Rat Model Of Psychosis Research Articles

Acid sphingomyelinase activity suggests a new antipsychotic pharmaco-treatment strategy for schizophrenia.

Schizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD's work only in a limited number of patients and may have cognition impairing side effects. A growing body of evidence points out the potential involvement of abnormal sphingolipid metabolism in the pathophysiology of schizophrenia. Here, an analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of SMPD1 and SMPD3 genes coding for acid- (ASM) and neutral sphingomyelinase-2 (NSM). In a rat model of psychosis using amphetamine hypersensitization, we found a locally restricted increase of ASM activity in the prefrontal cortex (PFC). Short-term haloperidol (HAL) treatment reversed behavioral symptoms and the ASM activity. A sphingolipidomic analysis confirmed an altered ceramide metabolism in the PFC during psychosis. Targeting enhanced ASM activity in a psychotic-like state with the ASM inhibitor KARI201 reversed psychotic like behavior and associated changes in the sphingolipidome. While effective HAL treatment led to locomotor decline and cognitive impairments, KARI201 did not. An RNA sequencing analysis of the PFC suggested a dysregulation of numerous schizophrenia related genes including Olig1, Fgfr1, Gpr17, Gna12, Abca2, Sox1, Dpm2, and Rab2a in the rat model of psychosis. HAL and KARI201 antipsychotic effects were associated with targeting expression of other schizophrenia associated genes like Col6a3, Slc22a8, and Bmal1, or Nr2f6a, respectively, but none affecting expression of sphingolipid regulating genes. Our data provide new insight into a potentially pathogenic mechanism of schizophrenia and suggest a new pharmaco-treatment strategy with reduced side effects.

Neuroprotective effect of agomelatine in rat model of psychosis: Behavioural and histological evidence

• Ketamine caused hyper-locomotion, increased stereotypy, ataxia, and decreased social withdrawal. • Agomelatine reversed the behavioural effects of ketamine. • Ketamine decreased neuronal count in the hippocampus and increased it in the amygdala. • The ketamine effects on neuronal count were reversed by agomelatine. • Agomelatine has the potential to alleviate negative symptoms of schizophrenia. Schizophrenia is a complex psychiatric disorder associated with positive (delusion, hallucination, and disorganised speech) and negative (affective flatering, avolition and social withdrawal) symptoms. Agomelatine (AGO) has been used as an anti-depressant to improve the negative symptoms in schizophrenia patients with co-morbid major depressive disorder. Therefore, the present study aimed to investigate the anti-psychotic effect of AGO in ketamine (KET)-induced psychosis rat model. Four groups ( n = 12/ group) of wistar rats were administered normal saline, KET (20 m/kg, i.p) and KET + AGO (20 and 40 mg/kg, i.p) for seven days. Behavioural tests were conducted on the seventh day after drug administration. Seven days administration of AGO at two different doses decreased the KET induced stereotypic and ataxic behaviour as compared with KET treated rats. In addition, AGO increased the social interaction time and decreased the horizontal and vertical locomotor behaviour in KET treated rats. Histologically, KET adminstration decreased hippocampal and increased basolateral amygdala (BLA) neuronal counts. AGO administration (at two different doses) significantly reversed the KET induced neuronal loss in the two brain areas. These findings suggest that AGO has a protective effect against KET-induced psychosis in this rat model. This study warrants further research to delineate the possible role of AGO in experimental model of psychosis particularly neurochemical and neuromolecular aspects.

P.2.005 - Knock-down of G protein-coupled receptor 88 in the striatum reduces psychiatric symptoms in a rat non-motor model of Parkinson’s disease

Although Parkinson's disease (PD) is commonly defined as a progressive motor disorder, it entails many psychiatric non-motor symptoms (NMS) such as depression and cognitive alterations that are irresponsive to L-DOPA treatment and are thus in need of new and more specific targets for their treatment. This underpins interest in Gpr88, a brain-specific orphan G-protein coupled receptor whose expression in the striatal medium spiny neurons is modulated by L-DOPA as well as 6-hydroxydopamine (6OHDA) lesions [1]. Knock-down (KD) of Gpr88 in the ventral striatum (STR) normalizes motor and cognitive alterations in a rat model of psychosis [2], so in this study, we evaluated the impact of Gpr88-KD on depressed mood, sensorimotor gating and social recognition in a model of psychiatric NMS of PD. Partial lesions reproducing several psychiatric symptoms of PD were induced by bilateral stereotaxic injections of 6OHDA (12µg/hemisphere), or control saline, in the dorsolateral STR of rats. Then, Gpr88 was knocked-down using a lentiviral vector co-expressing the emerald Green Fluorescent Protein (emGFP) marker and either a specific (miR-Gpr88) or control (miR-neg) microRNA. These vectors were bilaterally injected into either the ventral (v), dorsomedial (dm), or dorsolateral (dl) STR (2 or 6µl/hemisphere, in the ventral or dorsal regions respectively). The rats were then tested for: depression with the forced swim test (FST); sensorimotor filtering with the Prepulse Inhibition test (PPI, prepulses ranging from 70-80dB and pulse = 110dB); and social recognition with the social novelty discrimination (SND) test, which measures discrimination of a novel from a familiar juvenile rat (score ≥ 3 in controls). The efficacy of the 6-OHDA lesion was quantified by the loss of Tyrosine Hydroxylase (TH) immunofluorescence, and the lentiviral transduction extent and location was validated by emGFP detection. Statistical analyses were performed using one-way ANOVA followed by Bonferroni corrections. Results are expressed as means ± SEM. The 6-OHDA lesion was limited to the dlSTR where it induced a significant loss of TH immunoreactivity (-57.10% ± 4.23, p Taken together, these results indicate that striatal Gpr88 KD moderates striatal dopamine depletion related alterations in mood, sensory motor gating and social discrimination in a model of NMS of PD. This study thus highlights the relevance of GPR88 as a potential target for the control of the psychiatric symptoms of PD, and possibly of other neuropsychiatric diseases.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

Inhibition of apomorphine-induced behavioral sensitization in rats pretreated with fluoxetine.

Despite a number of clinically useful effects, there is growing evidence that psychosis and impulse control disorders develop in patients on apomorphine therapy. Evidence suggests a critical role of serotonin-1A receptors in psychosis, drug abuse, and in the mechanism of action of the prototypical selective serotonin reuptake inhibitor fluoxetine. We investigated whether fluoxetine can prevent apomorphine-induced behavioral sensitization in a rat model of psychosis. Animals treated with fluoxetine (5 and 10 mg/kg) for 2 weeks were subsequently cotreated with apomorphine (1.0 mg/kg) for 7 days. A single injection of apomorphine increased motor activity, whereas repeated daily injections produced a progressive sensitization of motor behavior. The sensitization effects of apomorphine did not occur in fluoxetine-pretreated and subsequently cotreated animals. To further elucidate the mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-treated animals, we found that apomorphine-induced motor behavior was much greater in repeated apomorphine-treated than repeated saline-treated animals. It was also greater in apomorphine and fluoxetine-cotreated animals, but not in animals pretreated and cotreated with fluoxetine. The mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-pretreated animals is discussed. The findings introduce an innovative approach for extending the therapeutic use of apomorphine and classical psychostimulant drugs.

MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis.

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons.

Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter‐1 (GlyT1)

N-methyl-D-aspartate (NMDA) receptor hypofunction is believed to comprise a central factor in the cognitive symptoms of psychotic illnesses such as schizophrenia. In the MK801 model of psychosis in rats, NMDA hypofunction also occurs, and animals display a profound impairment of both hippocampus-dependent learning and synaptic plasticity. The NMDA receptor may thus comprise a useful target for therapeutic amelioration of the symptoms of psychosis. However, direct activation of the receptor could lead to disturbed synaptic information storage. One possibility, however, is to enhance NMDA receptor function indirectly through elevation of glycine levels. We investigated the effects of inhibition of the glycine transporter-1, GlyT1, on long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus of freely behaving rats that had been treated previously with MK801. LTP, but not LTD, was impaired in MK801-treated animals. Systemic application of the GlyT1-inhibitor N[3-(4'-flurophenyl)-3-(4'-phenylphenoxy) propyl]sarcosine (NFPS) rescued LTP but had no effect on LTD in MK801-treated animals. Application of the antagonist to vehicle-treated controls resulted in a disruption of LTP but not LTD. NFPS significantly ameliorated reference memory deficits in a radial maze that occurred following MK801 treatment. NFPS-treated controls performed less well, however, than vehicle-injected controls. These data support that treatment with a glycine transporter inhibitor can ameliorate deficits in both LTP and learning that occur in a rat model of psychosis, and may therefore prove a useful strategy to address cognitive disruption in psychotic illnesses. Use of the inhibitor in healthy subjects is neither beneficial to synaptic plasticity nor hippocampus-dependent learning.