamate neurotransmitter systems provides the long-needed etiological concept, which combines the neurodegenerative hypothesis with the hypothesis of impaired neurodevelopment in schizophrenia. Pharmaco-magnetic resonance imaging is a neuroimaging method that can provide a translation of scientific knowledge about the neural networks and the disruptions in and between different brain regions, into clinically applicable and effective therapeutic results in the management of severe psychotic disorders.

Spectroscopic, quantum computational, molecular docking and biological parameters of 4-phenylbutyrophenone: a neuroleptic agent

In this work, density functional theory and vibrational spectroscopic studies are carried out to elucidate the structure, physiochemical parameters and biological behaviors of 4-phenylbutyrophenone. By using energy minimization, the optimized structure of 4-phenylbutyrophenone (4PBP) is obtained. The functional group present in the compound and its properties are obtained by FT-IR, FT-Raman and NMR methods, and it is compared with simulated scaled values along with assignments by potential energy distribution. The inter- and intramolecular charge transfer and stability of the molecule are obtained by natural bond orbital analysis. The reactive areas of the molecule are studied quantitatively and qualitatively by Fukui function analysis and molecular electrostatic potential diagram, respectively. By using frontier molecular orbital theory, the highest occupied molecular orbital, lowest unoccupied molecular orbital and other various parameters are calculated and compared with the known antipsychotic drug melperone. The electronic transition is obtained by experimental UV–Vis spectrum, and it is compared with the time-dependent DFT method with various solvents. The effect of temperature on the molecule is discussed to know the thermal stability of the molecule. The drug-likeness values of 4PBP are compared with known human drugs to confirm the same neuroleptic activities, and it confirms the drug nature of 4PBP. In addition, comparative molecular docking was analyzed with this ligand and melperone (an a typical antipsychotic) with the suitable target protein. Lipophilicity studies compared with other drugs show that this has good transport well inside the human lipid system. Molecular docking supports the neurological activity of the compound with a low binding energy value of −7.55 kcal/mol to bound easily without additional energy with the target proteins confirms 4PBP is a good neuroleptics potential candidate.

Isolation and Characterization of Anti Psychotic Compound From Cassia Occidentalis Leaf

The aim of the current work was mainly to find the neuroleptic effects of responsible compounds isolated from Cassia occidentalis leaves, on condiontioning avoidance and catalepsy induced psychotic wistar rats. Psychosis was induced by condiontioning avoidance and catalepsy induced in albino wistar rats. An isolated fraction of the ethanolic extract of Cassia occidentalis was ingested orally at 100 mg/kg, p.o dose. Haloperidol was considered as standard neuroleptic drug (10 mg/kg, p.o.). The isolated fractions from the column chromatography showing for the higher neuroleptic activity that facilitated for isolating the pure constituent, that was named trivially as name CO- 1.Precise analysis of the previous investigations with Ethanolic extract of Cassia occidentalis (ETCO) have encouraged us to isolate anti-psychotic responsible consituents from the leaves of Cassia occidentalis for managing the anti-psychotic activity. Collected pooled fractions were subjected to anti-psychotic activity in conditioning avoidance and catalepsy induced wistar rats. The fraction F from ETCO showed strong neuroleptic activity when compared with the commercial standard drug Haloperidol. To propose the constituents that possess anti psychotic activity related to F respectively. Besides, column chromatography analysis was performed with ‘F’ using different solvents and the isolated compound which is named as CO-1. This amorphous powder was extracted from the column with decomposition point. CO-1 is a phenolic compound that was confirmed by IR, Mass Spectrum and NMR analysis.

Anti Psychotic Evaluation and GC-MS Analysis of Cassia occidentalis Leaves

Aim: To evaluate the effect of an active fraction from Cassia occidentalis leaves on Wistar rats against psychosis were investigated.
 Place and Duration of Study: This study was carried out in the Aditya Bangalore Institute of Pharmacy Education and Research, Bangalore, India between June -2019 to July – 2020.
 Methods: For the assessment of neuroleptic activity of the Cassia occidentalis leaves with different antipsychotic animal models, Chloroform and ethanol extract (200 mg.kg-1) were used for the study with different animal models. The extract showing higher anti psychotic activity was subjected to column chromatography and led to the isolation of an active fraction and examined in GC-MS analysis.
 Results: A significant decrease of amphetamine-caused stereotype and conditioned avoidance reaction turned into found with extract treated animals as in comparison to control. Phencyclidine induced weird sample of locomotor activity and social withdrawal test in test extracts does no longer proven any significant activity as in comparison to control. Minor symptoms of catalepsy have been seen extract-treated group and decreased dopamine level in the frontal cortex and corpus striatum in comparison to the control group. GC-MS evaluation was identified two active principles present in the eluted fraction.
 Conclusion: The study revealed that the ethanol extract of Cassia occidentalis may possess the property to alleviate the positive symptoms of psychosis.

Препараты группы нейролептиков в практике гастроэнтеролога: опасаться или назначать

The mechanism of action of neuroleptics (antipsychotics) is complex and diverse, therefore, the scope of their application is not limited to the therapy of psychosis. The drugs of this group can be useful in somatic medicine (in particular, gastroenterology), but at present they are an underutilized resource for increasing the effectiveness of the treatment of the patients. The article discusses the indications for the use of neuroleptics in patients with gastroenterological diseases somatic diseases, gives recommendations on the choice of the drug, the determination of its dose and the duration of the course of the treatment. Particular attention is paid to potential side effects and the prevention of their developmen

Evaluation of Antipsychotic Activity of Ethanolic Extract of Dhatryadi Ghrita on Wistar Rats

Objective: Herbal formulations based on plants are effective against psychosis. The effects of Dhatryadi Ghrita on Wistar rats against psychosis were investigated. Background: An increased preference nowadays is obvious towards the use of herbal drugs in the treatment of chronic ailments. Treatment of psychiatric diseases has become easier, but the extrapyramidal motor disorders are the major adverse effect exists with most of the antipsychotic drugs. Methods: For the assessment of neuroleptic activity of the ethanolic extract of Dhatryadi Ghrita, prepared with different antipsychotic animal models, three doses of the extract (100, 200 and 300 mg/kg) were used for the study with different animal models. Result: A significant reduction of amphetamine-induced stereotype and conditioned avoidance response was observed in the extract-treated animals compared to control. Minor signs of catalepsy were visible in the extract-treated group as compared to the control group. Conclusion: The study revealed that the extract may be possessing the property to alleviate the positive symptoms of Psychosis.

Analytical review of Prochlorperazine side effects and acute poisonings

Topicality. The article presents the analytical review data of the toxicological effects of prochlorperazine usage. Prochlorperazine is a sufficiently used drug with neuroleptic and antiemetic activity. It’s produced as a generic drug in many countries in the world in the form of tablets, suppositories and injection. Aim . To conduct an analytical review of prochlorperazine side effects and acute poisonings of controlled and uncontrolled usage. Results and discussion . According to information sources, in the period from 2010 till 2016 year were registered 258 cases of prochlorperazine acute poisoning in the world. The main causes of acute prochlorperazine poisoning noted with side effects of the treatment of it in therapeutic doses. Prochlorperazine is incompatible with drugs that suppress the central nervous system and increases the risk of neonatal complications if pregnant women use. Approximately 10 % of prochlorperazine numbers of acute poisonings are lethal cases of overdose. They are often due to suicide drug overdose. The drugs that were used simultaneously with prochlorperazine for suicide were defined: clonazepam, lorazepam, aprazolam, ibuprofen, naproxen, diazepam, seroquel, depacote, etc. Conclusions . It is shown that if the methods of chemical-toxicological analysis of prochlorperazine will be presented in corresponding institutions of forensic medical expertise the number of registered cases of poisoning significantly increase, particularly in Ukraine.

Role of Phospholipase C in the Dopamine D2 Signaling Pathway in the Control of Lateral Cilia in Gill of Crassostrea virginica

Lateral cell cilia of gill of Crassostrea virginica are controlled by serotonergic‐dopaminergic innervations from their ganglia. Dopamine is the neurotransmitter causing cilio‐inhibition, serotonin cilio‐excitation. Previous work of our lab showed the post‐synaptic dopamine receptors present in lateral cells are D2‐type. Dopamine D2 receptors (D2R) are G protein‐coupled metabotropic receptors. Ligand binding to D2R splits its Gi/o protein into the Gβγ and Gαi/o subunits. Gαi/o inhibits adenylyl cyclase; while Gβγ opens GIRK channels, closes L‐type Ca2+ channels and activates phospholipase C (PLC). The inhibition of adenylyl cyclase and subsequent lowering of cAMP is known to slow lateral cilia; however, the role of PLC in the signaling pathway has not been well studied with respect to control of lateral cilia. Using immunohistofluorescence, our lab visualized PLC in lateral cell. In this study we hypothesized that the PLC component of the D2 pathway also plays a role in the cilio‐inhibition. To test this we utilized PLC activators and inhibitors on excised gill to determine their effects on lateral cilia. Cilia beating rates were measured using stroboscopic microscopy. In control gill, applying a dose response of dopamine (10−6 – 10−3M) is cilio‐inhibitory, decreasing beating rates of lateral cilia to 0. Applying m‐3M3FBS (10−5 – 10−4M), a PLC activator, caused a moderate decrease in cilia beating rates. Applying U73122 (10−4M), a phosphatidylinositol 4,5‐bisphosphate specific PLC inhibitor, did not alter cilia beating rates by itself, but did effect the dose response to dopamine (10−5 – 10−3M). In the presence of the inhibitor, while the 10−5M dose of dopamine caused the expected decrease in cilia beating rates, the addition of higher doses of dopamine was unable to reduce beating rates any further. As expected, the drug D609, a PLC inhibitor but specific for phosphatidylcholine, had no effects on cilia beating rates or the actions of dopamine. The results of this study supports our hypothesis that the PLC component of the D2R signal transduction pathway plays a role in the inhibitory control of gill lateral cilia. The results show that both components of the D2R pathway, the adenylyl cyclase component and the PLC component are involved in controlling lateral cilia beating. In humans the D2R signal transduction pathway is significantly involved in the actions of antidepressants, neuroleptics, and drugs of abuse, as well as implicated in neuropsychiatric and neurodegenerative disorders. This physiology study is helpful in furthering the understanding of the pathway and should help to generate further investigations.Support or Funding InformationThis work was supported in part by grant 2R25GM06003 of the Bridge Program of NIGMS, NIH grant K12GM093854‐07A1 IRACDA Program of Rutgers University and 604060048 of PSC‐CUNY.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

P.3.c.006 - Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia D. Osmanova(1), A.S. Boiko(1), O.Y. Fedorenko(1), I.V. Pozhidaev(1), M.B. Freidin(2), E.G. Kornetova(3), S.A. Ivanova(1), B. Wilffert(4), A.J.M. Loonen(5) (1)Mental Health Research Institute- Tomsk NRMC, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Research Institute of Medical Genetics, Tomsk NRMC, Laboratory of Population Genetics, Tomsk, Russia (3)Mental Health Research Institute- Tomsk NRMC, Department of Clinical and Social Psychiatry and Addiction, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1,2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorphisms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36–0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accordingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits.

Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics.

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.

Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide.

Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.

Synthesis, physical-chemical properties and research of acute toxicity of 1,2,4-triazole derivatives containing thiophene core

The aim of research. Modern drugs must have certain characteristics, such as low toxicity and high efficiency. Special attention should be given to esthers of 2-(1,2,4-triazoles-3-iltio)acetic acids. It has been found that compounds of this class are able to show analgesic, neuroleptic, diuretic, anti-inflammatory, mild antimicrobial and other biological activities and also can be intermediates for the synthesis of amides, hydrazides, ilidenhidrazides and bicyclic structures.Therefore, we synthesized a series of esthers of 2-(4-R-5- (thiophene-2-yl)-4H-1,2,4-triazoles-3-iltio)acetic acids, to explore their physical and chemical properties, to explore the acute toxicity of the obtained compounds, to identify the nature and severity of their damaging effects on the body of experimental animals.Materials and methods. Esthers of 2-((4-R-5-(thiophene-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acids have been obtained by the etherification of the corresponding 2-((4-R-5-(thiophene-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acids with methyl, ethyl, isopropyl and butyl alcohols in the presence of the catalytic amount of concentrated sulfuric acid.The tabular rapid method of V. B. Prozorovskiy which was used in a number of scientists practical research, has been selected for the acute toxicity study. Test compounds were introduced intraperitoneally in doses from the logarithmic scale.Results. 16 new derivatives of 2-((4-R-5-(thiophene-2-yl)-4H-1,2,4-triazoles-3-yl)thio)acetic acids have been synthesized. Physical-chemical constants have been checked for all synthesized compounds and their structure has been confirmed by using elemental analysis, 1H NMR- and IR-spectroscopy.The indicators of acute toxicity have been studied for all synthesized compounds. The acute toxicity study of the esters of 2-((4-R-5-(thiophene-2-yl)-4H-1,2,4-triazoles-3-yl)thio)acetic acid shows that all compounds belong to the 4th or 5th grade of toxicity, they are practically non-toxic and low-toxic and their LD50 is in the range of 525±51 mg/kg to 2250±200 mg/kg.

Long-term treatment with haloperidol affects neuropeptide S and NPSR mRNA levels in the rat brain.

The brainstem-derived neuropeptide S (NPS) has a multidirectional regulatory activity, especially as a potent anxiolytic factor. Accumulating data suggests that neuroleptics affect peptidergic signalling in various brain structures. However, there is no information regarding the influence of haloperidol on NPS and NPS receptor (NPSR) expression. We assessed NPS and NPSR mRNA levels in brains of rats treated with haloperidol using quantitative real-time polymerase chain reaction. Chronic haloperidol treatment (4 weeks) led to a striking upregulation of NPS and NPSR expression in the rat brainstem. Conversely, the NPSR mRNA expression was decreased in the hippocampus and striatum. This stark increase of NPS in response to haloperidol treatment supports the hypothesis that this neuropeptide is involved in the dopamine-dependent anxiolytic actions of neuroleptics and possibly also in the pathophysiology of mental disorders. Furthermore, our findings underline the complex nature of potential interactions between dopamine receptors and brain peptidergic pathways, which has potential clinical applications.