Antipsychotic Activity Research Articles

Understanding Why Muscarinic Receptor Agonists Have Antipsychotic Properties

All current antipsychotics have direct dopamine (DA) D2 receptor activity, which is associated with problems such as dysphoria, EPS, or prolactin elevation. Muscarinic receptor agonists have shown antipsychotic-like activity across preclinical models and clinical trials. This poster reviews preclinical evidence as to how muscarinic receptor agonists, such as the M1/M4 preferring agonist xanomeline, might have clinically relevant antipsychotic effects. Highlight the novel mechanisms through which muscarinic receptor agonists are associated with antipsychotic effects without having any direct dopaminergic D2 receptor activity. The muscarinic receptor family is composed of 5 G protein-coupled receptors (GPCRs). One of the leading hypotheses explaining the antipsychotic activity of muscarinic receptor agonists is preclinical studies of muscarinic receptor modulation of those DA circuits associated with psychosis. Both M1 and M4 receptors are expressed in DA neural circuits implicated in psychosis, and provide unique regulation of these circuits. Xanomeline has both functional M1 and M4 receptor agonist activity, and shows robust antipsychotic-like effects in several animal models that require the presence of functional M1 and M4 receptors. M4 receptors are autoreceptors on cholinergic neurons that regulate DA circuits in two locations: ventral tegmental area (VTA) and nucleus accumbens (NAc). Cholinergic-rich neurons from the hindbrain at the VTA, where they release acetylcholine (ACh) into DA-rich synaptic spaces. M4 autoreceptors are present on these neurons, and their activation reduces ACh release and lowers ambient synaptic ACh concentrations, leading to reduced DA cell firing. Cholinergic interneurons residing in the NAc also express M4 autoreceptors. These ACh interneurons regulate ACh release with M4 activation also turning off ACh release. Therefore, M4 receptors serve as DA regulators at VTA and NAc, both key sites for dopamine's role in psychotic processes. M1 receptors regulate DA circuits in a different, "top down" manner. M1 receptors are found on cortical inhibitory interneurons. When activated, inhibitory drive onto excitatory output neurons is enhanced, which leads to reduced excitatory tone to VTA DA neurons. Over the last 25years, a growing body of evidence has shown potential for muscarinic receptor agonists to become a new class of medicines with potent antipsychotic activity. Preclinical data at micro-and macro-circuit levels suggest that the M1 and M4 receptor subtypes are most relevant in the regulation of DA circuits. The antipsychotic effects of muscarinic agonists effects may arise from influencing these key muscarinic receptor subtypes that are integral to the regulation of DA neural circuits. In summary, there has been great progress in understanding the potential for muscarinic receptor agonists for the treatment of psychosis. Karuna Therapeutics.

Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum.

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies.

Therapeutic use of melatonin in schizophrenia-more than meets the eye!

Adjunctive melatonin use in schizophrenia, as supported by a modicum of evidence, has multiple transcending chronobiotic actions, including fixing concurrent sleep problems to bona fide augmentative antipsychotic actions, mitigating the risk of tardive dyskinesias, curbing the drastic metabolic syndrome and ultimately providing neuroprotective actions. Its use is rather an art than science!

Quercetin Mitigates Methamphetamine-Induced Anxiety-Like Behavior Through Ameliorating Mitochondrial Dysfunction and Neuroinflammation.

Methamphetamine (MA) abuse results in neurotoxic outcomes, including increased anxiety and depression. Studies have reported an association between MA exposure and anxiety, nonetheless, the underlying mechanism remains elusive. In the present study, we developed a mouse model of anxiety-like behavior induced by MA administration. RNA-seq was then performed to profile the gene expression patterns of hippocampus (HIPP), and the differentially expressed genes (DEGs) were significantly enriched in signaling pathways related to psychiatric disorders and mitochondrial function. Based on these, mitochondria was hypothesized to be involved in MA-induced anxiety. Quercetin, as a mitochondrial protector, was used to investigate whether to be a potential treatment for MA-induced anxiety; accordingly, it alleviated anxiety-like behavior and improved mitochondrial impairment in vivo. Further experiments in vitro suggested that quercetin alleviated the dysfunction and morphological abnormalities of mitochondria induced by MA, via decreasing the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and increasing the oxygen consumption rate (OCR) and ATP production. Moreover, the study examined the effect of quercetin on astrocytes activation and neuroinflammation, and the results indicated that it significantly attenuated the activation of astrocytes and reduced the levels of IL-1β, TNFα but not IL-6. In light of these findings, quantitative evidence is presented in the study supporting the view that MA can evoke anxiety-like behavior via the induction of mitochondrial dysfunction. Quercetin exerted antipsychotic activity through modulation of mitochondrial function and neuroinflammation, suggesting its potential for further therapeutic development in MA-induced anxiety.

The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors.

α2‐Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain α2C‐adrenoceptor blockade has also been suggested to be beneficial for antipsychotic action. However, comparing α2‐adrenoceptor subtype affinity is difficult due to significant species and methodology differences in published studies. Here, 3H‐rauwolscine whole cell binding was used to determine the affinity and selectivity of 99 α‐antagonists (including antidepressants and antipsychotics) in CHO cells expressing human α2A, α2B, or α2C‐adrenoceptors, using an identical method to β and α1‐adrenoceptor measurements, thus allowing direct human receptor comparisons. Yohimbine, RX821002, RS79948, and atipamezole are high affinity non‐selective α2‐antagonists. BRL44408 was the most α2A‐selective antagonist, although its α1A‐affinity (81 nM) is only 9‐fold greater than its α2C‐affinity. MK‐912 is the highest‐affinity, most α2C‐selective antagonist (0.15 nM α2C‐affinity) although its α2C‐selectivity is only 13‐fold greater than at α2A. There are no truely α2B‐selective antagonists. A few α‐ligands with significant β‐affinity were detected, for example, naftopidil where its clinical α1A‐affinity is only 3‐fold greater than off‐target β2‐affinity. Antidepressants (except mirtazapine) and first‐generation antipsychotics have higher α1A than α2‐adrenoceptor affinity but poor β‐affinity. Second‐generation antipsychotics varied widely in their α2‐adrenoceptor affinity. Risperidone (9 nM) and paliperidone (14 nM) have the highest α2C‐adrenoceptor affinity however this is only 5‐fold selective over α2A, and both have a higher affinity for α1A (2 nM and 4 nM, respectively). So, despite a century of yohimbine use, and decades of α2‐subtype studies, there remains plenty of scope to develop α2‐subtype selective antagonists.

Design and Synthesis of Arylpiperazine Serotonergic/Dopaminergic Ligands with Neuroprotective Properties.

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT1A, 5-HT2A, 5-HT7 receptor, and dopamine D2 receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood–brain barrier. We identified compound 12a that combines an affinity profile compatible with antipsychotic activity (5-HT1A Ki = 41.5 nM, 5-HT2A Ki = 315 nM, 5-HT7 Ki = 42.5 nM, D2 Ki = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT1A Ki = 23.9 nM, 5-HT2A Ki = 39.4 nM, 5-HT7 Ki = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound 9b, which might be suitable for studies in vivo.

Dual 5-HT3 and 5-HT6 Receptor Antagonist FPPQ Normalizes Phencyclidine-Induced Disruption of Brain Oscillatory Activity in Rats.

Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.

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.

Extraction and isolation of Isoflavonoids from stem bark of Bauhinia purpurea (L): Its biological antipsychotic and analgesic activities

The present research work reports the solvent extraction and isolation of Isoflavonoids from Bauhinia purpurea stem bark and their antipsychotic with analgesic activities were studied. Flavonoids are one of the medicinal herbs abundant in plant resources showed excellent pharmacological activities. The isolation of Isoflavonoids was achieved by column chromatography technique and its structural confirmations were studied by 1H NMR, 13C NMR, CHNS Analysis, Ultraviolet and Mass Spectral techniques. The percentage of carbon and hydrogen contents in isolated compound was found to be 71.485% and 4.718% respectively examined by CHNS technique. The UV spectrum of isolated compound exhibited two bands (279.40 & 216.80 ​nm) characteristic of flavones. The multiplets for aromatic protons of flavonoid were observed in the range δ 6.04–7.65 recorded by using 1H NMR spectroscopy. The alkyl groups of flavonoids at C-6, C-6″, C-8, C-8″ positions and the alkyl proton appeared in NMR spectra δ 2.20. LC/MS (positive mode) studies shows the strong molecular peak at m/z 470 and its base peak at highest intensity (m/z 295) revealing the presence of flavonoid compound. The phytoconstituent flavonoids present in the Bauhinia purpurea stem bark extract showed significant antipsychotic and analgesic activities are discussed in details.

Thioarylation of anilines using dual catalysis: two-step synthesis of phenothiazines.

A two-step synthesis of phenothiazines has been developed using a dual-catalytic ortho-thioarylation reaction of anilines as the key step. Activation of N-(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient ortho-thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.

Meticulous parade on naringin respecting its pharmacological activities and novel formulations.

Objective:Medicinal plants having antioxidant potential possess numerous constituents which are responsible for different beneficial effects and are used as an alternative resource of medicine to lessen diseases linked with oxidative stress. Flavonoids are identified in the plants since ages and display wide spectrum of biological actions that might be able to stimulate the steps which are disturbed in different diseases. Flavonoids are significant natural compounds with various biologic properties, among which the most common is the anti-oxidant potential. Citrus flavonoids establish an important stream of flavonoids. Naringin, very common flavonoids present in the diet, belongs to the family of flavanone. It is the principal constituent of citrus family that contains flavonoids for example tomatoes, grapefruits and oranges. Materials and Methods:In this article, we reviewed naringin with respect to sources, chemical property, pharmacokinetics, pharmacological activity, and novel formulations. The literature survey has been done by searching different databases such as Psyc INFO, Science Direct, PubMed, EMBASE, Google, Google Scholar, Medline. Results: Naringin is known to behave as an antioxidant and possess anti-inflammatory, anti-apoptotic, anti-atherosclerotic, neuroprotective, anti-psychotic, anti-asthmatic, anti-diabetic, hepatoprotective, anti-tussive, cardioprotective, and anti-obesity activity. Further clinical studies using large sample sizes remain essential to obtain the appropriate dose and form of naringin for averting diseases. Furthermore, the therapeutic approach of these bioflavonoids is significantly inappropriate due to the lack of clinical evidence. Different plants must be explored further to find these bioflavonoids in them.Conclusion:The results of this exploration provides biological actions of bioflavonoid (naringin), predominantly on pharmacological and novel dosage forms of naringin.

In Silico Investigations on the Probable Macromolecular Drug Targets Involved in the Anti-Schizophrenia Activity of Terminalia bellerica

Background: Schizophrenia is a severe mental disorder that affects around 1% of the population worldwide. The available antipsychotics alleviate the positive symptoms of the illness. However, their effect on the negative and cognitive symptoms is limited. The fruit powder of Terminalia bellerica has been found to possess antipsychotic activity, which might be useful in treating the symptoms of schizophrenia. Objective: The present study was performed to evaluate the affinity of the active constituents of Terminalia bellerica towards macromolecular drug targets involved in the pathophysiology of schizophrenia and, thereby, determine the structural features of the ligands involved in the interactions with the proposed targets. Methods: A molecular docking study was carried out on ten active constituents of Terminalia bellerica with four-drug targets involved in the aetiology of schizophrenia. These targets are dopamine, N-methyl- D-aspartate, Gamma-aminobutyric acid, and phosphodiesterase 10A receptors. The binding interactions between the target proteins and the ligands with the highest affinities were studied thoroughly. Results: β-sitosterol, ellagic acid, and quercetin displayed high binding affinity toward all the macromolecular drug targets. β -sitosterol possesses a high binding affinity for the dopamine receptor, while quercetin has high binding affinities for both dopamine and N-methyl-D-aspartate receptor. On the other hand, ellagic acid formed stronger binding interactions with Gamma-aminobutyric acid and phosphodiesterase 10A. Conclusion: Terminalia bellerica can serve as a new anti-psychotic drug from natural sources with more promising development.

Atypical, but Not Typical, Antipsychotic Drugs Reduce Hypersynchronized Prefrontal-Hippocampal Circuits during Psychosis-Like States in Mice: Contribution of 5-HT2A and 5-HT1A Receptors.

Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone.

Accumulating evidence suggests that the epigenetic alterations induced by antipsychotics contribute to the therapeutic efficacy. However, global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics remain poorly understood. We conducted a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with antipsychotics. The cells were cultured with low and high concentrations of haloperidol or risperidone for 8 days. DNA methylation assay was performed with the Illumina HumanMethylation450 BeadChip. We found that both haloperidol and risperidone tended to cause hypermethylation changes and showed similar DNA methylation changes closely related to neuronal functions. A total of 294 differentially methylated probes (DMPs), including 197 hypermethylated and 97 hypomethylated DMPs, were identified with both haloperidol and risperidone treatment. Gene ontology analysis of the hypermethylated probe-associated genes showed enrichment of genes related to the regulation of neurotransmitter receptor activity and lipoprotein lipase activity. Pathway analysis identified that among the DMP-associated genes, SHANK1 and SHANK2 were the major genes in the neuropsychiatric disorder-related pathways. Our data would be valuable for understanding the mechanisms of action of antipsychotics from an epigenetic viewpoint.

Effects of an Atypical Antipsychotic, Zotepine, on Astroglial L-Glutamate Release through Hemichannels: Exploring the Mechanism of Mood-Stabilising Antipsychotic Actions and Antipsychotic-Induced Convulsion.

Accumulating neuropsychopharmacological evidence has suggested that functional abnormalities of astroglial transmission and protein kinase B (Akt) contribute to the pathophysiology and/or pathomechanisms of several neuropsychiatric disorders, such as epilepsy, schizophrenia, affective disorders and antipsychotic-induced convulsions. Therefore, to explore the pathophysiology of mood-stabilising antipsychotics and the proconvulsive actions of atypical antipsychotics, the present study determined the effects of a mood-stabilising, atypical, antipsychotic agent, zotepine (ZTP), on astroglial L-glutamate release and the expression of connexin43 (Cx43) protein in cortical, primary, cultured astrocytes using ultra-high-pressure liquid chromatography and capillary immunoblotting systems. Both acute and subchronic administrations of therapeutically relevant concentrations of ZTP did not affect astroglial L-glutamate release or Cx43 expression in plasma membranes; however, chronic administration of a therapeutically relevant concentration of ZTP increased astroglial L-glutamate release and Cx43 expression in the plasma membrane. Subchronic administrations of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release and Cx43 expression in the plasma membrane, whereas acute administration of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release without affecting Cx43 expression. These stimulatory effects of ZTP on astroglial L-glutamate release through activated hemichannels and Cx43 trafficking to the astroglial plasma membrane were suppressed by the Akt inhibitor. These results suggest that ZTP enhances astroglial L-glutamate release in a concentration-dependent and time-dependent manner due to the enhanced function of astroglial hemichannels, probably via activation of Akt signalling. Therefore, the enhanced astroglial L-glutamatergic transmission induced by ZTP is, at least partially, involved in the mood-stabilising antipsychotic and proconvulsive actions of ZTP.

Evaluation of Anti-Psychotic potential of Phytocompound rich Fractions of Methanolic extract of Lagenaria siceraria (Bottle Gourd) fruits in Murine Models of Schizophrenia

Context: Psychosis is a mental disorder, which is characterized as the reducing association with certainty and conviction. Around 1-2% of the world's population suffers from psychosis. The people affected by psychosis have hallucinations, delusions, forgetfulness, abolition, and anhedonia. Currently existing most of the anti- psychotic medications express the adverse drug reactions. Thus for the management of psychosis, satisfactory and adequate remedies are not available. Lagenaria siceraria (Molina) Standley (LS) (Cucurbitaceae) fruits, popularly known as “bottle gourd” (English) and “Lauki” (Hindi), exhibit numerous intrinsic therapeutic properties and actions. However limited scientific investigations have been performed to determine the neuroprotective potential of LS fruits. With this background, the present study was intended to investigate LS fruits for the assessment of anti-psychotic activity. Aims and Objectives: The rationale of this study was to evaluate the anti-psychotic activity of the phytocompound rich fractions of the methanolic extract of LS i.e., chloroform fraction of the methanolic extract (CFME), and acetone fraction of the methanolic extract (AFME) by using experimental models of cataleptic and stereotypic behavior in Swiss Albino mice. Materials and Methods: Haloperidol-induced catalepsy and apomorphine-induced stereotypy were the experimental screening tests performed for the assessment of anti-psychotic activity of the phytocompound rich fractions of methanolic extract of LS fruits at the doses of 100, 200, and 400mg/kg, p.o. in mice. Results: CFME and AFME, 100-400 mg/kg, significantly reduced cataleptic score and stereotypic behavior in mice, in dose-dependent manner. At doses of 200 and 400mg/ kg, AFME (P<0.001) exhibited more significant effect than CFME. In addition CFME and AFME did not generate motor dysfunction in mice. Preliminary phytochemical screening on CFME revealed the presence of saponins, phytosterols, and terpenoids, while phytochemical investigations on AFME indicated the presence of saponins, phenolic compounds, flavonoids and tannins. This was the first scientific report, which indicates that the LS fruits exhibit anti-psychotic action, confirming the folklore claims. Future investigations and studies should emphasize separation, characterization, and identification of the bioactive phytoconstituents and also on evaluating the precise mechanism involved in the anti-psychotic activity of both the fractions.

Dopamine, Serotonin, and Structure/Function Brain Defects as Biological Bases for Treatment Response in Delusional Disorder: A Systematic Review of Cases and Cohort Studies.

Although blockade of dopamine receptors D2 and D3 appears to be the main mechanism of antipsychotic action, treatment response variability calls for an examination of other biological systems. Our aim is to systematically review reports of treatment response in delusional disorder (DD) in order to help determine its biological bases. Computerized searches of ClinicalTrials.gov, PubMed, and Scopus databases (from 1999 to September 2021) were systematically reviewed, in keeping with PRISMA directives. We used the search terms: (treat * OR therap * AND (delusional disorder)). We included all studies that explored the biological mechanisms of treatment response in DD, as diagnosed by ICD or DSM criteria. A total of 4344 records were initially retrieved, from which 14 papers were included: case reports, case series, and cohort studies. Findings point to (1) dopaminergic dysfunction (based on biochemical and genetic studies), (2) serotonergic dysfunction (based on partial agonism/antagonism of drugs), and (3) brain structure/function impairment, especially in the temporal and parietal lobes, as crucial factors in treatment response. Further studies with higher levels of evidence are needed to help clinicians determine treatment.

Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice.

Background: Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown.Methods: We co-treated selective class 1 HDAC inhibitor tacedinaline (CI-994) at different doses (10, 20, and 30 mg/kg) with HAL (0.05 mg/kg) in young (3 months) and aged (21 months) mice for 14 consecutive days, then motor and memory behavioral tests were conducted, followed by biochemical measurements.Results: CI-994 at doses of 10 and 20 mg/kg could decrease HAL-induced cataleptic episodes but only 20 mg/kg was sufficient to improve motor coordination in aged mice. Additionally, CI-994 at 10 and 20 mg/kg mitigate HAL-induced memory impairment in aged mice. Biochemical analyses showed increased acetylation of histone marks H3K27ac and H3K18ac at the dopamine 2 receptor (D2R) gene (Drd2) promoter and increased expression of the Drd2 mRNA and D2R protein in the striatum of aged mice after administration of CI-994 at 20 mg/kg.Conclusions: Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the Drd2 promoter, thereby restoring D2R expression and improving antipsychotic drug action.

Repeated co-treatment with mirtazapine and aripiprazole reversed the schizophrenia-like behaviors and increased the brain-derived neurotrophic factor mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal brain development.

Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.

In Silico Screening of Novel α1-GABAA Receptor PAMs towards Schizophrenia Based on Combined Modeling Studies of Imidazo [1,2-a]-Pyridines.

The ionotropic GABAA receptor (GABAAR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABAARs with potent antipsychotic activities, have been reported recently. To better clarify the pharmacological essentiality of these PAMs and explore novel antipsychotics hits, three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) were performed on 33 imidazo [1,2-a]-pyridines. The constructed 3D-QSAR models exhibited good predictive abilities. The dockings results and MD simulations demonstrated that hydrogen bonds, π–π stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABAAR binding pocket. Four hit compounds (DS01–04) were then screened out by the combination of the constructed models and computations, including the pharmacophore model, Topomer Search, molecular dockings, ADME/T predictions, and MD simulations. The compounds DS03 and DS04, with higher docking scores and better predicted activities, were also found to be relatively stable in the binding pocket by MD simulations. These results might provide a significant theoretical direction or information for the rational design and development of novel α1-GABAAR PAMs with antipsychotic activities.