Animal Model Of Negative Symptoms Research Articles

Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models.

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a “U-shaped” dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats

Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3-([1,1′-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia.

Social interaction of rats is related with baseline prepulse inhibition level

The symptoms of schizophrenia are evaluated in three general categories: positive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model positive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by using a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively assigned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was assigned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a significant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were significantly lower, and the average distance between rat pairs was significantly longer than HI rats. In the EPM test LI and HI rats showed similar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.

Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia

To investigate the potential of white blood cells as probes for central processes we have measured gene expression in both the anterior cingulate cortex and white blood cells using a putative animal model of negative symptoms in schizophrenia. The model is based on the capability of ketamine to induce psychotic symptoms in healthy volunteers and to worsen such symptoms in schizophrenic patients. Classical fear conditioning is used to assess emotional processing and cognitive function in animals exposed to sub-chronic ketamine vs. controls. Gene expression was measured using a commercially sourced whole genome rat gene array. Data analyses were performed using ANOVA (Systat 11). In both anterior cingulate cortex and white blood cells a significant interaction between ketamine and fear conditioning could be observed. The outcome is largely supported by our subsequent metagene analysis. Moreover, the correlation between gene expression in brain and blood is about constant when no ketamine is present (r~0.4). With ketamine, however, the correlation becomes very low (r~0.2) when there is no fear, but it increases to ~0.6 when fear and ketamine are both present. Our results show that under normal conditions ketamine lowers gene expression in the brain, but this effect is completely reversed in combination with fear conditioning, indicating a stimulatory action. This paradoxical outcome indicates that extreme care must be taken when using gene expression data from white blood cells as marker for psychiatric disorders, especially when pharmacological and environmental interactions are at play.

P.3.d.005 Activity of phosphodiesterase 10A inhibitors in a novel animal model of negative symptoms of schizophrenia

P.3.d.005 Activity of phosphodiesterase 10A inhibitors in a novel animal model of negative symptoms of schizophrenia

MK-801 produces a deficit in sucrose preference that is reversed by clozapine, d-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: Relevance to negative symptoms associated with schizophrenia?

Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and d-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration–consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.

Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: Implications for abnormalities of glutamate release and NMDA–CaMKII signaling

In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the enhancement of immobility (emotional deficit) in a forced swimming test in mice treated with phencyclidine (PCP: 10 mg/kg/day for 14 days) repeatedly, which is regarded as an animal model for negative symptoms. A decrease in spontaneous extracellular glutamate release and increase in levels of the glutamate transporter GLAST, were observed in the prefrontal cortex (PFC) of PCP-treated mice, compared to saline-treated mice. NMDA receptor subunit 1 (NR1) and Ca 2+/calmoduline kinase II (CaMKII) were markedly activated in the PFC of saline-treated mice, but not PCP-treated mice, immediately after the forced swimming test. The facilitation of the function of NMDA receptors by d-cycloserine (30 mg/kg i.p.), an NMDA receptor glycine-site partial agonist, reversed the enhancement of immobility in the forced swimming test and impairment of CaMKII activation in the PCP-treated mice. Microinjection of dl-threo-β-benzyloxyaspartate (10 nmol/site/bilaterally), a potent blocker of glutamate transporters, into the PFC of PCP-treated mice also had an attenuating effect. In addition, activation of glial cells and a decrease of neuronal cell size were observed in the PFC of PCP-treated mice. These results suggest that repeated PCP treatment disrupts pre- and post-synaptic glutamatergic neurotransmission and induces morphological changes in the PFC and that such changes cause the emotional deficits exhibited in PCP-treated mice.

Neonatal Handling Prevents the Effects of Phencyclidine in an Animal Model of Negative Symptoms of Schizophrenia

Environmental factors during the neonatal period have long-lasting effects on the brain. Neonatal handling, an early mild stress, enhances the ability to cope with stress in adult rats. In humans, inappropriate stress responses increase the risk of schizophrenia in genetically predisposed individuals. We studied the effect of neonatal handling on the phencyclidine (PCP)-induced immobility time of rats in the forced swimming test (FST, an animal model of negative symptoms of schizophrenia) and on plasma adrenocorticotropic hormone (ACTH) as a measure of hypothalamic-pituitary-adrenal axis (HPA) reactivity. Pups were removed from their mothers 15 min/21 days after birth. Postnatal day 65: animals were submitted to restraint stress. Postnatal day 75: after PCP treatment (5 mg/kg/5 days) animals were submitted to the FST. Neonatal handling reduced HPA reactivity to passive stress (restraint) but not to active coping stress (forced swimming). Immobilization time was significantly lower in saline- and PCP-treated, handled animals than in non-handled ones. Handling prevented the ACTH increase induced by PCP that was observed in the non-handled rats after FST. First, neonatal handling protects animals from acquiring the schizophrenic-like behavior provoked by sub-chronic PCP treatment, which was associated with a reduced HPA activity. Second, the beneficial properties of handling in stress responses seem to depend on the type of stress.

ChemInform Abstract: Neuropsychopharmacological Study on an Animal Model for Negative Symptom of Schizophrenia Induced by Repeated Phencyclidine Treatment

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 receptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.

フェンシクリジン誘発精神分裂病陰性症状動物モデルの神経精神薬理学的研究

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 receptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.

Disruption of social behaviour by phencyclidine: An animal model of negative symptoms

Disruption of social behaviour by phencyclidine: An animal model of negative symptoms

Distinct effects of d-amphetamine and phencyclidine on the social behaviour of rats

d-Amphetamine and phencyclidine (PCP) can induce a model psychosis in humans that resembles schizophrenia. Both drugs reproduce the positive symptoms of schizophrenia, but apparently only PCP mimics the negative symptoms. The purpose of this study was to determine the pharmacological profiles of d-amphetamine and PCP in the social interaction test, and to determine if they have disruptive effects on social behaviour in rats that may be comparable to the social isolation characteristic of negative symptoms. Acute and subchronic (daily for 5 days) administration of d-amphetamine (0.7-22µmol/kg) produced stereotyped behaviour at dosages of 10.4µmol/kg and upwards without any consistent effects on social behaviour. In contrast, acute and subchronic PCP (0.9-29µmol/kg) produced dose-dependent increases in stereotyped behaviour and ataxia as well as dose-dependent reductions in the social behaviour at dosages of 3.6µmol/kg and upwards. Thus, d-amphetamine and PCP had distinct effects on the social behaviour of rats. Both drugs produced stereotyped behaviour and locomotor hyperactivity, but only PCP dose-dependently disrupted social behaviour. This raises the possibility that PCP-induced social isolation in rats corresponds to the social isolation reported in humans under the influence of PCP, and that it can be used as an animal model of negative symptoms.