olanzapine and Disease-Models--Animal

Antipsychotic (AP) medications are associated with an increased risk for developing metabolic side effects including weight gain, dyslipidemia, hypertension, type 2 diabetes (T2D), and cardiovascular disease. Previous reviews have focused on the chronic metabolic side effects associated with AP use. However, an underappreciated aspect of APs are the rapid perturbations in glucose and lipid metabolism that occur with each dose of drug. The purpose of this narrative review is to summarize work examining the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances. We also discuss recent studies that have attempted to elucidate treatment approaches to mitigate AP-induced impairments in fuel metabolism.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Metabolic Diseases; Olanzapine

The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms.

Topics: Animals; Benzodiazepines; Disease Models, Animal; Energy Intake; Energy Metabolism; Humans; Models, Biological; Olanzapine; Predictive Value of Tests; Rats; Weight Gain

The mechanisms underlying olanzapine-induced weight gain have not yet been fully elucidated. To examine the effects of long-term treatment with olanzapine on different aspects of energy balance, we administered olanzapine to male rats. Osmotic minipumps were chosen as preferred mode of administration because the half-life of olanzapine is only 2(1/2) h in rats compared to 30 h in humans. We discovered that, within one week, degradation of olanzapine occurred in the solution used to fill the minipump reservoir. This resulted in a decrease in delivered olanzapine and declining plasma levels over the course of the experiment. Therefore, we caution other researchers for the limitations of using osmotic minipumps to administer olanzapine for longer periods of time.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Drug Administration Schedule; Eating; Infusion Pumps, Implantable; Male; Olanzapine; Pharmaceutical Solutions; Rats; Rats, Wistar; Weight Gain

Novel 'atypical' antipsychotic drugs represent a substantial improvement on older 'typical' drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. This interferes with compliance with drug taking and has expected effects on morbidity and mortality. In this review, we summarize current thinking on: (i) the extent to which different 'atypical' drugs induce weight gain; (ii) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction; and (iii) the state of development of animal models in this area. We also outline major areas for future research.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Female; Humans; Male; Neuropeptides; Obesity; Olanzapine; Rats; Receptors, Biogenic Amine; Weight Gain

Topics: Animals; Antipsychotic Agents; Cholinergic Agonists; Disease Models, Animal; Dopamine Antagonists; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Mice; Mice, Transgenic; Nitric Oxide Synthase; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotensin; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Disease Models, Animal; Double-Blind Method; Humans; Olanzapine; Placebos; Receptors, Metabotropic Glutamate; Schizophrenia

Anorexia nervosa (AN) patients often show extreme hypophagia and excessive physical activity. Activity-based anorexia (ABA) is considered an animal model of AN and mimics food restriction and hyperactivity in rats. This study investigated whether treatment with olanzapine (Zyprexa) reduces the development of ABA in rats. The effect of olanzapine treatment in AN patients was also evaluated in a small open-label study.. Rats were chronically (1 week) infused with olanzapine (7.5 mg/kg) and exposed to the ABA model or ad libitum feeding. Hyperactive AN patients were followed for up to 3 months of olanzapine treatment (5 mg/kg).. Olanzapine treatment reduced development of ABA in rats by reducing running wheel activity, starvation-induced hypothermia and activation of the hypothalamus-pituitary-adrenal axis. Olanzapine treatment reduced activity levels of AN patients compared with untreated AN patients, without affecting body weight and plasma leptin levels.. Olanzapine treatment reduced wheel running and thereby diminished development of ABA in rats. Olanzapine treatment also reduced physical activity in hyperactive AN patients in a small open-label study. These data support the need for controlled studies investigating the putative beneficial effects of olanzapine treatment in AN patients.

Topics: Adipose Tissue; Adolescent; Adrenocorticotropic Hormone; Animals; Anorexia; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Temperature; Body Weight; Corticosterone; Disease Models, Animal; Drug Administration Schedule; Eating; Female; Humans; Male; Motor Activity; Olanzapine; Radioimmunoassay; Rats; Rats, Wistar; Running; Time Factors

Motor disturbances are observed in schizophrenia patients, but the neuroanatomical background is unknown. Our aim was to investigate the pyramidal cells of the primary motor cortex (BA 4) in both hemispheres of postmortem control and schizophrenia subjects-8 subjects in each group-with 2.5-5.5 h postmortem interval. The density and size of the Sternberger monoclonal incorporated antibody 32 (SMI32)-immunostained pyramidal cells in layer 3 and 5 showed no change; however, the proportion of larger pyramidal cells is decreased in layer 5. Giant pyramidal neurons (Betz cells) were investigated distinctively with SMI32- and parvalbumin (PV) immunostainings. In the right hemisphere of schizophrenia subjects, the density of Betz cells was decreased and their PV-immunopositive perisomatic input showed impairment. Part of the Betz cells contained PV in both groups, but the proportion of PV-positive cells has declined with age. The rat model of antipsychotic treatment with haloperidol and olanzapine showed no differences in size and density of SMI32-immunopositive pyramidal cells. Our results suggest that motor impairment of schizophrenia patients may have a morphological basis involving the Betz cells in the right hemisphere. These alterations can have neurodevelopmental and neurodegenerative explanations, but antipsychotic treatment does not explain them.

Topics: Aged; Aged, 80 and over; Aging; Animals; Antipsychotic Agents; Autopsy; Datasets as Topic; Disease Models, Animal; Female; Functional Laterality; Haloperidol; Humans; Immunohistochemistry; Intermediate Filaments; Male; Middle Aged; Motor Cortex; Olanzapine; Parvalbumins; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Regression Analysis; Schizophrenia

The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzapine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investigated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libitum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue. We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further exploring intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness.

Topics: Administration, Intranasal; Animals; Anorexia; Anorexia Nervosa; Body Weight; Disease Models, Animal; Eating; Olanzapine; Rats

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Topics: Animals; Antipsychotic Agents; Autism Spectrum Disorder; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Female; Humans; Male; Memory Disorders; Neurons; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Social Behavior; Valproic Acid

Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Olanzapine; Phencyclidine; Schizophrenia

Second-generation antipsychotics are the drugs of choice for the treatment of neurodevelopmental-related mental diseases such as schizophrenia. Despite the effectiveness of these drugs to ameliorate some of the symptoms of schizophrenia, specifically the positive ones, the mechanisms beyond their antipsychotic effect are still poorly understood. Second-generation antipsychotics are reported to have anti-inflammatory, antioxidant and neuroplastic properties. Using the neonatal ventral hippocampus lesion (nVHL) in the rat, an accepted schizophrenia-related model, we evaluated the effect of the second-generation antipsychotic olanzapine (OLZ) in the behavioral, neuroplastic, and neuroinflammatory alterations exhibited in the nVHL animals. OLZ corrected the hyperlocomotion and impaired working memory of the nVHL rats but failed to enhance social behavior disturbances of these animals. In the prefrontal cortex (PFC), OLZ restored the pyramidal cell structural plasticity in the nVHL rats, enhancing the dendritic arbor length, the spinogenesis and the proportion of mature spines. Moreover, OLZ attenuated astrogliosis as well as some pro-inflammatory, oxidative stress, and apoptosis-related molecules in the PFC. These findings reinforce the evidence of anti-inflammatory, antioxidant, and neurotrophic mechanisms of second-generation antipsychotics in the nVHL schizophrenia-related model, which allows for the possibility of developing more specific drugs for this disorder and thus avoiding the side effects of current schizophrenia treatments.

Topics: Animals; Antioxidants; Antipsychotic Agents; Disease Models, Animal; Hippocampus; Neuronal Plasticity; Olanzapine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Schizophrenia

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

Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Disease Models, Animal; Female; Haloperidol; Intra-Abdominal Fat; Methylazoxymethanol Acetate; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Proteomics; Rats; Rats, Sprague-Dawley; Risperidone; Schizophrenia; Signal Transduction; TOR Serine-Threonine Kinases

The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats.. Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis.. Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine.. Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Blood Glucose; Cytokines; Disease Models, Animal; Epididymis; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Macrophages; Male; Metformin; Olanzapine; Phenotype; Rats, Sprague-Dawley; Signal Transduction; Weight Gain

The aim of the present study was to evaluate the effect of 1MeTIQ on fear memory and social interaction in an MK-801-induced model of schizophrenia. The results obtained after administration of 1MeTIQ were compared with those obtained with olanzapine, an antipsychotic drug.. Sprague-Dawley rats received a single injection of MK-801 to induce behavioral disorders. 1MeTIQ was given either acutely in a single dose or chronically for 7 consecutive days. Olanzapine was administered once. In groups receiving combined treatments, 1MeTIQ or olanzapine was administered 20 min before MK-801 injection. Contextual fear conditioning was used to assess disturbances in fear memory (FM), and the sociability of the rats was measured in the social interaction test (SIT). Biochemical analysis was carried out to evaluate monoamine levels in selected brain structures after treatment.. Our results are focused mainly on data obtained from neurochemical studies, demonstrating that 1MeTIQ inhibited the MK-801-induced reduction in dopamine levels in the frontal cortex and increased the 5-HT concentration. The behavioral tests revealed that acute administration of MK-801 caused disturbances in both the FM and SIT tests, while neither 1MeTIQ nor olanzapine reversed these deficits.. 1MeTIQ, although pharmacologically effective (i.e., it reverses MK-801-induced changes in monoamine activity), did not influence MK-801-induced social and cognitive deficits. Thus, our FM tests and SIT did not support the main pharmacological hypotheses that focus on dopamine system stabilization and dopamine-serotonin system interactions as probable mechanisms for inhibiting the negative symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Fear; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Interaction; Tetrahydroisoquinolines

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Disease Models, Animal; Female; Male; Maternal Deprivation; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Schizophrenia

One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons.. Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction.. In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection.. This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Topics: Animals; Anticonvulsants; Clozapine; Dentate Gyrus; Disease Models, Animal; Epilepsy, Temporal Lobe; Evoked Potentials; G-Protein-Coupled Receptor Kinases; Gene Editing; Hippocampus; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Neurotransmitter; Seizures

Antipsychotics, in particular olanzapine, are first-line medications for schizophrenia. The prefrontal cortex (PFC) is an important region for antipsychotics' therapeutic effects. The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis. However, the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear. We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats. Since the inflammatory and immune pathways are related to endoplasmic reticulum (ER) stress, we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress.. Expression of pro-inflammatory markers including IkappaB kinase β (IKKβ), nuclear factor kappa B (NFκB), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and IL-1β, and immune-related proteins including inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) were examined by Western blotting.. Olanzapine treatments for 1, 8 and 36 days significantly activated the inflammatory IKKβ/NFκB signaling, and increased the expression of TNF-α, IL-6, IL-1β and immune-related proteins such as iNOS, TLR4 and CD14. Olanzapine treatment for 1 day, 8 and 36 days also induced ER stress in the PFC. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced inflammation and the immune response in the PFC.. These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects. Olanzapine induces PFC inflammation and immune response, possibly via activating ER stress signaling.

Topics: Animals; Apoptosis; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Humans; I-kappa B Kinase; Immunity; Inflammation; Interleukin-1beta; Interleukin-6; Nitric Oxide Synthase Type II; Olanzapine; Oxidative Stress; Prefrontal Cortex; Rats; Schizophrenia; Signal Transduction; Toll-Like Receptor 2

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Schizophrenia is a chronic, disabling neurological illness. This study investigated the effect of rosuvastatin (RSU) addition to the antipsychotic drug: olanzapine (OLZ) in treatment of post-weaning isolation rearing (IR) damaging effect and assessed behavioral impairment, metabolic and hepatic abnormalities, oxidative stress, and inflammatory markers.. Treatment with OLZ (6 mg/kg, P.O.) and/or RSU (10 mg/kg, I.P.) have been started 6 weeks after isolation. We assessed behavioral tests, serum cortisol level, and hippocampal content of neurotransmitters. In addition, we assessed histopathology, inflammatory and oxidative stress markers of hippocampus, liver and adipose tissue RESULTS: Treatment of IR animals with OLZ, and/or RSU significantly counteracted the changes in hippocampus, liver and adipose tissue induced by post-weaning IR. Co-treatment of IR rats with both OLZ and RSU showed additive effects in some areas like improving both tumor necrosis factor alpha (TNFα) in both hippocampus and liver, histopathology of liver, oxidative stress markers of adipose tissue, β. post-weaning IR as a model has behavioral, hippocampal, hepatic and marked metabolic changes more relevant to schizophrenia than drug-induced models. These effects were ameliorated by RSU and/or OLZ that are explained by their antioxidant, anti-inflammatory, anti-stress and anti-hyperlipidemic properties. Interestingly, co-treatment with both drugs showed a better effect.

Topics: Animals; Antipsychotic Agents; Cognitive Dysfunction; Disease Models, Animal; Drug Therapy, Combination; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Liver Diseases; Male; Olanzapine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium; Schizophrenia; Social Isolation; Tumor Necrosis Factor-alpha

Enrichment environment conditions, as well as tobacco smoke exposure, may affect cognitive function (e.g. spatial memory) in an animal model of schizophrenia and schizophrenic patients. The aim of this study was to find whether spatial memory function impairment is found in methylazoxymethanol acetate treated rats (an animal model of schizophrenia) and whether aripiprazole (1.5 mg/kg) and olanzapine (0.5 mg/kg) modify these functions. We also were able to determine whether tobacco smoke exposure and enrichment environment conditions have an impact on drug efficacy. The effect of methylazoxymethanol acetate, tobacco smoke exposure, enrichment environment and the use of drugs were studied in the Morris Water Maze test (spatial memory). The results of our study clearly show that enriched environment may have a procognitive effect while tobacco smoke and methylazoxymethanol acetate have a contradictory effect. This paper also confirmed that the use of neuroleptics, namely ARI and OLA, reduced the process of spatial memory deterioration tested in the Morris water maze both in terms of the number of escape latencies and crossed quadrants.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Behavior, Animal; Cognition; Disease Models, Animal; Female; Male; Methylazoxymethanol Acetate; Morris Water Maze Test; Neurotoxins; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Schizophrenia; Spatial Memory; Tobacco Smoke Pollution; Treatment Outcome

Paeoniflorin, a prominent component in some Chinese formulas for hyperprolactinemia-associated disorders, has been found to inhibit prolactin secretion in prolactinoma cells.. To examine the efficacy of paeoniflorin on hyperprolactinemia and the underlying mechanisms of action.. Hyperprolactinemia in female rats was generated by administration of olanzapine (5 mg/kg, by a gavage method, once daily, × 13 weeks). The rats were co-treated with paeoniflorin (10 and 50 mg/kg). Prolactin and TGF-β1 concentrations were detected by ELISA. Protein expression was determined by Western blot. The effect in MMQ cells was also examined.. Paeoniflorin inhibited olanzapine-induced increases in plasma prolactin concentration and prolactin protein overexpression in the pituitary and hypothalamus of rats. Further, paeoniflorin restored olanzapine-induced downregulation of pituitary and hypothalamic dopamine D2 receptor (D2R) protein expression. More importantly, paeoniflorin attenuated olanzapine-suppressed protein expression of transforming growth factor (TGF)-β1 and its downstream genes, type II TGF-β receptor, type I TGF-β receptor and phosphorylated SMAD3 in the tissues. However, paeoniflorin did not affect plasma TGF-β1 concentration and hepatic TGF-β1 protein expression. In accord, olanzapine-induced increase in prolactin concentration, upregulation of prolactin protein expression, and downregulation of protein expression of the D2R and TGF-β1 signals in MMQ cells were attenuated.. This study demonstrates that paeoniflorin ameliorates olanzapine-induced hyperprolactinemia in rats by attenuating impairment of the D2R and TGF-β1 signaling pathways in the hypothalamus and pituitary. Our findings may provide evidence to support the use of paeoniflorin-contained Chinese herbs and formulas for hyperprolactinemia and its associated disorders.

Topics: Animals; Antipsychotic Agents; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Female; Glucosides; Hyperprolactinemia; Hypothalamus; Monoterpenes; Olanzapine; Pituitary Gland; Prolactin; Rats, Sprague-Dawley; Receptors, Dopamine D2; Signal Transduction; Transforming Growth Factor beta1

Mortality in psychiatric patients with severe mental illnesses reaches a 2-3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Female; Haloperidol; Lipid Metabolism; Male; Metabolome; Methylazoxymethanol Acetate; Olanzapine; Rats, Sprague-Dawley; Risperidone; Schizophrenia

We used the acute NMDA receptor hypoactivity model of schizophrenia in mice to compare the efficacy of a long-term ketogenic diet and a commonly used antipsychotic, olanzapine, and to explore the interaction between these treatments. We found that a ketogenic diet in female mice was as effective as olanzapine to diminish MK-801-induced disruption of prepulse inhibition (PPI). Furthermore, combination of the diet with olanzapine treatment resulted in a similar effect compared to either treatment alone. These results suggest that ketogenic diet can be used effectively together with antipsychotics drugs over an extended period.

Topics: Animals; Combined Modality Therapy; Diet, Ketogenic; Disease Models, Animal; Dizocilpine Maleate; Female; Long-Term Care; Mice; Mice, Inbred C57BL; Olanzapine; Prepulse Inhibition; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Sex Factors

Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.

Topics: 3T3-L1 Cells; Adipocytes; Adult; Animals; Antipsychotic Agents; Blood Glucose; Cytokines; Disease Models, Animal; Duration of Therapy; Female; Glucose Transporter Type 4; Humans; Inflammation Mediators; Insulin Resistance; Male; Metabolic Syndrome; Mice; Models, Biological; NF-kappa B; Olanzapine; Rats; Schizophrenia; Young Adult

Pulmonary hypertension (PH) due to left heart disease (LHD), or group 2 PH, is the most prevalent form of PH worldwide. PH due to LHD is often associated with metabolic syndrome (MetS). In 12% to 13% of cases, patients with PH due to LHD display vascular remodeling of pulmonary arteries (PAs) associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are nonexistent, and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling.. We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in group 2 PH.. Using supracoronary aortic banding, we induced diastolic dysfunction in rats. Then we induced MetS by a combination of high-fat diet and olanzapine treatment. We used metformin treatment and anti-IL-6 (interleukin-6) antibodies to inhibit the IL-6 pathway. Compared with sham conditions, only supracoronary aortic banding+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in supracoronary aortic banding+MetS was associated with macrophage accumulation and increased IL-6 production in lung. PH was also associated with STAT3 (signal transducer and activator of transcription 3) activation and increased proliferation of PA smooth muscle cells, which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels, and STAT3 activation in the lung of group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human PA smooth muscle cell proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation, and human PA smooth muscle cell proliferation. In vivo, in the supracoronary aortic banding+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH due to LHD.. We developed a new preclinical model of group 2 PH by combining MetS with LHD. We showed that MetS exacerbates group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of group 2 PH and human patients.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Humans; Hypertension, Pulmonary; Interleukin-6; Macrophages; Male; Metabolic Syndrome; Olanzapine; Pulmonary Artery; Rats; Rats, Wistar; Vascular Remodeling; Ventricular Dysfunction

Topics: Animals; Antipsychotic Agents; Biomarkers; Cytokines; Disease Models, Animal; Energy Metabolism; Female; Glucose Intolerance; Inflammation Mediators; Insulin Resistance; Locomotion; Metabolic Diseases; Mice; Motor Activity; Olanzapine; Probiotics

Topics: Administration, Oral; Akathisia, Drug-Induced; Animals; Antipsychotic Agents; Benzodiazepines; Catalepsy; Corpus Striatum; Dendritic Spines; Disease Models, Animal; Dopamine Antagonists; Drug Synergism; Drug Therapy, Combination; Haloperidol; Humans; Male; Methamphetamine; Mice; Mice, Inbred ICR; Neurons; Olanzapine; Phosphodiesterase Inhibitors; Prolactin; Pyrazoles; Pyridazines; Rats; Rats, Sprague-Dawley; Synaptic Potentials; Treatment Outcome

The purpose of present investigation was to nano-encapsulate atypical antipsychotic such as Olanzapine in polymeric nanoparticles in order to explore the possibility of minimizing drug associated extrapyramidal adverse effects. The polymeric nanoparticulate systems were prepared using FDA approved polymer, polycaprolactone, by simple technique of nanoprecipitation using factorial design by DoE approach. The significant factors selected for the optimization during formulation development process were polymer content and surfactant concentration at three different levels (3

Topics: Administration, Intravenous; Animals; Antipsychotic Agents; Benzodiazepines; Catalepsy; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Male; Nanoparticles; Olanzapine; Particle Size; Polyesters; Rats; Rats, Wistar; Surface-Active Agents

Deficits in olfactory abilities are frequently observed in schizophrenia patients. However, whether olfactory dysfunction is found in animal models is not known. Here, we examined whether two well-established schizophrenia rat models exhibit olfactory-relevant dysfunction that is similar to schizophrenia patients. Olfactory sensitivity was tested in rats that were acutely (3.3mg/kg) or postnatally (10mg/kg, at postnatal day 7, 9 and 11) treated with phencyclidine (PCP) as schizophrenia models. Electrophysiological recordings were conducted to measure the olfactory-relevant local field potential after acute PCP treatment. Olfactory-relevant neural connections were tested via virus tracing in rats postnatally treated with PCP. We also assessed the reversal effects of olanzapine (OLZ) treatment on both models. We found that acute PCP treatment induced a decline in olfactory sensitivity (p=0.01) and significantly lower beta- and higher gamma-band oscillations (p=0.03, and p=0.00 respectively) which were partly attenuated by OLZ treatment (2mg/kg and 4mg/kg). Postnatal PCP exposure also resulted in an olfactory sensitivity deficit during adulthood (p=0.012 for males and p=0.009 for females), and an abnormal development of neural circuits (p=0.000). Together, our research indicated that olfactory dysfunction found in schizophrenia patients can also be observed on animal models.

Topics: Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Female; Male; Neurons; Olanzapine; Olfactory Bulb; Olfactory Perception; Perceptual Disorders; Phencyclidine; Rats, Sprague-Dawley; Schizophrenia; Sex Factors

The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Dopamine; Male; Motor Activity; Nucleus Accumbens; Olanzapine; Prepulse Inhibition; Random Allocation; Rats, Sprague-Dawley; Risperidone; Schizophrenia; Sexual Maturation; Social Isolation; Time Factors

Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.

Topics: Adipose Tissue, White; Animals; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Clozapine; Disease Models, Animal; Glucose; Glucose Metabolism Disorders; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Liver; Metabolic Networks and Pathways; Olanzapine; Rats; Sterol Regulatory Element Binding Proteins; Weight Gain

Cognitive impairment is the core symptom of schizophrenia, significantly impacting the functional outcome. Improvement of cognitive function has been an important aspect of the treatment of schizophrenia. Therefore, this study is to demonstrate the effects of first-generation antipsychotic haloperidol, second-generation antipsychotic olanzapine and ziprasidone, and alpha-7 nicotinic acetylcholine receptor agonist PHA-543613 on spatial learning and memory.. C57BL/6 mice received intraperitoneal injections of haloperidol (2 mg/kg), olanzapine (2.5 mg/kg), ziprasidone (2 mg/kg), and PHA-543613 (1 mg/kg), and cognitive dysfunctions were induced by MK-801 (0.1 mg/kg). Morris water maze was used for investigating the effects of all agents.. Mk-801 significantly increased the mean escape latency to the platform and decreased the number of platform area crossings. Ziprasidone had no effect on the mean escape latency to platform and the number of platform area crossings in naïve mice, but haloperidol, olanzapine, and PHA-543613 did not. Haloperidol and olanzapine significantly increased the mean escape latency to platform and decreased the number of platform area crossings, while ziprasidone and PHA-543613 did not. All the agents had no effect on swimming speed.. Ziprasidone and alpha-7 nicotinic acetylcholine receptor agonist PHA-543613 might be helpful in the treatment of CIAS.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Haloperidol; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Olanzapine; Piperazines; Quinuclidines; Schizophrenia; Spatial Learning; Thiazoles; Treatment Outcome

Schizophrenia is a psychotic disorder with severe and disabling symptoms, such as hallucinations, delusions, blunted affect and social withdrawal. The neuropathology remains elusive, but disturbances in immunity-related processes, neuronal connectivity and myelination have consistently been linked to schizophrenia. Antipsychotic drugs can be efficient in reducing symptoms, acting primarily on the dopamine system, but additional biological targets are likely to exist. Here we have screened for novel mechanisms of action in an animal model, using adult rats exposed to long-acting olanzapine, achieving stable and clinically relevant antipsychotic drug concentrations. By microarray-based examination of global gene expression in the fronto-medial cortex, at the single gene- and gene-set level, we observed downregulation of two neuropeptide-encoding genes, Vgf and Cort (fold change -1,25 and -1,48, respectively) in response to olanzapine exposure. Furthermore, we demonstrated significant upregulation of five out of ~2000 GO predefined gene sets after olanzapine exposure. Strikingly, all were linked to myelination and oligodendrocyte development; "Ensheathment of neurons", "Axon ensheathment", "Myelination", "Myelin sheath" and "Oligodendrocyte development" (FDR-values < 25). Sixteen of the leading edge genes in these gene sets were analysed independently by qPCR, of which 11 genes displayed significant upregulation, including Plp1, Mal, Mag and Cnp (fold change: 1,30, 1,50, 1,30 and 1,15, respectively). Several of the upregulated genes (e.g. MAG, MAL and CNP) have previously been reported as downregulated in post-mortem brain samples from schizophrenia patients. Although caution needs to be taken when extrapolating results from animal studies to humans, the data suggest a role for olanzapine in alleviating myelination-related dysfunction in schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Female; Gene Expression; Microarray Analysis; Myelin Proteins; Myelin Sheath; Olanzapine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions.. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine.. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Topics: Amino Acids; Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nucleus Accumbens; Olanzapine; Phencyclidine; Prefrontal Cortex; Protein Binding; Receptors, GABA-A; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Schizophrenia is a common disease which affect about 1% of global population. In that point of view animal model of schizophrenia seem to be an important tool for better understanding the key theories related to the disease. The aim of the study was to find whether anxiety-like behavior is found in prenatally stressed rats (animal model of schizophrenia) and whether aripiprazole (ARI, 1.5mg/kg) and olanzapine (OLA, 0.5mg/kg) modify those functions. We also were able to determine whether ethyl alcohol consumption has an impact on ARI's and OLA's efficacy as well as anxiety-like behavior of animals.. The anxiolytic effects of ARI, OLA and ethyl alcohol were determined in a two compartment exploratory test. The anxiolytic effect was studied in the NSCG (non-stressed control group), NSAG (non-stressed alcohol group), and PSG (prenatally stressed group), PSAG (prenatally stressed alcohol group).. Single and chronic treatment of both ARI and OLA produced a statistically significant increase in the number of entries in the white compartment of the two compartment exploratory test in the NSCG rats. In turn in the PSG rats only ARI showed the anxiolytic effect. Moreover ethyl alcohol intake showed anxiolytic effect in both NSAG and PSAG rats. Results also indicate that after prolonged administration of drugs, tolerance related to the anxiolytic effect was observed.. ARI and OLA can reduce the level of anxiety which proves drugs effectiveness in course anxiety-like behavior. On the other hand only ARI generated anxiolytic effect in exposure to ethyl alcohol conditions.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Aripiprazole; Behavior, Animal; Benzodiazepines; Disease Models, Animal; Ethanol; Female; Male; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Schizophrenia; Stress, Psychological

Dysfunction of prefrontal cortex (PFC) inhibitory neurons that express the calcium-binding protein parvalbumin or the neuropeptide somatostatin in schizophrenia may be related to disturbances in the migration, phenotypic specification, and/or maturation of these neurons. These pre- and postnatal developmental stages are regulated in a cell type-specific manner by various transcription factors and co-activators, fibroblast growth factor receptors (FgfR), and other molecular markers. Consequently, we used quantitative PCR to quantify mRNA levels for these developmental regulators in the PFC of 62 schizophrenia subjects in whom parvalbumin and somatostatin neuron disturbances were previously reported, and in antipsychotic-exposed monkeys. Relative to unaffected comparison subjects, subjects with schizophrenia exhibited elevated mRNA levels for 1) the transcription factor MafB, which is expressed by parvalbumin and somatostatin neurons as they migrate from the medial ganglionic eminence to the cortex, 2) the transcriptional coactivator PGC-1α, which is expressed postnatally by parvalbumin neurons to maintain parvalbumin levels and inhibitory function, and 3) FgfR1, which is required for the migration and phenotypic specification of parvalbumin and somatostatin neurons. Elevations in these markers were most prominent in younger schizophrenia subjects and were not present in antipsychotic-exposed monkeys. Finally, expression levels of other important developmental regulators (i.e. Dlx1, Dlx5, Dlx6, SATB1, Sip1/Zeb2, ST8SIA4, cMaf, Nkx6.2, and Arx) were not altered in schizophrenia. The over-expression of a subset of molecular markers with distinct roles in the pre- and postnatal development of parvalbumin and somatostatin neurons might reflect compensatory mechanisms to sustain the development of these neurons in the face of other insults.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Female; Gene Expression; Haloperidol; Humans; Macaca fascicularis; MafB Transcription Factor; Male; Middle Aged; Neurons; Olanzapine; Parvalbumins; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Prefrontal Cortex; Receptor, Fibroblast Growth Factor, Type 1; RNA, Messenger; Schizophrenia; Somatostatin

Behavioral and psychological symptoms of dementia (BPSD) include apathy, sleep problems, irritability, wandering, elation, agitation/aggression, and mood disorders such as depression and/or anxiety. Elderly patients are usually treated with second-generation antipsychotics; however, they present not enough efficacy against all symptoms observed. Hence, there still is an unmet need for novel pharmacotherapeutic agents targeted BPSD. A novel arylsulfonamide derivative ADN-1184 has been developed that possesses a preclinical profile of activity corresponding to criteria required for treatment of both psychosis and depressive symptoms of BPSD without exacerbating cognitive impairment or inducing motor disturbances. To broaden its pharmacological efficacy toward anxiety symptoms, its anxiolytic properties have been examined in common animal preclinical models in rats and mice. ADN-1184 significantly increased the number of entries into open arms measured in the elevated plus-maze test; however, it simultaneously increased parameters of exploratory activity. In the Vogel conflict drinking test, ADN-1184 dose-dependently and significantly increased the number of shocks accepted and the number of licks. Moreover, in mice, it also had specific anxiolytic-like activity in the four-plate test, and only negligible one at a specific mid-range dose measured in the spontaneous marble burying test. The obtained findings reveal that ADN-1184 displays anxiolytic-like activity in animal models of anxiety which employed punished stimuli. In its unusual combination of some anxiolytic action with already proven antipsychotic and antidepressant properties, and lack of any disruptive impact on learning and memory processes and motor coordination, ADN-1184 displays a profile that would be desired for a novel therapeutic for BPSD.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Aripiprazole; Behavior, Animal; Benzodiazepines; Conditioning, Psychological; Conflict, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Isoxazoles; Male; Maze Learning; Mice; Motor Activity; Olanzapine; Punishment; Rats, Wistar; Reaction Time; Receptors, Serotonin; Risperidone; Serotonin Antagonists; Sulfonamides

Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg(-1)), clozapine (5 mg kg(-1)), olanzapine (5 mg kg(-1)), LY379268 (3 mg kg(-1)), NFPS (sarcosine, 1 mg kg(-1)), d-serine (1800 mg kg(-1)) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg(-1)), ketamine (5 mg kg(-1)) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.

Topics: Amino Acids; Animals; Antipsychotic Agents; Benzodiazepines; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Haloperidol; Ketamine; Male; Olanzapine; Prepulse Inhibition; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine.. Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis.. Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus.. Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Topics: Aminopyridines; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety; Benzodiazepines; Buspirone; Clozapine; Conditioning, Classical; Dibenzocycloheptenes; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Fear; Heterocyclic Compounds, 4 or More Rings; Hippocampus; Indoles; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stress, Psychological

A novel series of arylpiperazinylalkyl purine-2,4-diones (4-27) and purine-2,4,8-triones (31-38) was synthesized and tested to evaluated their affinity for the serotoninergic (5-HT1A, 5-HT6, 5-HT7) and dopaminergic (D2) receptors. Compounds with purine-2,4-dione nucleus generally had affinity values higher than the corresponding purine-2,4,8-trione compounds. A spectrum of receptor activities was observed for compounds with a substituent at the 7-position of the imidazo[2,1-f]purine-2,4-dione system and some potent 5-HT1A (18, 25), 5-HT7 (14) and mixed 5-HT1A/5-HT7 (8, 9) receptor ligands with additional affinity for dopamine D2 receptors (15) has been identified. Moreover, docking studies proved that a substituent at the 7-position of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione could be essential for receptor affinity and selectivity, especially towards 5-HT1A and 5-HT7. The results of the preliminary pharmacological in vivo studies of selected derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione, including 9 as a potential anxiolytic, 8 and 15 as potential antidepressants, and 18 and 25 as potential antidepressant and anxiolytic agents.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Binding Sites; Disease Models, Animal; Models, Molecular; Molecular Structure; Piperazine; Piperazines; Purines; Pyrimidinones; Structure-Activity Relationship

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

Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. Previously, we reported that DGKβ knockout (KO) mice showed mania-like behaviors such as hyperactivity, reduced anxiety, and cognitive impairment. Furthermore, lithium ameliorated the hyperactivity and reduced anxiety of DGKβ KO mice. In this study, we investigated the effects of the clinically active antimanic drugs valproate and olanzapine on the abnormal behaviors of DGKβ KO mice.. Valproate (100mg/kg/day) and olanzapine (1mg/kg/day) were administered intraperitoneally. Following drugs treatments, behavioral tests were performed to investigate locomotor activity, anxiety levels, and cognitive function of the mice.. A single treatment of valproate and olanzapine did not ameliorate the hyperactivity or abnormal anxiety level of DGKβ KO mice. Chronic treatment with valproate and olanzapine significantly decreased locomotor activity and abnormal anxiety levels of DGKβ KO mice. Additionally, valproate also ameliorated cognitive function of DGKβ KO mice.. These results suggest that the abnormal behaviors of DGKβ KO mice is responsive to antimanic drugs, and that DGKβ KO mice are useful as an animal model of mania.

Topics: Animals; Anxiety; Benzodiazepines; Cognition Disorders; Diacylglycerol Kinase; Disease Models, Animal; Drug Therapy, Combination; Male; Maze Learning; Mice; Mice, Knockout; Motor Activity; Olanzapine; Valproic Acid

The combination of the selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotic drugs shows better therapeutic efficacy than SSRI monotherapy in the treatment of depression. However, the underlying mechanisms responsible for the augmenting effects of olanzapine are not fully understood. Here, we report that olanzapine enhances the SSRI-induced increase in extracellular serotonin (5-HT) levels and antidepressant-like effects by inhibiting GABAergic neurons through 5-HT6 receptor antagonism in the dorsal raphe nucleus (DRN). In organotypic raphe slice cultures, treatment with olanzapine (1-100 μM) enhanced the increase in extracellular 5-HT levels in the presence of fluoxetine (10 μM) or citalopram (1 μM). The enhancing effect of olanzapine was not further augmented by the GABAA receptor antagonist bicuculline. Electrophysiological analysis revealed that olanzapine (50 μM) decreased the firing frequency of GABAergic neurons in acute DRN slices. Among many serotonergic agents, the 5-HT6 receptor antagonist SB399885 (1-100 μM) mimicked the effects of olanzapine by enhancing the SSRI-induced increase in extracellular 5-HT levels, which was not further augmented by bicuculline or olanzapine. SB399885 (50 μM) also decreased the firing frequency of GABAergic neurons in the DRN. In addition, an intraperitoneal administration of SB399885 (10 mg/kg) to mice significantly enhanced the antidepressant-like effect of a subeffective dose of citalopram (3 mg/kg) in the tail-suspension test. These results suggest that olanzapine decreases local inhibitory GABAergic tone in the DRN through antagonism of 5-HT6 receptors, thereby increasing the activity of at least part of serotonergic neurons, which may contribute to the augmentation of the efficacy of SSRIs.

Topics: Animals; Antidepressive Agents; Benzodiazepines; Bicuculline; Citalopram; Depressive Disorder; Disease Models, Animal; Dorsal Raphe Nucleus; Female; Fluoxetine; GABA-A Receptor Antagonists; GABAergic Neurons; Male; Mice, Inbred C57BL; Neural Inhibition; Olanzapine; Piperazines; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonergic Neurons; Serotonin Antagonists; Sulfonamides; Tissue Culture Techniques

Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5'-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed.

Topics: Amphetamine; Animals; Animals, Newborn; Antipsychotic Agents; Avoidance Learning; Benzodiazepines; Cell Proliferation; Central Nervous System Stimulants; Disease Models, Animal; Female; Hippocampus; Hyperkinesis; Male; Maternal Deprivation; Motor Activity; Olanzapine; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reflex, Abnormal; Schizophrenia; Stem Cells; Vocalization, Animal

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Down-Regulation; Exercise Therapy; Female; Hippocampus; Metabolic Diseases; Nerve Tissue Proteins; Olanzapine; R-SNARE Proteins; Rats; Rats, Sprague-Dawley; SNARE Proteins

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

Topics: Amisulpride; Animals; Anorexia Nervosa; Benzodiazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Eating; Female; Indoles; Mice; Mice, Inbred BALB C; Motor Activity; Nitriles; Olanzapine; Piperidines; Receptors, Dopamine D3; Salicylamides; Sulpiride; Tetrahydroisoquinolines; Weight Loss

Based on the recent findings from animal studies, it has been proposed that the therapeutic use of valnoctamide, an anxiolytic drug developed in the early 1960s, be extended to treat other neurological disorders such as epilepsy and bipolar disease. Given the scarcity of adequate data on its prenatal toxicity, a comparative teratogenicity study of valnoctamide and two of the most commonly used drugs to treat bipolar disorder, risperidone and olanzapine, was carried out in a mouse model system.. Pregnant dams were treated with the aforementioned three drugs at the dose levels calculated as an equal proportion of the respective LD50 values of these drugs. The main reproductive indices examined included the numbers of implantations and resorptions, viable and dead fetuses, and fetal gross, visceral and skeletal abnormalities.. The outcomes of the present study indicated that olanzapine was the most teratogenic of the three drugs, inducing maternal-, embryo-, and fetotoxicity. Risperidone also exerted a significant prenatal toxicity, but its adverse effect was less pronounced than that induced by olanzapine. Valnoctamide did not show any teratogenic effect, even when used in relatively higher dosages than olanzapine and risperidone. The observed increased skeletal abnormalities in one of the valnoctamide treatment groups were nonspecific and, as such, signaled a modest developmental delay rather than an indication that the compound could induce structural malformations.. Under our experimental conditions, valnoctamide demonstrated the lowest prenatal toxicity of the three tested drugs.

Topics: Amides; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Disease Models, Animal; Female; Male; Mice; Olanzapine; Pregnancy; Pregnancy Complications; Risperidone; Teratogenesis

The aim of the study was to explore the effects of increased levels of blood sugar and cytokines on impaired cognitive function in the olanzapine-induced obesity rat model. A total of 40 rats were randomly divided into 2 groups; the control and olanzapine groups (N = 20 per group). The control rats were fed regular food, while the olanzapine rats received olanzapine-enriched (1.2 mg/kg) food by gavage for 4 weeks to establish the olanzapine-induced obese rat model. Enzyme-linked immunosorbent assays were used to measure the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Serum glucose content was measured by biochemical colorimetry. Learning and memory capacity was measured using a Y-maze, and the time before escape from a Morris water maze was recorded. Body weight and levels of blood glucose, lipids, TNF-α, IL-6, and CRP increased in the olanzapine group. In addition, the number of shocks received before reaching the learning and memory standard and the time before escape from the Morris water maze were higher in the olanzapine group than in the control group. Olanzapine causes disorders in glucose and lipid metabolism. Increase in blood glucose promotes the toxicity of cytokines and leads to cognitive dysfunction in rats.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; C-Reactive Protein; Cognition Disorders; Disease Models, Animal; Interleukin-6; Lipid Metabolism; Lipids; Memory; Obesity; Olanzapine; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.

Topics: Animals; Baclofen; Behavior, Animal; Benzazepines; Benzodiazepines; Body Weight; Bulimia; Disease Models, Animal; Eating; Feeding Behavior; Female; Idazoxan; Lisdexamfetamine Dimesylate; Naltrexone; Olanzapine; Prazosin; Prodrugs; Raclopride; Rats; Rats, Wistar; Rolipram

Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Benzodiazepines; Delayed-Action Preparations; Disease Models, Animal; Eating; Female; Gene Expression; Gene Knockdown Techniques; Liver; Metabolic Diseases; Olanzapine; Rats; Triglycerides; Ventromedial Hypothalamic Nucleus; Weight Gain

Second generation antipsychotic drugs are routinely used as treatment for psychotic disorders. Many of these compounds, including olanzapine, cause metabolic side-effects such as impaired glucose tolerance and insulin resistance. Individual antidiabetic drugs can help control elevated glucose levels in patients treated with antipsychotics, but the effects of combining antidiabetics, which routinely occurs with Type 2 diabetes mellitus patients, have never been studied. Presently, we compared the effects of the three different antidiabetics metformin (500mg/kg, p.o.), rosiglitazone (30mg/kg, p.o.) and glyburide (10mg/kg, p.o.) on metabolic dysregulation in adult female rats treated acutely with olanzapine. In addition, dual combinations of each of these antidiabetics were compared head-to-head against each other and the individual drugs. The animals received two daily treatments with antidiabetics and were then treated acutely with olanzapine (10mg/kg, i.p.). Fasting glucose and insulin levels were measured, followed by a 2h glucose tolerance test. Olanzapine caused a large and highly significant glucose intolerance compared to vehicle treated rats. Rosiglitazone decreased glucose levels non-significantly, while both metformin and glyburide significantly decreased glucose levels compared to olanzapine-only treated animals. For antidiabetic dual-drug combinations, the rosiglitazone-metformin group showed an unexpected increase in glucose levels compared to all of the single antidiabetic drugs. However, both the metformin-glyburide and rosiglitazone-glyburide groups showed significantly greater reductions in glucose levels following olanzapine than with single drug treatment alone for metformin or rosiglitazone, bringing glucose levels down to values equivalent to vehicle-only treated animals. These findings indicate that further study of antidiabetic dual-drug combinations in patients treated with antipsychotic drugs is warranted.

Topics: Animals; Benzodiazepines; Disease Models, Animal; Drug Therapy, Combination; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Glyburide; Hypoglycemic Agents; Insulin; Metformin; Olanzapine; Rats; Rats, Sprague-Dawley; Rosiglitazone; Selective Serotonin Reuptake Inhibitors; Thiazolidinediones; Time Factors

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (-45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (-51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Benzodiazepines; Betahistine; Disease Models, Animal; Feeding Behavior; Female; Hypothalamus; Lipid Droplets; Liver; Olanzapine; Organ Size; Rats, Sprague-Dawley; Weight Gain

Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Haloperidol; Hippocampus; Male; Memory, Short-Term; Neuronal Plasticity; Olanzapine; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Schizophrenia; Spatial Learning

Schizophrenia is a group of mental disorders of unclear origin, affecting around 1% of global population, most commonly young people. Of various treatment methods, pharmacotherapy using atypical neuroleptics such as aripiprazole (ARI) and olanzapine (OLA) seems to be the most effective. The aim of this paper was to show that prenatal stress causes impairment of cognitive functions in adolescent rats.. The effect of chronic stress used in pregnant rats and the use of drugs such as ARI (1.5 mg/kg) and OLA (0.5 mg/kg) were studied in the Morris Water Maze (spatial memory) and Porsolt test (antidepressant effect).. The behavioral tests showed that ARI improved spatial memory both in the non-stressed control group (NSCG) (after single and chronic treatment) and in the prenatally stressed group (PSG) (only in 14 and 21 days of treatment). An antidepressant effect was observed in the NSCG (only in 1 and 7 days) and the PSG (after single and chronic administration). OLA also showed memory improvement in the NSCG (chronic treatment - 14 and 21 days) and the PSG (all days of treatment) rats, but the antidepressant effect was noted only in single administration in both study groups (NSCG and PSG).. Results suggest that ARI and OLA may prove effective in treating both schizophrenia and depression and may improve disturbed memory functions observed in these diseases.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Behavior, Animal; Benzodiazepines; Cognition Disorders; Depression; Disease Models, Animal; Drug Administration Schedule; Female; Male; Maze Learning; Memory Disorders; Olanzapine; Piperazines; Pregnancy; Prenatal Exposure Delayed Effects; Quinolones; Rats; Rats, Wistar; Schizophrenia; Stress, Psychological; Time Factors

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Attention; Benzodiazepines; Body Weight; Cocaine; Conditioning, Operant; Depression; Disease Models, Animal; Dopamine Uptake Inhibitors; Electroencephalography; Hallucinogens; Haloperidol; Humans; Macaca fascicularis; Magnetic Resonance Imaging; Male; Mental Recall; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microinjections; Motor Activity; Mutation; Olanzapine; Oocytes; Oxazoles; Phencyclidine; Phenethylamines; Protein Binding; Pyrrolidinones; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Reinforcement, Psychology; Schizophrenia; Swimming; Telemetry; Tritium; Xenopus

The aim of this study was to investigate the neuroprotective effect of olanzapine (OLA), an atypical antipsychotic drug, on N-methyl-d-aspartate (NMDA)-induced retinal injury.. Retinal neuronal ischemia was induced by NMDA in Wistar rats. OLA was administered intraperitoneally in 2 different dosages: 2 and 12 mg/kg. At the end of 2 weeks of OLA treatment, 1 eye of each animal was enucleated for histopathologic examination. We also measured malondialdehyde (MDA) levels in retinal homogenates as a marker of ischemic injury.. The retinal ganglion cell (RGC) count was significantly higher in cases where we used OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0032 and P=0.0005, respectively). We also found that MDA was significantly reduced by OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0001 and P=0.0001, respectively). There was no statistically significant difference between OLA 2 mg/kg or OLA 12 mg/kg groups in terms of RGC count and MDA levels (P>0.05 for all).. Our data showed that OLA preserved RGCs from NMDA-induced retinal injury; thus, it may have potential neuroprotective effects.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Ischemia; Male; Malondialdehyde; N-Methylaspartate; Neuroprotective Agents; Olanzapine; Rats; Rats, Wistar; Retina; Retinal Diseases; Retinal Ganglion Cells; Retinal Neurons

Atypical antipsychotic medications are effective for treating both the positive and negative symptoms of schizophrenia. Olanzapine is an atypical antipsychotic that blocks dopaminergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors. In this study, we used rodents to investigate whether olanzapine could suppress the hyperlocomotion, rewarding effect, and discriminative stimulus effect induced by the prototypic μ-opioid morphine, which are all considered to reflect the abuse potential or psychoactive effects of μ-opioids. Olanzapine at doses that failed to induce motor coordination produced a dose-dependent reduction in hyperlocomotion induced by morphine in mice. Olanzapine at a dose that did not produce motor dysfunction also inhibited the significant place preference induced by morphine in mice. Furthermore, the discriminative stimulus effect induced by morphine in rats was dose-dependently and significantly attenuated by olanzapine at the dose that did not induce the motor dysfunction. These results suggest that treatment with both μ-opioids and olanzapine at a dose lower than that at which it induces motor dysfunction could be very useful for preventing the abuse potential and/or psychoactive effects of μ-opioids.

Topics: Analgesics, Opioid; Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Male; Mice; Mice, Inbred ICR; Morphine; Olanzapine; Opioid-Related Disorders; Rats; Rats, Inbred F344; Reward

Anorexia nervosa (AN) is an eating disorder characterized by extreme hypophagia, hyperactivity, and fear of weight gain. No approved pharmacological treatments exist for AN despite high mortality rates. The activity-based anorexia (ABA) phenomenon models aspects of AN in rodents, including progressive weight loss, reduced food intake, and hyperactivity. First, we optimized the ABA paradigm for mice. We compared mouse strains (Balb/cJ, A/J) for susceptibility with ABA, and evaluated the effects of different food access durations (2, 4, 6, 8, and 10 h) on ABA parameters. Balb/cJ mice exhibited significantly shorter survival time (days until 25% bodyweight loss) in the ABA paradigm compared with A/J mice. Furthermore, 6 h of food access reduced survival in mice housed with wheels without reducing survival in mice housed without wheels. We then evaluated the effects of chronic treatment with fluoxetine (4 weeks) or subchronic treatment with olanzapine (OLZ) (1 week) on ABA in BALB/cJ mice. OLZ (12 mg/kg/day) significantly increased survival and reduced food anticipatory activity (FAA). However, OLZ did not alter food intake or running wheel activity during ad-lib feeding (baseline) or restriction conditions, or in mice housed without wheels. Fluoxetine (18 mg/kg/day) increased food intake and reduced FAA, but did not alter survival. Here, we report for the first time that OLZ, but not fluoxetine, reduces ABA in mice. Our findings indicate further need for clinical investigations into the effects of OLZ, but not selective serotonin reuptake inhibitors, on core features of AN.

Topics: Animals; Anorexia; Benzodiazepines; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Female; Fluoxetine; Mice; Motor Activity; Olanzapine; Running; Selective Serotonin Reuptake Inhibitors; Survival Rate

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H₁ receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H₁ receptor agonist and H₃ receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H₃ receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H₁ receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.

Topics: Animals; Antipsychotic Agents; Appetite Depressants; Behavior, Animal; Benzodiazepines; Betahistine; Disease Models, Animal; Drug Interactions; Exploratory Behavior; Feeding Behavior; Female; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Motor Activity; Olanzapine; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Weight Gain

Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug-drug interactions. However, the pharmacological and behavioral mechanisms underlying drug-drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug-drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Benzodiazepines; Citalopram; Conditioning, Psychological; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Haloperidol; Male; Olanzapine; Polypharmacy; Random Allocation; Rats; Rats, Sprague-Dawley; Schizophrenia

Tianeptine is an atypical antidepressant drug that has a different mechanism of action than other antidepressants. Olanzapine is an atypical antipsychotic drug used for the treatment of schizophrenia. The present study was undertaken to investigate effects of chronic administration of tianeptine or olanzapine on unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice compared to a widely used SSRI antidepressant, fluoxetine.. Male inbred BALB/c mice were subjected to different kinds of stressors several times a day for 7weeks and were treated intraperitoneally with tianeptine (5mg/kg), olanzapine (2.5mg/kg), fluoxetine (15mg/kg) or vehicle for 5weeks (n=7-8 per group).. All the drugs tested prevented stress-induced deficit in coat state during UCMS procedure, in grooming behavior in the splash test, decreased the attack frequency in the resident intruder test and decreased the immobility time in the tail suspension test. In the open field test olanzapine had anxiolytic-like effects in both stressed and non-stressed mice. Tianeptine, olanzapine and fluoxetine decreased the enhanced levels of plasma ACTH and IL-6. Chronic treatment with tianeptine resulted in a significant increase in both total number and density of BrdU-labeled cells in stressed animals, while fluoxetine and olanzapine had a partial effect.. The results of this study support the hypothesis that tianeptine can be as effective as fluoxetine for the treatment of depression in spite of the differences in the mechanism of action of these drugs. Moreover, olanzapine could be used effectively in psychotic patients with depression.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Behavior, Animal; Benzodiazepines; Depression; Disease Models, Animal; Fluoxetine; Injections, Intraperitoneal; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Olanzapine; Stress, Psychological; Thiazepines

Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Feeding Behavior; Hyperphagia; Male; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Weight Gain

Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits.. We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed.. The cognitive deficit was induced by infusion of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the rat medial prefrontal cortex (mPFC). In vivo microdialysis was used to compare the effects of aripiprazole, olanzapine and haloperidol on CPP-induced glutamate (GLU) and serotonin (5-HT) release in the mPFC of conscious rats.. Oral aripiprazole (1.0 and 3.0 mg/kg) and olanzapine (0.3 and 1.0 mg/kg), but not haloperidol (0.1 mg/kg), abolished the CPP-induced accuracy deficit and GLU release. Haloperidol and aripiprazole, but not olanzapine, reduced perseverative over-responding, while anticipatory responding was best controlled by olanzapine. However, these effects were not associated with changes in GLU release. No association was found between the effects of these antipsychotics on CPP-induced attentional performance deficits in the 5-CSRTT and 5-HT efflux.. The data confirm that excessive GLU release in the mPFC is associated with attentional deficits. Thus, suppression of GLU release may be a target for the development of novel antipsychotic drugs with greater effect on some aspects of cognitive deficits.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Aripiprazole; Behavior, Animal; Benzodiazepines; Choice Behavior; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Haloperidol; Impulsive Behavior; Male; Microdialysis; Neuropsychological Tests; Olanzapine; Piperazines; Prefrontal Cortex; Quinolones; Rats; Reaction Time; Schizophrenia; Serotonin; Time Factors

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Topics: Animals; Antimanic Agents; Behavior, Animal; Benzodiazepines; Bipolar Disorder; Body Weight; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Lithium Chloride; Mice; Olanzapine; Sexual Behavior, Animal; Sleep; Swimming

Animal models can face unique challenges in mirroring what occurs in humans. This is the case for antipsychotics in rodents, where these drugs are metabolized much more rapidly. One strategy to address this issue has been the use of osmotic minipumps to ensure continuous antipsychotic exposure over prolonged intervals, which is routinely the case when these same drugs are administered to humans. More recently, it has been identified that with olanzapine this approach may be compromised by oxidative degradation, a process that can be observed within days. Further, in vivo evidence has reported progressive decreases in plasma levels over a 1-month interval. To address this issue in vitro, osmotic minipumps (n=4), with olanzapine at a concentration resulting in a dose of 7.5mg/kg/day in vivo, were placed in saline-filled Falcon tubes and immersed in a water bath. Olanzapine concentrations were assessed in the minipumps as well as the surrounding water bath at baseline, 1h, and days 1, 7, 14, 21, and 28. Minipump results indicated a monophasic exponential decay and a half-life of 14.8 days (95% CI=13.1-17.1 days). Results from the water bath demonstrated a linear increase in olanzapine up to and including day 21, followed thereafter by a decrease to day 28. It is concluded that administration of olanzapine via osmotic minipump is viable in animal models to mirror what occurs in humans, although the interval should be confined to 2 weeks. As well, strategies in dissolving olanzapine to diminish oxidation are discussed.

Topics: Animals; Benzodiazepines; Disease Models, Animal; Humans; Infusion Pumps, Implantable; Liquid-Liquid Extraction; Models, Animal; Olanzapine; Osmotic Pressure

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D(2/3) antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Benzodiazepines; Cerebral Cortex; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Agonists; Freezing Reaction, Cataleptic; In Vitro Techniques; Male; Membrane Potentials; Microdialysis; Morpholines; N-Methylaspartate; Olanzapine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reboxetine; Receptors, N-Methyl-D-Aspartate

In comparison with conventional, first-generation antipsychotics (e.g., haloperidol), the administration of atypical antipsychotics (AAPs) has been associated with a higher risk of metabolic derangements, including body weight increase, dysregulation of glucose homeostasis, fat accumulation, and even liability to develop type II diabetes. Since this is a serious clinical problem that may be further exacerbated in overweight schizophrenics, establishing animal models of AAP-induced adverse effects may contribute to clarifying the mechanisms underlying these effects. Here we present three basic protocols by which this problem has been modeled. The three protocols differ in many aspects (routes of administration, extent of the chronic treatment, diets, and dosage regimen), and the pros and cons of each procedure are systematically detailed throughout. It should be noted that several factors (e.g., species, sex, duration, and class of AAPs) could restrict the feasibility of these models, as well as their correspondence to the clinical condition.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Eating; Female; Infusion Pumps, Implantable; Metabolic Diseases; Mice; Mice, Mutant Strains; Olanzapine; Rats; Rats, Transgenic; Weight Gain

The rat conditioned avoidance response model is a well-established preclinical behavioral model predictive of antipsychotic efficacy. All clinically approved antipsychotic drugs disrupt conditioned avoidance responding - a feature that distinguishes them from other psychotherapeutics. We previously showed that the typical antipsychotic drug haloperidol disrupts avoidance responding by progressively attenuating the motivational salience of the conditioned stimulus (CS) in normal rats. In this study, using two pharmacological rat models of schizophrenia [e.g. phencyclidine (PCP) or amphetamine sensitization], we examined whether atypicals such as olanzapine or risperidone disrupt avoidance responding through the same behavioral mechanism. Rats were first pretreated with PCP, amphetamine, or saline under one of two different injection schedules for either 1 or 3 weeks. They were then trained to acquire avoidance responding to two types of CS (CS1 and CS2) that differed in their ability to predict the occurrence of the unconditioned stimulus. Finally, rats were tested repeatedly under olanzapine (1.0 mg/kg, subcutaneously) or risperidone (0.33 mg/kg, subcutaneously) daily for 5 or 7 consecutive days. We found that repeated olanzapine or risperidone treatment produced a progressive across-session decline in avoidance responding to both CS1 and CS2. Olanzapine and risperidone disrupted the CS2 (a less salient CS) avoidance to a greater extent than the CS1 avoidance. Pretreatment with PCP and amphetamine did not affect the disruptive effect of olanzapine or risperidone on avoidance responding. On the basis of these findings, we suggest that the atypical drugs olanzapine and risperidone, like the typical drug haloperidol, also disrupt avoidance responding primarily by attenuating the motivational salience of the CS.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Benzodiazepines; Conditioning, Psychological; Dextroamphetamine; Disease Models, Animal; Drug Interactions; Motivation; Motor Activity; Olanzapine; Phencyclidine; Rats; Rats, Sprague-Dawley; Risperidone; Schizophrenia; Schizophrenic Psychology

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.. The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.. Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01-0.3 mg/kg s.c.), Apo-PPI (0.001-0.3 mg/kg s.c.), DNMTP (0.01-0.1 mg/kg s.c.), and 5-CSR (0.003-0.3 mg/kg s.c.).. Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03-0.3 mg/kg; and risperidone, 0.01-0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05).. Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Attention; Benzodiazepines; Cognition; Dibenzocycloheptenes; Disease Models, Animal; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Male; Olanzapine; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Risperidone

Acute cocaine poisoning causes neuroexcitation and can be fatal. The toxic effects of cocaine can be attenuated by antagonists of serotonin, muscarinic cholinergic, and dopamine receptors. Olanzapine, an atypical antipsychotic medication, is an antagonist of these receptors. The objective of this study is to evaluate the efficacy of olanzapine pretreatment for attenuation of acute cocaine toxicity using a mouse model.. Eighty male CF-1 mice were randomly assigned to olanzapine (1 mg/kg) or placebo pretreatment. Fifteen minutes later, all animals received 103 mg/kg intraperitoneal cocaine.. Overall mortality was 11% for olanzapine-treated animals and 45% for placebo. Olanzapine also appeared to alter the characteristics of seizures due to cocaine.. In this model of acute cocaine toxicity, olanzapine pretreatment attenuated acute cocaine toxicity. Olanzapine should be evaluated further as a potential treatment for acute cocaine poisoning.

Topics: Animals; Benzodiazepines; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Drug Antagonism; Injections, Intraperitoneal; Longevity; Male; Mice; Mice, Inbred Strains; Olanzapine; Poisoning; Seizures; Selective Serotonin Reuptake Inhibitors; Vasoconstrictor Agents

Polydipsia is a severe complication of long-term schizophrenia and, despite its unknown pathogenesis, is empirically treated with typical or atypical antipsychotics. In the rat, nonregulatory water intake is induced by repeated administration of amphetamine-like compounds or by the D2/3 agonist, quinpirole.. This study is aimed at determining the potential activity of antipsychotic compounds with different affinities for D2 receptors in preventing and/or reversing quinpirole-induced polydipsia.. Male Sprague-Dawley rats were treated with five injections of quinpirole (0.5 mg/kg i.p.) to induce polydipsia. The oral effects of haloperidol, olanzapine, clozapine, and ST2472 on QNP-induced polydipsia were analyzed in the following two schedules. In the preventive schedule, haloperidol (0.2, 0.4, and 0.8 mg/kg), olanzapine (1.5, 3, and 6 mg/kg), ST2472 (1 and 2 mg/kg), and clomipramine (5, 10, and 20 mg/kg) were given in combination with quinpirole from day 1 to day 5. In the reversal schedule, rats showing quinpirole-induced polydipsia on the third day received haloperidol (0.4 mg/kg), olanzapine (1.5 and 3 mg/kg), clozapine (10, 20, and 40 mg/kg), ST2472 (1, 2, 5, and 10 mg/kg), and clomipramine (5, 10, and 20 mg/kg) before quinpirole on days 4 and 5.. Haloperidol both prevented and reversed quinpirole-induced polydipsia, whereas olanzapine and ST2472 only reversed it. Clomipramine prevented but did not reverse quinpirole-induced polydipsia, and clozapine did not reverse it either.. We suggest that, once developed, polydipsia is governed by dopaminergic D2 mechanisms. In contrast, either an increase in the serotoninergic tone or an inhibition of D2 receptors can modulate the development of quinpirole-induced excessive drinking.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Clomipramine; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Haloperidol; Male; Olanzapine; Piperazines; Pyrroles; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Thiazepines

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hyperinsulinism; Insulin Resistance; Locomotion; Olanzapine; Rats; Rats, Sprague-Dawley

Most schizophrenia patients do not inhibit their P50 auditory evoked potential to the second of duplicate auditory stimuli, reflecting a failure to inhibit responses to irrelevant sensory input. Typical antipsychotic drugs do not improve this deficit while some atypical antipsychotics do. A previous study using an animal model, deficient P20-N40 (which corresponds to the human P50) inhibitory processing in DBA/2 mice found that sensory inhibition was improved by clozapine, the prototypical atypical antipsychotic, but not by haloperidol, a typical antipsychotic. The improvement after clozapine was mediated by alpha7 nicotinic receptors. The present study addresses whether another atypical antipsychotic, olanzapine, will also improve sensory inhibition deficits in the mouse model. In vivo electrophysiological recordings of the P20-N40 auditory evoked potential in anesthetized DBA/2 mice, which spontaneously exhibit a schizophrenia-like inhibitory processing deficit, were obtained after olanzapine alone (0.01, 0.033, 0.1, 0.33 mg/kg, IP) and the efficacious dose of olanzapine (0.033 mg/kg, IP) in combination with either the alpha7 nicotinic receptor antagonist alpha-bungarotoxin or the alpha4beta2 nicotinic receptor antagonist di-hydro-beta-erythroidine. All doses of olanzapine produced improved P20-N40 inhibitory processing in DBA/2 mice. The normalization observed after the 0.033 mg/kg dose of olanzapine was due to a selective decrease in response to the second auditory stimulus indicating an increase in inhibitory processing. This improvement was blocked by pre-administration of alpha-bungarotoxin but not di-hydro-beta-erythroidine. Like clozapine, olanzapine acts via alpha7 nicotinic receptors to elicit improved inhibitory processing of auditory stimuli.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Antipsychotic Agents; Attention; Auditory Perceptual Disorders; Benzodiazepines; Bungarotoxins; Conditioning, Classical; Dihydro-beta-Erythroidine; Disease Models, Animal; Drug Interactions; Evoked Potentials, Auditory; Field Dependence-Independence; Inhibition, Psychological; Male; Mice; Mice, Inbred DBA; Nicotinic Antagonists; Olanzapine; Schizophrenia; Statistics, Nonparametric

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; C-Peptide; Disease Models, Animal; Glucose; Glucose Clamp Technique; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Time Factors

This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.

Topics: Animals; Antipsychotic Agents; Apoptosis; Behavior, Animal; Benzodiazepines; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid; In Situ Nick-End Labeling; Male; Methamphetamine; Motor Activity; Neural Inhibition; Neuroprotective Agents; Olanzapine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Risperidone; Schizophrenia; Time Factors

Atypical antipsychotics, such as olanzapine, have been reported to display anxiolytic properties as shown in several preclinical and clinical studies. Furthermore, several experimental evidences have shown that olanzapine reduces fear and anxiety in activated anxiety-like behavior test such as Geller-Seifter test, ultrasonic vocalization test and stress-induced EtOH consumption. Here, we hypothesized that the anxiolytic action of olanzapine might be due to via an indirect activation of the gamma-amino butyric acid (GABA)-ergic system through 3alpha-hydroxy-5alpha-pregnan-20-one [allopregnanolone (ALLO)], a potent neuroactive steroid that positively modulates the benzodiazepine-gamma-aminobutyric acid type A (GABA(A))/benzodiazepine receptors complex. To address this question, we used a preclinical animal test to screen for novel anxiolytic compounds - the elevated plus-maze (EPM) - in basal condition and after 45 min restrain stress after acute or repeated (21 days) administration of olanzapine (0.5mg/kg, i.p.). In this condition, we therefore study the effect of the 5-alpha-reductase inhibitor finasteride (FIN) (50mg/kg) after co-administration with olanzapine. FIN is an inhibitor of steroidogenic enzymes which acts by inhibiting type II 5-alpha reductase, the enzyme that converts into 5-alpha-reduced metabolites like the GABA(A) positive neuroactive steroid ALLO. Results showed an anxiolytic effect of the acute, but not of the chronic, treatment with olanzapine only in stressed rats. This anxiolytic effect was counteracted by the co-administration with FIN. These evidences suggest that the anxiolytic effects of olanzapine might be due to possible action of olanzapine on steroid function via activation of GABA system.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety Disorders; Benzodiazepines; Brain; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Enzyme Inhibitors; Finasteride; gamma-Aminobutyric Acid; Male; Maze Learning; Olanzapine; Pregnanolone; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Restraint, Physical; Stress, Psychological

Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain; Chlorpromazine; Clozapine; Cross-Over Studies; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Haloperidol; Lipid Peroxidation; Male; Membrane Lipids; Olanzapine; Rats; Rats, Wistar; Risperidone; Schizophrenia; Superoxide Dismutase

Although it is generally accepted that atypical antipsychotics differ in their risk for diabetic side effects, the underlying pharmacological mechanisms are unknown. Studies on the mechanisms of antipsychotic-induced hyperglycemia or insulin resistance are often confounded by the concomitant weight gain and dyslipidemia, known diabetic risk factors. To investigate whether antipsychotics can acutely cause metabolic effects before any change in body composition, we studied the effects of four atypical antipsychotics on whole-body insulin resistance. Using the hyperinsulinemic, euglycemic clamp technique in conscious rats, insulin and somatostatin were infused at a constant rate to provide constant hyperinsulinemia and to suppress pancreatic insulin secretion. Glucose was infused at a variable rate, adjusted to maintain euglycemia. At steady state, animals were administered vehicle (V) or antipsychotic and the glucose infusion rate was monitored as an index of insulin sensitivity. Clamp experiments using radiotracers and studies on glucose uptake into isolated skeletal muscle were conducted to differentiate between effects on hepatic glucose production (HGP) and on peripheral glucose uptake. Olanzapine (OLAN) and clozapine (CLOZ) acutely impaired whole-body insulin sensitivity in a dose-dependent manner (P<0.001 vs V), whereas ziprasidone and risperidone had no effect. CLOZ also induced profound insulin resistance after dosing 10 mg/kg/day for 5 days (P<0.05 vs V). Tracer studies indicated that acute changes mainly reflect increased HGP, consistent with the lack of effect on glucose uptake. OLAN and CLOZ can thus rapidly induce marked insulin resistance, which could contribute to the hyperglycemia and ketoacidosis reported for patients receiving those therapies.

Topics: Acute Disease; Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Glucose; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Olanzapine; Rats; Rats, Wistar; Somatostatin

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

To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.. Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.. Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.. A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Clozapine; Disease Models, Animal; Energy Intake; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine; Sex Factors

Recent clinical studies have suggested that treatment with atypical antipsychotic drugs, such as olanzapine, may slow progressive changes in brain structure in patients with schizophrenia. To investigate the possible neural basis of this effect, we sought to determine whether treatment with olanzapine would inhibit the loss of hippocampal neurons associated with the administration of the excitotoxin, kainic acid, in neonatal rats. At post-natal day 7 (P7), rats were exposed to kainic acid via intracerebroventricular administration. Neuronal loss within the CA2 and CA3 subfields of the hippocampus and neurogenesis within the dentate gyrus of the hippocampus were then assessed at P14 by Fluoro-Jade B and BrdU labeling, respectively. Daily doses of olanzapine (2, 6, or 12 mg/day), haloperidol (1.2 mg/kg), melatonin (10 mg/kg), or saline were administered between P7 and P14. Melatonin is an anti-oxidant drug and was included in this study as a positive control, since it has been observed to have neuroprotective effects in a variety of animal models. The highest dose of olanzapine and melatonin, but not haloperidol, ameliorated the hippocampal neuronal loss triggered by kainic acid administration. However, drug administration did not have a significant effect on the rate of neurogenesis. These results suggest that olanzapine has neuroprotective effects in a rat model of neurodevelopmental insult, and may be relevant to the observed effects of atypical antipsychotic drugs on brain structure in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Disease Models, Animal; Female; Injections, Intraventricular; Kainic Acid; Neuroprotective Agents; Olanzapine; Rats; Rats, Sprague-Dawley

Most of atypical antipsychotics (AAPs) are highly related to a major risk of metabolic drawbacks leading to dyslipidemia and obesity.. To set up a mouse model of the AAP-associated weight gain in mice under the influence of chronic olanzapine regimen.. Female mice were housed in pairs and habituated to spontaneous feeding with a high-palatable diet (10% sucrose wet mash). Firstly, we orally administered olanzapine (0.75, 1.5 and 3 mg/kg), evaluating body weight and periuterine fat mass, as well as insulin, non-esterified fatty acids, triglycerides, and glucose levels. In a second experiment, we assessed the effect of olanzapine on energy expenditure through indirect calorimetry (IC). A third experiment was conducted to investigate the effects of olanzapine on a high fat-high sweet palatable diet (10% sucrose + 30% fat, HF-HS) in mice implanted with subcutaneous osmotic mini-pumps. Locomotor activity was also assessed.. In experiment 1, the highest dose of chronically administered olanzapine (3 mg/kg) induced significant weight gain accompanied by augmentation of periuterine fat depots, with no changes in locomotor activity. In experiment 2, chronic administration did not alter energy expenditure, whereas, decreased respiratory quotient (RQ). In experiment 3, subcutaneously infused olanzapine evidenced a dose and time-dependent increase of body weight and HF-HS diet consumed. Notably, serum analyses revealed a hyperinsulinemia together with increased levels of triglycerides and glucose.. In this study, we describe in female mice metabolic alterations matching the metabolic syndrome, thus resembling the clinical situation of schizophrenic patients taking AAPs.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Calorimetry, Indirect; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Fatty Acids; Female; Infusion Pumps, Implantable; Insulin; Intra-Abdominal Fat; Lipid Metabolism; Mice; Motor Activity; Obesity; Olanzapine; Time Factors; Triglycerides

Weight gain is a common and severe side effect of antipsychotic drugs. A usual tool to study the side effects of psychotropic drugs is animal models. However, attempts to create an animal model of antipsychotic-induced weight gain were not successful so far. Female rodents are sensitive to the effects of antipsychotics, but not males. This does not match the human clinical situation. Antipsychotics have different pharmacokinetic properties in rats and humans, and rats and humans have different spontaneous diets.. In the present study, we tested the hypothesis that the insensitivity of male rats to the weight-promoting effects of antipsychotics could be related to the mode of administration of antipsychotics and to the animals' diet. Antipsychotics were mixed with the food, and rats were fed a diet resembling the human diet. Rats were treated with 0.01, 0.1, 0.5, and 2 mg/kg of olanzapine or with a control solution for 6 weeks. Their weight and food intake were recorded, and their body composition were analyzed. The effects on weight and food intake of olanzapine (1 mg/kg), haloperidol (1 mg/kg), and ziprasidone (10 mg/kg) were also compared in a 3-week treatment experiment.. The results showed that 0.5 and 2 mg of olanzapine, but not lower doses, increase body weight and subcutaneous fat deposition. After the 3-week treatment, olanzapine-treated rats, but not haloperidol- or ziprasidone-treated rats, had significantly increased their weight.. This study shows that a rat model of obesity induced by antipsychotics can be created under specific conditions of drug administration, diet, and dose.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Circadian Rhythm; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Haloperidol; Male; Obesity; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors; Weight Gain

Intracerebroventricular (ICV) administration of ouabain, a potent sodium pump inhibitor, has been used to model mania. Antipsychotic agents have demonstrated efficacy in the management of acute mania. This study was undertaken to determine the prophylactic efficacy of olanzapine and haloperidol in the ouabain mania model.. Male Sprague-Dawley rats (4-8/group) were treated with two haloperidol decanoate intramuscular shots one week apart (21 mg/kg) or twice daily olanzapine intraperitoneal injections at low dose (1 mg/kg/day) or high dose (6 mg/kg/day) for 7 days prior to ICV administration of ouabain. Open field locomotion was quantified at baseline and after ouabain administration.. Ouabain caused a significant increase in open field locomotion (253.7+/-SEM 55.12 vs control 53.1+/-12.13 squares traversed in 30 min in the olanzapine experiments, P<0.05; and 236.5+/-41.42 vs 129.3+/-38.23, P<0.05 in the haloperidol experiments). Olanzapine alone at low dose (102.2+/-37.7) or high dose (151.2+/-49.2) did not alter open field activity. Low dose olanzapine (176.6+/-73.27) but not high dose (307.5+/-167.32) caused a modest reduction of the ouabain effect. Haloperidol alone significantly reduced motoric activity compared to control (55.6+/-18.0, P<0.05), and prevented ouabain-induced hyperactivity (60.3+/-33.1, P<0.05).. Haloperidol, but not olanzapine, demonstrated efficacy in this mania model, but methodological details may have reduced the effect of olanzapine.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Bipolar Disorder; Disease Models, Animal; Drug Evaluation; Drug Interactions; Enzyme Inhibitors; Exploratory Behavior; Haloperidol; Male; Olanzapine; Ouabain; Rats; Rats, Sprague-Dawley

Atypical antipsychotic drugs are widely used in the treatment of schizophrenia. These agents are discovered to have some additional beneficial effects beyond their effectiveness as antipsychotic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of olanzapine after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Olanzapine (0.1 and 1 mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Olanzapine (0.1 and 1 mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Laser-Doppler Flowmetry; Male; Mice; Nerve Degeneration; Neuroprotective Agents; Olanzapine; Tetrazolium Salts; Treatment Outcome

Continuous, but not intermittent, infusion with a conventional antipsychotic (haloperidol, HAL) can induce the vacuous chewing movement (VCM) syndrome in rats. The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs.. Experiment 1: Animals were treated with 7.5 mg/kg/day of OLZ or vehicle (VEH) via either minipump (MP) or daily subcutaneous (SC) injections for 8 weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day of OLZ, or 1 mg/kg/day of HAL or VEH via MP for 8 weeks. Dopamine D2 receptor occupancy levels were measured, ex vivo, with [3H]-raclopride.. Experiment 1: Rats receiving 7.5 mg/kg/day of OLZ via MP (51% D2 occupancy), but not those receiving the same dose via daily SC injections (94% peak D2 occupancy), showed significant VCM levels compared with control animals (p = .02). Experiment 2: Both OLZ (67% D2 occupancy) and HAL (79% D2 occupancy) led to similar increases in VCMs compared with VEH (p = .005).. This study provides strong evidence that even an atypical antipsychotic like OLZ, which rarely gives rise to tardive dyskinesia in the clinic, can lead to the VCM syndrome in rats if the antipsychotic is administered in a method (via MP) that leads to continuous presence of the drug in the brain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzodiazepines; Disease Models, Animal; Dopamine Antagonists; Drug Administration Routes; Dyskinesia, Drug-Induced; Haloperidol; Infusion Pumps; Male; Mastication; Olanzapine; Raclopride; Radioligand Assay; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Selective Serotonin Reuptake Inhibitors; Time Factors; Tritium

A model of schizophrenia, the chakragati (ckr) mouse was serendipitously created as a result of a transgenic insertional mutation. The apparent loss-of-function of an endogenous gene produced mice that, when homozygous, displayed an abnormal circling behavior phenotype. To determine whether this phenotype could be corrected by atypical antipsychotics, we compared the effects of clozapine and olanzapine on rotational turns and hyperactivity. Both of these drugs successfully ameliorated circling behavior and hyperactivity in homozygous mice. The increased motor activity of these mutant mice was both qualitatively and quantitatively similar to that observed in wild-type animals treated with dizocilpine, an N-methyl-D-aspartate receptor antagonist that produces behaviors resembling positive symptoms of schizophrenia. Mice either homozygous or heterozygous for the mutation also displayed enlargement of the lateral ventricles, which was accompanied only in the homozygous genotype by a loss of individual myelinated axons in the striatum and agenesis of the corpus callosum. These structural brain deficits were selective in that the nigro-striatal dopamine system was normal in these homozygous mice. In addition, two types of interneurons in the neostriatum, namely those producing acetylcholine or nitric-oxide synthase were also devoid of significant structural abnormalities. These results indicate that the ckr mouse mutant could be used as a possible animal model to study the pathophysiology of schizophrenia and suggest possible strategies for treating the behavioral aspects of this brain disease.

Topics: Animals; Behavior, Animal; Benzodiazepines; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Female; Genetic Testing; Lateral Ventricles; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Olanzapine; Renin; Schizophrenia

Several clinical reports have demonstrated that most antipsychotics of the new generation, but not the typical antipsychotic haloperidol, induce weight gain in schizophrenic patients. Since weight gain induces serious health complications in humans, it is crucial to test upcoming antipsychotic compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic not inducing weight gain in clinic (haloperidol), on food and water intake and body weight gain in rats. We included both female and male rats in this study. To reduce spontaneous high food intake in rats, and to be able to evaluate the treatment effect on a potential increase of food intake or metabolic changes, we allowed animal to receive only low-palatability chow. In male rats, none of the two compounds induced weight gain, but in female rats, both compounds induced weight gain. Consequently, the effect observed in rats does not match the clinical situation, and Wistar rats in this set-up cannot be considered a relevant model for antipsychotic-induced weight gain in humans.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Female; Food Preferences; Haloperidol; Humans; Male; Olanzapine; Pirenzepine; Rats; Rats, Wistar; Sex Characteristics; Weight Gain

Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 +/- 0.5 degrees C in 5 mg/kg clozapine-treated rabbits and 39.0 +/- 0.2 degrees C in olanzapine-treated rabbits, less than untreated animals (41.5 +/- 0.3 degrees C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 +/- 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 +/- 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 +/- 0.5 degrees C, <38.6 +/- 0.3 degrees C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 +/- 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 +/- 1 cm/sec) and the pre-MDMA level (17 +/- 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.

Topics: Anesthesia; Animals; Antipsychotic Agents; Benzodiazepines; Body Temperature; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Ear; Fever; N-Methyl-3,4-methylenedioxyamphetamine; Olanzapine; Pirenzepine; Rabbits; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Skin; Sympathetic Nervous System; Tail; Treatment Outcome; Vasoconstriction; Wakefulness

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Models, Animal; Fever; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Olanzapine; Serotonin Antagonists

Neonatal ventral hippocampal (NVH) lesions in rats have been shown to induce behavioral abnormalities at adulthood thought to simulate some aspects of positive, negative and cognitive deficits classically observed in schizophrenic patients. Such lesions induced a post-pubertal emergence of prepulse inhibition deficits reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. Here we have investigated the capacity of typical and atypical antipsychotics to reverse PPI deficits seen in NVH-lesioned rats. We show that three atypical antipsychotics (clozapine, olanzapine and risperidone) were able to reverse lesion-induced PPI deficits, in contrast to haloperidol, a classical neuroleptic. These results show that the NVH lesion model seems to be endowed with a fair predictive validity as, like in schizophrenic patients, PPI deficits in lesioned animals were reversed by atypical antipsychotics but not by the typical neuroleptic haloperidol.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Models, Animal; Haloperidol; Hippocampus; Male; Olanzapine; Pirenzepine; Rats; Rats, Sprague-Dawley; Reflex, Startle; Reserpine; Schizophrenia