quetiapine-fumarate and Disease-Models--Animal

Overdoses with cardio-depressive medications can result in toxin-induced cardiogenic shock (TICS), a life-threatening condition characterized by severe hypotension and ineffective tissue perfusion. Vasopressors are often employed in the treatment of shock to increase heart rate and blood pressure. We sought to conduct a systematic review of the literature to evaluate the effectiveness of vasopressors in improving hemodynamic function and survival in the treatment of TICS.. We searched PubMed, EMBASE, TOXLINE, and International Pharmaceutical Abstracts.. We included studies evaluating the use of vasopressors in humans or animals with TICS. We limited human study types to randomized controlled trials, clinical trials, observational studies, and case reports.. Our search yielded 913 citations and 144 of these met our inclusion criteria. 130 were human case reports and 14 were animal studies.. Human case report data showed vasopressors were ineffective more often than they were partially or fully effective. In the majority of animal studies, vasopressor treatment failed to improve hemodynamic parameters and resulted in decreased survival.. Human case reports and controlled animal experiments lead to different conclusions about vasopressors in TICS. Most animal studies indicate that vasopressors impair hemodynamic function and increase mortality. In contrast, human case reports suggest that vasopressors are often ineffective but not necessarily harmful.

Topics: Animals; Antidepressive Agents, Tricyclic; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Drug Overdose; Glucagon; Heart Rate; Hemodynamics; Humans; Observational Studies as Topic; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Shock, Cardiogenic; Vasoconstrictor Agents

Quetiapine is a novel dibenzothiazepine atypical antipsychotic. Quetiapine shows affinity for various neurotransmitter receptors including serotonin, dopamine, histamine, and adrenergic receptors and has binding characteristics at the dopamine-2 receptor similar to those of clozapine. In animal models, the drug has a preclinical profile suggestive of antipsychotic activity with a reduced tendency to cause extrapyramidal symptoms (EPS) and sustained prolactin elevation. For example, quetiapine alters neurotensin neurotransmission and c-fos expression in limbic but not motor brain regions. The drug also demonstrates clozapine-like activity in a range of behavioral and biochemical tests and may possess neuroprotective properties. In humans, quetiapine exhibits linear pharmacokinetics with a mean terminal half-life of 7 hours. The primary route of elimination of quetiapine is through hepatic metabolism. Although not affected by smoking, alterations in quetiapine disposition due to age or hepatic impairment are manageable by appropriate dosage reduction. The optimal dosing range for quetiapine is 150 to 750 mg/day, and recent results suggest that once-daily dosing may be suitable for some patients. Finally, imaging studies with positron emission tomography confirm significant differences between quetiapine and typical antipsychotics that may be indicative of their differences in mechanism of action and propensity for producing EPS.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Gene Expression; Genes, Immediate-Early; Humans; In Vitro Techniques; Psychotic Disorders; Quetiapine Fumarate; Receptors, Neurotransmitter; Tomography, Emission-Computed

Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were as follows: to evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant, and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine (20 mg/kg), imipramine (30 mg/kg), and escitalopram (10 mg/kg). At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 (IL-6) levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Depressive Disorder, Major; Disease Models, Animal; Inflammation; Interleukin-6; Oxidative Stress; Quetiapine Fumarate; Rats; Stress, Psychological

Low-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment.. Compared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model.. There is no medical consensus regarding lithium use in patients with schizophrenia.. More pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.

Topics: Animals; Cognition; Cognitive Dysfunction; Disease Models, Animal; Dizocilpine Maleate; Humans; Lithium; Mice; Pilot Projects; Quetiapine Fumarate; Task Performance and Analysis

The selective activation of the muscarinic M

Topics: Allosteric Regulation; Animals; Antipsychotic Agents; CHO Cells; Cognition; Cognitive Dysfunction; Cricetulus; Disease Models, Animal; Haloperidol; Humans; Memory, Short-Term; Mice; Mice, Transgenic; MicroRNAs; Muscarinic Agonists; Olanzapine; Quetiapine Fumarate; Receptor, Muscarinic M1; Recombinant Proteins; Schizophrenia; Social Behavior

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous

Topics: Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Drug Carriers; Female; Male; Microdialysis; Models, Biological; Nanocapsules; Quetiapine Fumarate; Rats; Rats, Wistar; Reflex, Startle; Schizophrenia

A versatile method was developed and validated for simultaneous determination of the monoamine neurotransmitters (MNT) dopamine (DA), 3-4-dyhydroxyphenilacetic acid (DOPAC), homovanilic acid (HVA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in rat brain microdialysate samples using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The method allowed for small sample volume, using positive and negative ionization mode in a single run analysis without any derivatization or cleanup steps. Analytes were quantified at concentrations ranging from 100 ng/mL to 0.05, 10, 0.5, 0.1 or 1 ng/mL (lower limit of quantification, LLOQ) of DA, DOPAC, HVA, 5-HT and 5-HIAA, respectively, showing linearity (r > 0.98), accuracy, and precision (R.S.D ± 15%) according to validation limits accepted by international guidelines. The method was successfully applied for monitoring the concentration changes of MNT in microdialysate samples from medium prefrontal cortex of Wistar rats in a neurodevelopmental model of schizophrenia before and after quetiapine 5 mg/kg i.v. bolus dose administration. No alterations in MNTs were observed in schizophrenia phenotyped rats (SPR) in comparison to the baseline shading a light on the limited response rate to antipsychotic drugs observed in chronic schizophrenic patients.

Topics: Animals; Brain Chemistry; Chromatography, Liquid; Disease Models, Animal; Linear Models; Male; Microdialysis; Neurotransmitter Agents; Quetiapine Fumarate; Rats; Rats, Wistar; Reproducibility of Results; Schizophrenia; Sensitivity and Specificity; Tandem Mass Spectrometry

The antipsychotic effect of Quetiapine (Que) has been extensively studied and growing evidence suggests that Que has a beneficial effect, improving cognitive functions and promoting myelin repair. However, the effects of Que on the brain lipidome and the association between Que-associated cognitive improvement and changes in lipids remain elusive. In the present study, we assessed the cognitive protective effects of Que treatment and used a mass spectrometry-based lipidomic approach to evaluated changes in lipid composition in the hippocampus, prefrontal cortex (PFC), and striatum in a mouse model of cuprizone (CPZ)-induced demyelination. CPZ induces cognitive impairment and remarkable lipid changes in the brain, specifically in lipid species of glycerophospholipids and sphingolipids. Moreover, the changes in lipid classes of the PFC were more extensive than those observed in the hippocampus and striatum. Notably, Que treatment ameliorated cuprizone-induced cognitive impairment and partly normalized CPZ-induced lipid changes. Taken together, our data suggest that Que may rescue cognitive behavioral changes from CPZ-induced demyelination through modulation of the brain lipidome, providing new insights into the pharmacological mechanism of Que for schizophrenia.

Topics: Animals; Brain; Cognition; Cuprizone; Disease Models, Animal; Lipidomics; Male; Mice; Mice, Inbred C57BL; Quetiapine Fumarate; Schizophrenia

Diabetic patients are at increased risk for developing memory and cognitive deficit. Prior studies indicate that neuroinflammation might be one important underlying mechanism responsible for this deficit. Quetiapine (QTP) reportedly exerts a significant neuroprotective effect in animal and human studies. Here, we investigated whether QTP could prevent memory deterioration and cognitive impairment in a streptozotocin- (STZ-) induced diabetic mouse model. In this study, we found that STZ significantly compromised the behavioral performance of mice in a puzzle box test, but administering QTP effectively attenuated this behavioral deficit. Moreover, our results showed that QTP could significantly inhibit the activation of astrocytes and microglia in these diabetic mice and reduce the generation and release of two cytokines, tumor necrosis factor-

Topics: Animals; Astrocytes; Chemokine CCL2; Cognition Disorders; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Disease Models, Animal; Executive Function; Male; Memory; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Quetiapine Fumarate; Streptozocin; Tumor Necrosis Factor-alpha

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine's beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production. Graphical Abstract.

Topics: Animals; Antipsychotic Agents; Appetitive Behavior; Attention; Delirium; Disease Models, Animal; Drug Evaluation, Preclinical; Executive Function; Female; Frontal Lobe; Hydrocortisone; Inflammation; Lipopolysaccharides; Quetiapine Fumarate; Random Allocation; Rats; Rats, Sprague-Dawley; Reversal Learning; Reward; Set, Psychology; Tumor Necrosis Factor-alpha

Topics: Anesthetics, Local; Animals; Antipsychotic Agents; Aripiprazole; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Mice; Mice, Inbred BALB C; Quetiapine Fumarate; Seizures; Survival Rate

The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI.. The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 μM; 1 hour) followed by an inflammatory activator (20 μg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein β-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 μM; 1 hour) followed by chitosan (20 μg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (ΔI) represented BBB hyperpermeability. A matrix metalloproteinase-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo.. In silico studies showed quetiapine thermodynamically favorable binding to MMP-9. Junctional localization of zonula occludens-1 and β-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05).. Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity.. level IV.

Topics: Animals; Antipsychotic Agents; beta Catenin; Blood-Brain Barrier; Brain; Brain Injuries, Traumatic; Cells, Cultured; Chitosan; Computer Simulation; Disease Models, Animal; Electric Impedance; Endothelial Cells; Humans; Intravital Microscopy; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Microvessels; Models, Molecular; Permeability; Quetiapine Fumarate; Rats; Tight Junctions; Zonula Occludens-1 Protein

Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.. We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action.. Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635.. Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Conditioning, Operant; Dibenzothiazepines; Disease Models, Animal; Helplessness, Learned; Humans; Immobility Response, Tonic; Male; Mice; Norepinephrine Plasma Membrane Transport Proteins; Piperazines; Punishment; Pyridines; Quetiapine Fumarate; Radioligand Assay; Rats; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists

Atypical antipsychotics are associated with an increased risk of hyperglycaemia, thus limiting their clinical use. This study focused on finding the molecular mechanism underlying antipsychotic-induced hyperglycaemia. First, we searched for drug combinations in the FDA Adverse Event Reporting System (FAERS) database wherein a coexisting drug reduced the hyperglycaemia risk of atypical antipsychotics, and found that a combination with vitamin D analogues significantly decreased the occurrence of quetiapine-induced adverse events relating diabetes mellitus in FAERS. Experimental validation using mice revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. Further database analysis of the relevant signalling pathway and gene expression predicted quetiapine-induced downregulation of Pik3r1, a critical gene acting downstream of insulin receptor. Focusing on the phosphatidylinositol 3-kinase (PI3K) signalling pathway, we found that the reduced expression of Pik3r1 mRNA was reversed by cholecalciferol supplementation in skeletal muscle, and that insulin-stimulated glucose uptake into C2C12 myotube was inhibited in the presence of quetiapine, which was reversed by concomitant calcitriol in a PI3K-dependent manner. Taken together, these results suggest that vitamin D coadministration prevents antipsychotic-induced hyperglycaemia and insulin resistance by upregulation of PI3K function.

Topics: Animals; Antipsychotic Agents; Cell Line; Cholecalciferol; Class Ia Phosphatidylinositol 3-Kinase; Data Mining; Databases, Factual; Disease Models, Animal; Glucose Transporter Type 4; Humans; Hyperglycemia; Insulin Resistance; Mice; Quetiapine Fumarate; Signal Transduction; Vitamin D

Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Disease Models, Animal; Epilepsy; Haloperidol; Mental Disorders; Olanzapine; Quetiapine Fumarate; Rats; Risperidone; Seizures

It has been suggested that amphetamine abuse and withdrawal mimics the diverse nature of bipolar disorder symptomatology in humans. Here, we determined if a single paradigm of amphetamine sensitization would be sufficient to produce both manic- and depressive-related behaviors in mice. CD-1 mice were subcutaneously dosed for 5 days with 1.8 mg/kg d-amphetamine or vehicle. On days 6-31 of withdrawal, amphetamine-sensitized (AS) mice were compared to vehicle-treated (VT) mice on a range of behavioral and biochemical endpoints. AS mice demonstrated reliable mania- and depression-related behaviors from day 7 to day 28 of withdrawal. Relative to VT mice, AS mice exhibited long-lasting mania-like hyperactivity following either an acute 30-min restraint stress or a low-dose 1 mg/kg d-amphetamine challenge, which was attenuated by the mood-stabilizers lithium and quetiapine. In absence of any challenge, AS mice showed anhedonia-like decreases in sucrose preference and depression-like impairments in the off-line consolidation of motor memory, as reflected by the lack of spontaneous improvement across days of training on the rotarod. AS mice also demonstrated a functional impairment in nest building, an ethologically-relevant activity of daily living. Western blot analyses revealed a significant increase in methylation of histone 3 at lysine 9 (H3K9), but not lysine 4 (H3K4), in hippocampus of AS mice relative to VT mice. In situ hybridization for the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) further revealed heightened activation of corticolimbic structures, decreased functional connectivity between frontal cortex and striatum, and increased functional connectivity between the amygdala and hippocampus of AS mice. The effects of amphetamine sensitization were blunted in C57BL/6J mice relative to CD-1 mice. These results show that a single amphetamine sensitization protocol is sufficient to produce behavioral, functional, and biochemical phenotypes in mice that are relevant to bipolar disorder.

Topics: Anhedonia; Animals; Bipolar Disorder; Cerebral Cortex; Dextroamphetamine; Disease Models, Animal; Limbic System; Lithium Compounds; Male; Memory Consolidation; Mice; Mice, Inbred C57BL; Motor Activity; Nesting Behavior; Neural Pathways; Psychotropic Drugs; Quetiapine Fumarate; Restraint, Physical; Species Specificity; Stress, Psychological; Substance Withdrawal Syndrome

Quetiapine (QUE) and repetitive transcranial magnetic stimulation (rTMS) have been considered to be possible monotherapies for depression or adjunctive therapies for the treatment of the resistant depression, but the underlying mechanisms remain unclear. The present study aimed to assess the effects of combined QUE and rTMS treatment on depressive-like behaviors, hippocampal proliferation, and the in vivo and in vitro expressions of phosphorylated extracellular signal-regulated protein kinase (pERK1/2) and brain-derived neurotrophic factor (BDNF) in male Sprague-Dawley rats. The administration of QUE and rTMS was determined not only to reverse the depressive-like behaviors of rats exposed to chronic unpredictable stress (CUS) but also to restore the protein expressions of pERK1/2 and BDNF and cell proliferation in the hippocampus. Additionally, QUE and rTMS promoted the proliferation and increased the expression of pERK1/2 and BDNF in hippocampal-derived neural stem cells (NSCs), and these effects were abolished by U0126. Taken together, these results suggest that the antidepressive-like effects of QUE and rTMS might be related to the activation of the BDNF/ERK signaling pathway and the up-regulation of cell proliferation in the hippocampus.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Butadienes; Cell Proliferation; Cell Survival; Cells, Cultured; Depression; Disease Models, Animal; Hippocampus; Male; MAP Kinase Signaling System; Neural Stem Cells; Nitriles; Quetiapine Fumarate; Rats; Transcranial Magnetic Stimulation

Developmental delay, cognitive impairment, and refractory epilepsy are the most frequent consequences found in patients suffering from malformations of cortical development (MCD). However, therapeutic options for these psychiatric and neurological comorbidities are currently limited. The development of white matter undergoes dramatic changes during postnatal brain maturation, thus myelination deficits resulting from MCD contribute to its comorbid diseases. Consequently, drugs specifically targeting white matter are a promising therapeutic option for the treatment of MCD. We have used an in utero irradiation rat model of MCD to investigate the effects of postnatal quetiapine treatment on brain myelination as well as neuropsychological and cognitive performances and seizure susceptibility. Fatally irradiated rats were treated with quetiapine (10mg/kg, i.p.) or saline once daily from postnatal day 0 (P0) to P30. We found that postnatal administration of quetiapine attenuated object recognition memory impairment and improved long-term spatial memory in the irradiated rats. Quetiapine treatment also reduced the susceptibility and severity of pentylenetetrazol-induced seizures. Importantly, quetiapine treatment resulted in an inhibition of irradiation-induced myelin breakdown in the cerebral cortex and corpus callosum. These findings suggest that quetiapine may have beneficial, postnatal effects in the irradiated rats, strongly suggesting that improving MCD-derived white matter pathology is a possible underlying mechanism. Collectively, these results indicate that brain myelination represents an encouraging pharmacological target to improve the prognosis of patients with MCD.

Topics: Animals; Animals, Newborn; Anticonvulsants; Cerebral Cortex; Cognition Disorders; Corpus Callosum; Disease Models, Animal; Malformations of Cortical Development; Maze Learning; Myelin Sheath; Nootropic Agents; Pentylenetetrazole; Quetiapine Fumarate; Rats, Sprague-Dawley; Recognition, Psychology; Seizures; Severity of Illness Index; Spatial Memory; X-Rays

This study aimed at examining effects of quetiapine (QTP), an atypical antipsychotic, on the behaviors of mice which had consumed cuprizone (CPZ)-containing diet for one week and on inflammatory reactions and oligodendrocyte (OL) loss in brains of them. Young adult C57BL/6 mice, after fed CPZ-containing diet (0.2%, w/w) for one week, showed an increase in the locomotor activity in the open-field, and a decreased exploration time in the novel object recognition (NOR) test compared to controls. But, these changes were not seen in mice co-administered with QTP and CPZ. All mice in the four groups showed comparable performances in Y-maze test. After the behavioral tests, mice were killed and their brains were processed for immunohistochemical and immunofluorescence staining to examine OLs, astrocytes and microglia. The levels of proinflammatory cytokines TNF-α and IL-6 in certain brain regions were also evaluated by ELISA method. Mice in the NS+CPZ group showed fewer OLs, more activated astrocytes and microglia with higher immunofluorescence intensity in the examined brain regions of the corpus callosum, caudate putamen, cerebral cortex, and hippocampus. The levels of TNF-α and IL-6 in some of these brain regions were also increased. But these changes were completely blocked or effectively ameliorated in the QTP+CPZ group. These results demonstrated an anti-inflammatory effect of QTP in CPZ-exposed mice and this action may contribute to its protection on OLs and beneficial effects on the CPZ-induced behavioral changes in these mice.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cuprizone; Disease Models, Animal; Encephalitis; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior; Immunohistochemistry; Interleukin-6; Male; Maze Learning; Mice, Inbred C57BL; Motor Activity; Oligodendroglia; Quetiapine Fumarate; Tumor Necrosis Factor-alpha

Cuprizone is a copper-chelating agent and able to induce oligodendrocyte loss and demyelination in C57BL/6 mouse brain. Recent studies have used the cuprizone-fed mouse as an animal model of schizophrenia to examine putative roles of altered oligodendrocytes in this mental disorder. The present study reported the effects of cuprizone on the brain metabolites and oxidative parameters with the aim of providing neurochemical evidence for the application of the cuprizone mouse as an animal model of schizophrenia. In addition, we examined effects of quetiapine on the cuprizone-induced changes in brain metabolites and oxidative parameters; this atypical antipsychotic was shown to ameliorate the cuprizone-induced demyelination and behavioral changes in previous studies. C57BL/6 mice were fed a standard rodent chow without or with cuprizone (0.2% w/w) for four weeks during which period they were given sterilized saline or quetiapine in saline. The results of the proton magnetic resonance spectroscopy (1H-MRS) showed that cuprizone-feeding decreased (1)H-MRS signals of N-acetyl-l-aspartate (NAA), total NAA (NAA + NAAG), and choline-containing compounds (phosphorylcholine and glycerophosphorylcholine), suggestive of mitochondrial dysfunction in brain neurons. Biochemical analyses showed lower activities of catalase and glutathione peroxidase, but higher levels of malondialdehyde and H2O2 in the brain tissue of cuprizone-fed mice, indicative of an oxidative stress. These cuprizone-induced changes were effectively relieved in the mice co-administered with cuprizone and quetiapine, although the antipsychotic alone showed no effect. These findings suggest the toxic effects of cuprizone on mitochondria and an antioxidant capacity of quetiapine, by which this antipsychotic relieves the cuprizone-induced mitochondrial dysfunction in brain cells.

Topics: Animals; Antipsychotic Agents; Brain; Chelating Agents; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Hydrogen Peroxide; Male; Mice, Inbred C57BL; Neurons; Oligodendroglia; Quetiapine Fumarate

Quetiapine, an atypical antipsychotic drug, may have beneficial effects in Alzheimer's disease (AD), and the effect of quetiapine on object recognition memory in AD has never been measured. The aim of the present study was to evaluate the effects of quetiapine on object recognition memory and on oxidative stress that could be involved in the AD pathogenesis in an amyloid precursor protein/presenilin-1 double transgenic mouse model of AD. Nontransgenic and transgenic mice were treated with quetiapine (0 or 5 mg/kg/day) in drinking water from the age of 2 months. After 10 months of continuous quetiapine administration, object recognition memory impairment and the increased hippocampal protein expression of nitrotyrosine, a protein marker of oxidative stress, were attenuated in the AD mice. These results suggest that quetiapine can attenuate object recognition memory impairment and brain oxidative stress in an amyloid precursor protein/presenilin-1 transgenic mouse model of AD and indicate that the antioxidative effect of early quetiapine intervention may be associated with the beneficial effect of quetiapine on memory in AD.

Topics: Alzheimer Disease; Animals; Antipsychotic Agents; Behavior, Animal; Dibenzothiazepines; Disease Models, Animal; Female; Hippocampus; Memory Disorders; Mice; Mice, Transgenic; Oxidative Stress; Quetiapine Fumarate; Recognition, Psychology

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs.

Topics: Alkylation; Animals; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Behavior, Animal; Conditioning, Operant; Depressive Disorder, Major; Dibenzothiazepines; Disease Models, Animal; Male; Neurotensin; Quetiapine Fumarate; Rats, Sprague-Dawley; Receptors, Neurotensin; Reinforcement, Psychology

Stress is any condition that seriously affects the balance of the organism physiologically and psychologically. Stress activates the hypothalamic-pituitary-adrenal (HPA) releasing glucocorticoid hormones that produce generalized effects on different body systems including the nervous system. This study aimed to investigate the effect of acute restraint stress (ARS) on cognitive performance by measuring spatial working memory in Y-maze, behavior (anxiety and exploratory behavior) in open field test, expression of synaptophysin and glial fibrillary acidic protein (GFAP) in the hippocampus by immunohistochemistry, dopaminergic receptors (D2) in the basal ganglia by gene expression and comparing the effect of ghrelin and quetiapine on the previous parameters. 36 adult male albino rats constituted the animal model of this work and have been divided into six groups: control group, control group exposed to ARS, quetiapine group, quetiapine group exposed to ARS, ghrelin group and ghrelin group exposed to ARS. We demonstrated more neuroprotective effect for quetiapine compared to ghrelin on stress response, anxiety behavior and working spatial memory impairment due to ARS.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior; Gene Expression Regulation; Ghrelin; Glial Fibrillary Acidic Protein; Hydrocortisone; Male; Maze Learning; Quetiapine Fumarate; Rats; Receptors, Dopamine D2; Stress, Psychological

In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism.. Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aβ levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro.. Quetiapine improves behavioral performance, marginally affects total Aβ40 and Aβ42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aβ1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aβ1-42.. The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antipsychotic Agents; Cells, Cultured; Cerebral Cortex; Cytokines; Dibenzothiazepines; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Microglia; Mutation; NF-kappa B; Presenilin-1; Quetiapine Fumarate; Recognition, Psychology; Signal Transduction

Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D2 receptors. In the United States, quetiapine is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. Despite its widespread use, its cellular effects remain elusive. To address possible mechanisms, we chronically treated mice with quetiapine, haloperidol or vehicle and examined quetiapine-specific gene expression change in the frontal cortex. Through microarray analysis, we observed that several groups of genes were differentially expressed upon exposure to quetiapine compared with haloperidol or vehicle; among them, Cdkn1a, the gene encoding p21, exhibited the greatest fold change relative to haloperidol. The quetiapine-induced downregulation of p21/Cdkn1a was confirmed by real-time polymerase chain reaction and in situ hybridization. Consistent with single gene-level analyses, functional group analyses also indicated that gene sets associated with cell cycle/fate were differentially regulated in the quetiapine-treated group. In cortical cell cultures treated with quetiapine, p21/Cdkn1a was significantly downregulated in oligodendrocyte precursor cells and neurons, but not in astrocytes. We propose that cell cycle-associated intervention by quetiapine in the frontal cortex may underlie a unique efficacy of quetiapine compared with typical neuroleptics.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Astrocytes; Cell Cycle; Dibenzothiazepines; Disease Models, Animal; Frontal Lobe; Gene Expression; Haloperidol; In Situ Hybridization; Male; Methamphetamine; Mice; Neurons; Oligodendroglia; p21-Activated Kinases; Principal Component Analysis; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Schizophrenia

The antidepressant action of quetiapine has been demonstrated in clinical and preclinical studies. Nevertheless, little is known about its effectiveness in the treatment of frontal-like cognitive disturbances that may be associated with stress-related disorder. Therefore, the aim of the present study was to investigate whether quetiapine would prevent and/or reverse stress-induced cognitive impairments in a rat model of prefrontal cortex (PFC)-dependent attentional set-shifting task (ASST). Because quetiapine augmentation to selective serotonin reuptake inhibitors (SSRIs) has recently been proven to be beneficial in neuropsychiatric disorders, a separate experiment was designed to assess the impact of combined administration of inactive doses of quetiapine and escitalopram on ASST performance in rats. According to our previous studies, 1 h daily exposure to restraint stress for 7 days significantly and specifically impaired extra-dimensional (ED) set-shifting ability of rats. Quetiapine (2.5 mg/kg, PO) given to rats prior to the restraint sessions completely prevented this stress-induced cognitive inflexibility. Similar effect was demonstrated after pretreatment with the α1-adrenoceptor antagonist, prazosin (1 mg/kg, IP). Moreover, acute administration of quetiapine before the test reversed set-shifting deficits in stressed rats (0.63, 1.25 and 2.5 mg/kg, PO) and improved ED performance of cognitively unimpaired control animals (1.25 and 2.5 mg/kg, PO). Finally, the combined administration of inactive doses of quetiapine (0.63 and 0.3 mg/kg in control and stressed rats, respectively) and escitalopram (0.3 mg/kg, IP) facilitated set-shifting performance in either control or stressed rats. In conclusion, quetiapine administration either prevented or reversed stress-induced cognitive inflexibility in rats. In addition to promoting of set-shifting by itself, quetiapine also enhanced the procognitive efficacy of escitalopram. The potential contribution of the antagonism at α1-adrenoceptors to the mechanisms underlying the protective action of quetiapine requires further evaluation. These findings may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antidepressive Agents, Second-Generation; Behavior, Animal; Citalopram; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Male; Neurons; Nootropic Agents; Performance-Enhancing Substances; Prefrontal Cortex; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Restraint, Physical; Selective Serotonin Reuptake Inhibitors; Stress, Physiological; Stress, Psychological

Our previous study has shown the preventive effects of quetiapine, an atypical antipsychotic drug, on memory impairment and brain pathological changes in a mouse model of Alzheimer's disease (AD). The aim of the present study was to evaluate the therapeutic effects of quetiapine on memory deficit and neuropathology in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The APP/PS1 mice started to have detectable brain β-amyloid (Aβ) at 3 months of age. Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5 mg/(kg day)) in drinking water from the age of 4 months. After 8 months of continuous quetiapine administration, memory deficit was reversed and brain Aβ plaque pathology was attenuated in the AD mice. Quetiapine also decreased the soluble Aβ peptide levels in brain and cerebrospinal fluid (CSF), and attenuated the decreased synaptic protein levels in the AD mice. Furthermore, quetiapine normalized the abnormal activity of glycogen synthase kinase-3β (GSK-3β), an AD-involved kinase, in the AD mice. These results suggest that quetiapine can treat and alleviate the neuropathology in an APP/PS1 transgenic mouse model of AD, and indicate that quetiapine may have therapeutic effects in the treatment of AD.

Topics: Alzheimer Disease; Animals; Blotting, Western; Brain; Dibenzothiazepines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Quetiapine Fumarate

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioral and psychological symptoms in Alzheimer's disease (AD). However, it is presently unclear whether quetiapine has beneficial effects on memory and whether the effects of quetiapine on psychological symptoms are associated with its effect on memory in AD. The present study was designed to examine the effect of chronic administration of quetiapine on the conditioned (generalized) anxiety that is related to learning experience of open arm exposure in the elevated T-maze (ETM) test in an amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. In a 2nd experiment, the effect of quetiapine on memory per se was investigated in a Y-maze test in AD mice. Non-transgenic and transgenic mice were treated with quetiapine in drinking water from the age of 2 months. After continuous treatment with quetiapine (5 mg/kg/day) for 10 months, mice were tested for conditioned anxiety on the ETM task. After ETM testing, the expression of brain-derived neurotrophic factor (BDNF), a neuroprotective protein, was examined by immunohistochemistry in the basolateral amygdala (BLA) and hippocampus. In the 2nd experiment, the effect of quetiapine (2.5 or 5 mg/kg/day) on the short-term memory in AD mice was tested in a Y-maze test. After 10 months of administration, quetiapine prevented the decrease of conditioned anxiety and cerebral BDNF in AD mice. In addition, quetiapine also prevented memory impairment in the Y-maze test in AD mice. These findings suggest that the therapeutic mechanism of quetiapine on anxiety in AD may be associated with its beneficial effect on memory and its neuroprotective effect on cerebral BDNF expression.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antipsychotic Agents; Anxiety; Avoidance Learning; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Humans; Learning Disabilities; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Mutation; Presenilin-1; Quetiapine Fumarate; Reaction Time; Time Factors

Prefrontal cortical dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. Nevertheless, the effectiveness of second-generation antipsychotic drugs in treating specific prefrontal dysfunctions remains equivocal.. To model schizophrenia-like cognitive inflexibility in rats, we evaluated the effects of repeated administration of ketamine, the noncompetitive antagonist of the N-methyl-D: -aspartate receptor, after a washout period of 14 days in the attentional set-shifting task (ASST). Next, we investigated whether the atypical antipsychotics quetiapine and sertindole would alleviate the ketamine-induced set-shifting impairment.. Ketamine (30 mg/kg) was administered intraperitoneally to rats once daily for 5 or 10 consecutive days to assess its efficacy in producing cognitive impairment. The ASST was performed 14 days following the final drug administration. Quetiapine (0.63, 1.25 or 2.5 mg/kg) or sertindole (2.5 mg/kg) was administered per os 120 min before testing.. The results of the present study demonstrate that ketamine treatment for 10 but not 5 days significantly and specifically impaired rats' performance in the extra-dimensional shift (EDs) stage of the ASST. This cognitive inflexibility was reversed by acute administration of sertindole or quetiapine. Quetiapine also promoted set-shifting in cognitively unimpaired control animals.. The data presented here show that subchronic administration of ketamine induces cognitive inflexibility after a washout period. This cognitive deficit likely reflects clinically relevant aspects of cognitive dysfunction encountered in schizophrenic patients. The beneficial effects of quetiapine on set-shifting may have therapeutic implications for the treatment of schizophrenia and other disorders associated with frontal-dependent cognitive impairments.

Topics: Animals; Antipsychotic Agents; Attention; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Imidazoles; Indoles; Ketamine; Male; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Schizophrenia

Myelin and oligodendrocyte dysfunctions have been consistently found in patients with schizophrenia. The effect of antipsychotics on myelin disturbances is unknown. The present study examined the effects of quetiapine on oligodendrocyte regeneration and myelin repair in a demyelination animal model. C57BL/6 mice were fed with cuprizone (0.2% w/w) for 12 weeks to induce chronic demyelination and oligodendrocyte degeneration, after which cuprizone was withdrawn to allow recovery. Quetiapine (10mg/kg/day) or vehicle (water) was administrated orally to mice for 0, 2, 3, or 4 weeks after cuprizone withdrawal. Locomotor activity and Y-maze tests were used to evaluate behavioral changes in the mice. Immunohistochemical staining was used to detect morphological and biological changes in the brains. Cuprizone administration for 12 weeks resulted in severe demyelination, locomotor hyperactivity, and working memory impairment in mice. Remyelination occurred when cuprizone was withdrawn. Quetiapine treatment during the recovery period significantly improved the spatial working memory and increased myelin restoration. Quetiapine treatment also enhanced the repopulation of mature oligodendrocytes in the demyelinated lesions, which was associated with down-regulation of transcription factor olig2 in the process of cell maturation. The results of this study demonstrated that quetiapine treatment during the recovery period improves spatial working memory and promotes oligodendrocyte development and remyelination. This study supports the role of oligodendrocyte dysfunction in memory deficits in a schizophrenia mouse model and suggests that quetiapine may target oligodendrocytes and improve cognitive function.

Topics: Animals; Antipsychotic Agents; Chelating Agents; Cuprizone; Demyelinating Diseases; Dibenzothiazepines; Disease Models, Animal; Memory, Short-Term; Mice; Mice, Inbred C57BL; Motor Activity; Myelin Sheath; Oligodendroglia; Quetiapine Fumarate; Regeneration; Schizophrenia

White matter impairment is a feature of vascular depression. The anti-psychotic quetiapine has been shown to enhance the therapeutic effects of anti-depressants on vascular depression, but the mechanism remains unknown. In this study, we found that 2 weeks of treatment with quetiapine prior to bilateral carotid artery occlusion and reperfusion, in an animal model of vascular depression, resulted in reduced myelin breakdown and oligodendrocyte loss compared to placebo-treated mice on post-operative day (POD) 7. For late stage of recovery (POD40), quetiapine treatment resulted in enhanced oligodendrocyte maturation relative to placebo. The results suggest that quetiapine is a potential intervention for oligodendrocyte damage and this may contribute to its anti-depressant effects through white matter protection in vascular depression.

Topics: Analysis of Variance; Animals; Antigens; Antipsychotic Agents; Brain Ischemia; Bromodeoxyuridine; Carotid Artery Diseases; Cell Differentiation; Dibenzothiazepines; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hippocampus; Male; Mice; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Proteoglycans; Quetiapine Fumarate; Time Factors

Antipsychotic drug-induced sexual dysfunction is a common and problematic side effect, which may diminish quality of life and lead to treatment noncompliance. Up to date, there is still a scarcity of basic research regarding the chronic effects of most antipsychotic agents on sexual behavior.. The present study investigated the effect of a range of doses of three antipsychotic drugs (haloperidol, risperidone, and quetiapine) on male rat sexual competence following chronic administration.. Twelve groups of Sprague-Dawley rats (n = 7 each) received by gavage haloperidol (0.25, 0.5, or 1 mg/kg), risperidone (0.125, 0.25, or 0.5 mg/kg), quetiapine (10, 20, and 40 mg/kg) or vehicle (distilled water) in the corresponding control groups, respectively, once daily for 21 days. Sexual function was evaluated by the copulatory behavior test 10 hours after the last dose.. The male rat behavioral parameters of copulatory test.. Sexual function was widely and significantly suppressed by high dose haloperidol (1 mg/kg) after 21 days administration compared with the control group, which included both frequency and latency of intromission and ejaculation. Only ejaculation latency was significantly impaired after administration with 0.5 mg/kg haloperidol. Compared with the control group, high dose risperidone (0.5 mg/kg) significantly decreased the frequency of mounting. There were no significant changes in sexual behavior with the lower doses of either haloperidol or risperidone. Sexual behavior was not influenced by any dose of quetiapine.. Haloperidol and risperidone, but not quetiapine, could impair sexual competence in a dose-related manner in male rats.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Dibenzothiazepines; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Haloperidol; Humans; Male; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Risperidone; Serotonin Antagonists; Sexual Behavior, Animal; Sexual Dysfunction, Physiological; Statistics as Topic; Time Factors

Chronic pubertal cannabinoid treatment in rats has been suggested for modelling aspects of schizophrenia since it results in long-lasting behavioural alterations reflecting certain characteristics of schizophrenia symptomatology. Lasting deficits in sensorimotor gating, impaired short-term mnemonic processing, reduced motivation as well as inappropriate and deficient social behaviour have been reported after chronic cannabinod treatment during pubertal development. In addition, sensorimotor gating deficits were able to be restored by acute injections of the typical antipsychotic haloperidol. The aim of this study was to examine possible acute as well as lasting beneficial effects of the atypical antipsychotic drug quetiapine in adult animals undergoing chronic treatment of the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) (1.2 mg/kg) during puberty. Therefore, animals were tested repeatedly for their performance in social interaction and social recognition after acute and chronic quetiapine treatment. Chronic pubertal WIN treatment induced persistent deficits in social recognition and impaired social interaction. Acute quetiapine treatment was able to completely restore those deficits in social behaviour and social memory. Social recognition memory was affected again 1 wk after cessation of chronic quetapine treatment; however, in social interaction persistent improvements could be detected. In conclusion, the results indicate that the atypical antipsychotic drug quetiapine is able to acutely restore deficits in social behaviour induced by developmental cannabinoid exposure and even exert some persistent beneficial effects. Furthermore, the present data give further support and validity for the suitability of chronic pubertal cannabinoid administration as an animal model for aspects of schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoids; Dibenzothiazepines; Disease Models, Animal; Grooming; Male; Memory; Morpholines; Naphthalenes; Quetiapine Fumarate; Rats; Rats, Wistar; Recognition, Psychology; Schizophrenia; Sexual Maturation; Social Behavior; Time Factors

The purpose of this study was to determine preventive and protective effects of chronic orally administration with quetiapine (QUE) against anxiety-like behavior and cognitive impairments in rats exposed to the enhanced single prolonged stress (ESPS), an animal model that is used to study post-traumatic stress disorder (PTSD), and to detect changes in the expression of cortical phosphorylated p44/42 extracellular-regulated protein kinase (pERK1/2). Before or after exposure to ESPS paradigm, consisting of 2-h constraint, 20-min forced swimming, ether-induced loss of consciousness, and an electric foot shock, rats were given orally QUE (10 mg/kg daily) for 14 days. Animals were then tested in the open field (OF), elevated plus-maze (EPM), and Morris water maze (MWM). Brains were removed for immunohistochemical staining of pERK1/2. ESPS exposure resulted in pronounced anxiety-like behavior compared to unexposed animals. ESPS-exposed animals also displayed marked learning and spatial memory impairments. However, QUE treatment (both before and after ESPS exposure) significantly ameliorated anxiety-like behavior, learning and spatial memory impairments. ESPS also markedly reduced the expression of pERK1/2 in the prefrontal cortex, medial amygdala nucleus, and cingulate gyrus. Both before and after ESPS exposure QUE treatments significantly elevated the reduced pERK1/2 expression in the three brain regions. QUE has preventive and protective effects against stress-associated symptoms and the changes in pERK1/2 functions may be associated with the pathophysiology of traumatic stress and the therapeutic efficacy of anti-PTSD therapy.

Topics: Anesthetics, Inhalation; Animals; Antipsychotic Agents; Anxiety Disorders; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Electroshock; Ether; Extracellular Signal-Regulated MAP Kinases; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neurons; Prefrontal Cortex; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Swimming; Unconsciousness

Previously, we showed that quetiapine, an atypical antipsychotic drug, significantly attenuated neurodegeneration induced by global cerebral ischemia (GCI). The present work investigates the effects of quetiapine on neurogenesis.. Mice were treated with quetiapine (10 or 20 mg/kg/day; intraperitoneal injection) for 2 weeks and then subjected to GCI on day 15. Seven days after GCI, the mice were killed. Neuronal injury and neurogenesis were analysed using hematoxylin-eosin and 5-bromo-20-deoxyuridine stainings. Levels of nuclear factor kappaB (NF-kappaB) p65/p50 expressions were determined by immunohistochemistry and Western blot analysis.. Global cerebral ischemia resulted in neuronal injury, neurogenesis and NF-kappaB p65/p50 expressions in hippocampus, especially in the dentate gyrus. Pre-administration of quetiapine significantly alleviated neuronal injury, while inhibiting neurogenesis and down-regulating NF-kappaB p65/p50 expression.. NF-kappaB plays a key role in regulating neuron damage and neurogenesis. This work suggests that down-regulation of NF-kappaB expression may be one of the mechanisms by which quetiapine inhibits neurogenesis.

Topics: Animals; Antipsychotic Agents; Brain Ischemia; Bromodeoxyuridine; Cell Count; Cell Proliferation; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hippocampus; Male; Mice; Mice, Inbred ICR; Neurogenesis; NF-kappa B p50 Subunit; Quetiapine Fumarate; Transcription Factor RelA

Accumulating evidence suggests that alpha(1)-adrenoceptors may be involved in the mechanisms of action of some antipsychotic drugs. The present study was undertaken to examine the effects of quetiapine, an atypical antipsychotic drug with alpha(1)-adrenoceptor antagonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of quetiapine (1.0, 10, or 30 mg/kg, p.o.) attenuated PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose dependent manner. Furthermore, PCP (10 mg/kg)-induced cognitive deficits were also significantly ameliorated by subsequent subchronic (14 days) administration of the selective alpha(1)-adrenoceptor antagonist prazosin (1.0 mg/kg/day, p.o.). Moreover, Western blot analysis revealed that levels of two subtypes (alpha(1A) and alpha(1B)) of alpha(1)-adrenoceptors were significantly lower in the brains of PCP-treated mice than in those of saline-treated mice. These findings suggest that repeated PCP administration could decrease the density of alpha(1)-adrenoceptors in mouse brain, and that subsequent subchronic administration of quetiapine might ameliorate PCP-induced cognitive deficits via alpha(1)-adrenoceptors. Therefore, it is likely that antagonism at alpha(1)-adrenoceptors is involved in the mechanism underlying quetiapine's psychopharmacological action.

Topics: Adrenergic alpha-Antagonists; Analysis of Variance; Animals; Antipsychotic Agents; Brain; Cognition; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Male; Mice; Mice, Inbred ICR; Phencyclidine; Prazosin; Quetiapine Fumarate; Receptors, Adrenergic, alpha-1; Time Factors

Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Dibenzothiazepines; Dietary Fats; Disease Models, Animal; Eating; Exenatide; Food Preferences; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Obesity; Peptides; Pyrazines; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Venoms

Previous studies have suggested that quetiapine, an atypical antipsychotic drug, may have beneficial effects on cognitive impairment, and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the effects of quetiapine on memory impairment and pathological changes in an amyloid precursor protein (APP)/presenilin-1 (PS-1) double transgenic mouse model of Alzheimer's disease (AD). Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5mg/(kg day)) for 1, 4, and 7 months in drinking water from the age of 2 months. After 4 and 7 months of continuous quetiapine administration, memory impairment was prevented, and the number of beta-amyloid (Abeta) plaques decreased in the cortex and hippocampus of the transgenic mice. Quetiapine also decreased brain Abeta peptides, beta-secretase activity and expression, and the level of C99 (an APP C-terminal fragment following cleavage by beta-secretase) in the transgenic mice. Furthermore, quetiapine attenuated anxiety-like behavior, up-regulated cerebral Bcl-2 protein, and decreased cerebral nitrotyrosine in the transgenic mice. These findings suggest that quetiapine can alleviate cognitive impairment and pathological changes in an APP/PS1 double transgenic mouse model of AD, and further indicate that quetiapine may have preventive effects in the treatment of AD.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Antipsychotic Agents; Anxiety; Brain; Dibenzothiazepines; Disease Models, Animal; Female; Male; Memory Disorders; Mice; Mice, Transgenic; Plaque, Amyloid; Presenilin-1; Protease Nexins; Proto-Oncogene Proteins c-bcl-2; Quetiapine Fumarate; Receptors, Cell Surface; Tyrosine

Sensorimotor gating disruptions are seen in various psychiatric illnesses with putatively different pathologies, including schizophrenia and bipolar disorder. Interestingly, mice lacking the dopamine (DA) transporter (DAT) gene display markedly increased levels of DA, deficits in sensorimotor gating, and hyperactivity relative to wild-type mice. Atypical antipsychotics are effective treatments of schizophrenia and manic symptoms, presumably in part by antagonizing DA receptors. Here we report that treatment with clozapine (3 mg/kg) or quetiapine (2.5 mg/kg) attenuated prepulse inhibition deficits in male DAT knockout mice. Thus male DAT knockout mice may provide a useful animal model for predicting the efficacy of novel drugs in treating psychiatric illnesses characterized by a dysregulated DA system.

Topics: Animals; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Injections, Intraperitoneal; Mice; Mice, Knockout; Mice, Mutant Strains; Quetiapine Fumarate; Reflex, Startle; Schizophrenia

Recent human studies employing new magnetic resonance imaging techniques and micro-array analyses feature schizophrenia as a brain disease with alterations in white matter (WM), which is mainly composed of oligodendrocytes (OLs) and their processes wrapping around neuronal axons. To examine the putative role of OLs in the pathophysiology and treatment of schizophrenia, animal studies are essential. In the present study, C57BL/6 mice were given 0.2% cuprizone (CPZ) in their diet for five weeks during which they drank distilled water without or with quetiapine (QTP, 10 mg/kg). The mice fed with normal chow were used as controls. CPZ is a copper chelator and has been reported to induce consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs. QTP is an atypical antipsychotic widely used in the treatment of schizophrenia and other psychotic disorders. In accordance with previous studies, CPZ-exposed mice showed pervasive myelin breakdown and demyelination. The amount of myelin basic protein (MBP) in the cerebral cortex was decreased by CPZ-exposure as shown in Western-blot analysis. In addition, the demyelinated sites were teemed with activated microglia and astrocytes but a few myelin forming OLs. Moreover, the activity of copper-zinc superoxide dismutase decreased in the cerebral cortex of CPZ-exposed mice. However, all of these pathological changes in WM were either prevented or alleviated in CPZ-exposed mice co-administered with QTP. These results suggest that the CPZ-exposed C57BL/6 mouse is a potential animal model to study possible roles of OLs in the pathogenesis and treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Astrocytes; Blotting, Western; Brain; Brain Diseases; Chelating Agents; Cuprizone; Demyelinating Diseases; Dibenzothiazepines; Disease Models, Animal; Mice; Mice, Inbred C57BL; Microglia; Oligodendroglia; Quetiapine Fumarate

Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H(1) receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT(1A), 5-HT(1E), 5-HT(2A), 5-HT(2B), 5-HT(7) receptors, the alpha(1B)-adrenergic receptor, and the M(1), M(3), and M(5) muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT(1D), 5-HT(2C), 5-HT(3), 5-HT(5), 5-HT(6), alpha(1A), alpha(2A), alpha(2B), alpha(2C), H(2), M(2), M(4), and dopamine D(1), D(2), D(3), and D(4) receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K(i) of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT(1A) receptor. N-Desalkylquetiapine was an antagonist at 5-HT(2A), 5-HT(2B), 5-HT(2C), alpha(1A), alpha(1D), alpha(2A), alpha(2C), H(1), M(1), M(3), and M(5) receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT(1A) agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Antipsychotic Agents; Brain Chemistry; Cell Line; CHO Cells; Cricetinae; Cricetulus; Depressive Disorder; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Quetiapine Fumarate; Rats; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Vesicular Monoamine Transport Proteins

Cognitive deficits in schizophrenia are severe and do not respond well to available treatments. The development and validation of animal models of cognitive deficits characterizing schizophrenia are crucial for clarifying the underlying neuropathology and discovery of improved treatments for such deficits.. We investigated whether single and repeated administrations of the psychotomimetic phencyclidine (PCP) disrupt performance in the five-choice serial reaction time task (5-CSRTT), a test of attention and impulsivity. We also examined whether PCP-induced disruptions in this task are attenuated by atypical antipsychotic medications.. A single injection of PCP (1.5-3 mg/kg, s.c., 30-min pre-injection time) had nonspecific response-depressing effects. Repeated PCP administration (2 mg/kg for two consecutive days followed by five consecutive days, s.c., 30-min pre-injection time) resulted in decreased accuracy, increased premature and timeout responding, and increased response latencies. The atypical antipsychotic medications clozapine, risperidone, quetiapine, and olanzapine and the typical antipsychotic medication haloperidol did not disrupt 5-CSRTT performance under baseline conditions except at high doses. The response depression induced by a single PCP administration was exacerbated by acute clozapine or risperidone and was unaffected by chronic clozapine. Importantly, chronic clozapine partially attenuated the performance disruptions induced by repeated PCP administration, significantly reducing both the accuracy impairment and the increase in premature responding.. Disruptions in 5-CSRTT performance induced by repeated PCP administration are prevented by chronic clozapine treatment and may constitute a useful animal model of some cognitive symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Attention; Benzodiazepines; Clozapine; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Hallucinogens; Haloperidol; Impulsive Behavior; Male; Olanzapine; Phencyclidine; Quetiapine Fumarate; Rats; Rats, Wistar; Reaction Time; Risperidone; Schizophrenia

Recently, we have reported that quetiapine, an atypical antipsychotic drug, prevents memory impairment and hippocampus neurodegeneration induced by global cerebral ischemia (GCI). In the present study, we examined the possible effects of quetiapine on other behavioural deficits, including the depressive and anxiolytic-like behavioural consequences of GCI. Mice were treated with quetiapine (5 or 10mg/kg/day; intraperitoneal (i.p.)) for 14 days. On Day 15, the animals were subjected to GCI. GCI resulted in a decrease of striatal tyrosine hydroxylase (TH) immunostaining and induced depressive and anxiolytic-like behavioural changes. The behavioural changes were indicated by a significant increase in the immobility duration in a tail-suspension test, and an increase in the time spent in the light box in a light/dark box test. Pre-administration of quetiapine significantly alleviated the decreased TH immunostaining and attenuated the depressive and anxiolytic-like behavioural changes induced by GCI. These results enhance our understanding about the mechanisms of quetiapine and suggest a wider perspective for the clinical use of quetiapine.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Anxiety; Behavior, Animal; Brain Ischemia; Depression; Dibenzothiazepines; Disease Models, Animal; Exploratory Behavior; Hindlimb Suspension; Male; Mice; Putamen; Quetiapine Fumarate; Tyrosine 3-Monooxygenase

Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsychotics and antidepressants, compared to responses to either type of drugs alone. Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14 days); (3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Cell Proliferation; Chronic Disease; Cyclohexanols; Depressive Disorder; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hippocampus; Neuronal Plasticity; Neurons; Quetiapine Fumarate; Rats; Restraint, Physical; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Stem Cells; Stress, Psychological; Venlafaxine Hydrochloride

Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects.. The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone.. We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model.. Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED50 values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED50 values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT1A agonist.. The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Administration, Oral; Animals; Antipsychotic Agents; Basal Ganglia Diseases; Catalepsy; Chlorpromazine; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Haloperidol; Hyperkinesis; Injections, Intraperitoneal; Male; Methamphetamine; Mice; Piperazines; Pyridines; Quetiapine Fumarate; Receptor, Serotonin, 5-HT1A; Risperidone; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists

Topics: Animals; Antipsychotic Agents; Callithrix; Clozapine; Dibenzothiazepines; Disease Models, Animal; Dyskinesia, Drug-Induced; Humans; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Prepulse inhibition (PPI) of startle is impaired in schizophrenia and in rats after manipulations of limbic cortical and subcortical regions. The atypical antipsychotic quetiapine was used to reverse PPI deficits after basolateral amygdala (BLA) lesions in rats. BLA quinolinic acid lesions significantly disrupted PPI 1 week postsurgery. Tests with quetiapine (0 vs. 7.5 mg/kg) in a within-subject design 2-3 weeks postsurgery revealed a normalization of PPI. Carry-over effects lasted up to 3 weeks, with a return of lesion-induced deficits by Week 5 postsurgery. This dose of quetiapine also blocked the PPI-disruptive effects of phencyclidine. PPI deficits after BLA lesions are reversed by quetiapine, in a manner that is sustained beyond its acute pharmacological effects and which may be mediated downstream from the BLA.

Topics: Amygdala; Animals; Antipsychotic Agents; Dibenzothiazepines; Disease Models, Animal; Gait Disorders, Neurologic; Male; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia

The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antipsychotic Agents; Behavior, Animal; Dibenzothiazepines; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Male; Motor Activity; Oxidopamine; Parkinsonian Disorders; Quetiapine Fumarate; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Serotonin; Serotonin Antagonists

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Topics: Acoustic Stimulation; Adamantane; Animals; Antipsychotic Agents; Behavior, Animal; Brain; Conditioning, Classical; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Female; Haloperidol; Imidazoles; Inhibition, Psychological; Neurotensin; Photic Stimulation; Psychomotor Performance; Quetiapine Fumarate; Rats; Rats, Long-Evans; Reaction Time; Receptors, Neurotensin; Reflex, Startle; RNA, Messenger; Schizophrenia; Social Isolation; Synaptic Transmission

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Dibenzothiazepines; Disease Models, Animal; Drug Evaluation, Preclinical; Haplorhini; Humans; Quetiapine Fumarate; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Treatment Outcome