Phencyclidine Model Of Schizophrenia Research Articles

Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.

MSCs-Derived-EVs as Potential Protection Against Behavioral and Biochemical Deficits in a Phencyclidine Model of Schizophrenia

MSCs-Derived-EVs as Potential Protection Against Behavioral and Biochemical Deficits in a Phencyclidine Model of Schizophrenia

Mscs-derived evs as potential treatment in a phencyclidine model of schizophrenia

Background & Aim Schizophrenia is a debilitating mental disorder, a major contributor to the global health burden of disease. Although antipsychotic medication is very effective against the positive symptoms of the disease, such as hallucinations, such an effective treatment for the negative symptoms is not available. Phencyclidine (PCP) has been validated in rodents as a model for schizophrenia, shown to reliably induce both positive and negative symptoms in a multitude of behavioral tests. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Methods, Results & Conclusion In this study, we assessed the feasibility of intranasal delivery of MSCs-derived EVs to improve the positive and negative symptoms in a PCP model of schizophrenia. Our results show that mice treated with MSCs-EVs are beneficial for preventing both positive and negative symptoms in a PCP-model of schizophrenia. While PCP-treated mice showed a deficiency in social interaction and increased vulnerability to amphetamine, mice co-administered with PCP and MSCs-EVs behaved similarly to the sham group, treated with saline. Immunohistochemical studies demonstrated that the EVs prevented loss of Paravalbumin-expressing GABAergic neurons in the PFC of treated mice, where EVs were most congregated. We believe MSCs-derived EVs may be an invaluable treatment for schizophrenia. With the convenient intranasal administration and ability to arrive at the site of damage in the diseased brain, they may offer an unprecedented improvement in negative symptoms.

Does BDNF loss of function in the prefrontal cortex underlie cognitive deficits in the subchronic phencyclidine model of schizophrenia?

Does BDNF loss of function in the prefrontal cortex underlie cognitive deficits in the subchronic phencyclidine model of schizophrenia?

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia

The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.

A State Dependence of the Response to N-Methyl-D-Aspartate Receptor Antagonism

The best pharmacobehavioral model for psychosis associated with schizophrenia is the N-methyl-D-aspartate receptor (NMDAR) antagonist model ( 1 Javitt D.C. Zukin S.R. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991; 148: 1301-1308 Crossref PubMed Scopus (2565) Google Scholar , 2 Krystal J.H. Karper L.P. Seibyl J.P. Freeman G.K. Delaney R. Bremner J.D. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994; 51: 199-214 Crossref PubMed Scopus (2644) Google Scholar ). The NMDAR antagonists provide an invaluable tool for the investigation of cellular and circuit mechanisms responsible for a psychotic state that so closely resembles that of schizophrenia.

Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons.

Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions.

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.

Nitric Oxide Synthase Mediation of Darbepoetin's Cognitive Benefits: A Paradoxical Effect?

Recently, Kajitani et al (2010) reported observations to support that enhanced nitric oxide signaling might be the mechanistic basis for erythropoietin's cognitive benefits in schizophrenia. However, numerous studies have suggested that enhanced nitric oxide signaling might adversely impact schizophrenia. For example, increased nitric oxide signaling has been demonstrated to underlie the information-processing deficits in the phencyclidine model of schizophrenia (Palsson et al, 2010); intriguingly, the nitric oxide synthase inhibitor (N (G)-nitro-L-arginine methyl ester (L-NAME)) used by the authors in this study (Kajitani et al, 2010) has been reported to ameliorate the phencyclidine-induced cognitive deficits (Klamer et al, 2001). Moreover, treatment with minocycline, a nitric oxide synthase inhibitor, improved cognitive deficits in schizophrenia patients in a double-blind, randomized, placebo-controlled study (Levkovitz et al, 2010). Also, neuronal nitric oxide synthase haplotype association with schizophrenia has been speculated as an instance of increased predisposition towards this devastating disorder, yet also improving cognitive domains (Reif et al, 2006). Contextually, it is important to note that the beneficial effects of erythropoietin on cognitive deficits in schizophrenia have been demonstrated in patients that were stabilized with antipsychotic treatment; these patients did not have severe positive symptoms (Ehrenreich et al, 2007). If the enhanced nitric oxide signaling is indeed the predominant mechanistic basis for erythropoietin's benefits (Kajitani et al, 2010), then, this is an issue of concern because of the potential of this mechanism to worsen schizophrenia symptoms—perhaps with long-term use.

Information processing deficits and nitric oxide signalling in the phencyclidine model of schizophrenia

Schizophrenia-like cognitive deficits induced by phencyclidine (PCP), a drug commonly used to model schizophrenia in experimental animals, are attenuated by nitric oxide (NO) synthase inhibitors. Furthermore, PCP increases NO levels and sGC/cGMP signalling in the prefrontal cortex in rodents. Hence, a cortical NO/sGC/cGMP signalling pathway may constitute a target for novel pharmacological therapies in schizophrenia. The objective of this study was to further investigate the role of NO signalling for a PCP-induced deficit in pre-attentive information processing. Male Sprague-Dawley rats were surgically implanted with NO-selective amperometric microsensors aimed at the prefrontal cortex, ventral hippocampus or nucleus accumbens, and NO levels and prepulse inhibition (PPI) were simultaneously assessed. PCP treatment increased NO levels in the prefrontal cortex and ventral hippocampus, but not in the nucleus accumbens. The increase in NO levels was not temporally correlated to the deficit in PPI induced by PCP. Furthermore, pretreatment with the neuronal NO synthase inhibitor N-propyl-L-arginine dose-dependently attenuated both the increase in prefrontal cortex NO levels and the deficit in PPI. These findings support a demonstrated role of NO in the behavioural and neurochemical effects of PCP. Furthermore, this effect is brain region-specific and mainly involves the neuronal isoform of NOS. However, a temporal correlation between a PCP-induced disruption of PPI and an increase in prefrontal cortex NO levels was not demonstrated, suggesting that the interaction between PCP and the NO system is more complex than previously thought.

Increased cortical nitric oxide release after phencyclidine administration

Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg(-1)) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg(-1)). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia.

Guanosine possesses specific modulatory effects on NMDA receptor-mediated neurotransmission in intact mice

Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor “open-channel” blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor “open-channel” blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.

Mitogen-Activated Protein Kinase Signaling

The mechanism by which cells respond to extracellular stimuli involves a series of signal transduction events across the cell membrane and through the cytoplasm to the nucleus. Mitogen-activated protein (MAP) kinases are important mediators of signal transduction and play a key role in the regulation of many cellular processes, such as cell growth and proliferation, differentiation, and apoptosis. In mammalian cells, three major groups of MAP kinases have been identified: extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAP kinase. It is well documented that ERK is typically stimulated by growth-related signals, whereas the JNK and p38 MAP kinase cascades are activated by various stress stimuli. Studies have indicated that MAP kinases are expressed abundantly in the central nervous system (CNS) and that ERK is involved in long-lasting neuronal plasticity, including long-term potentiation and memory consolidation. While the role of ERK in neuronal plasticity and behavioral adaptation is beginning to emerge, the role of MAP kinase signal transduction cascades in major psychiatric disorders, including schizophrenia, is not well understood. This review outlines the intermediates of this signaling cascade and downstream transcription factor targets and recent evidence implicating MAP kinases to important biological functions in the CNS. Evidence from human post-mortem studies, as well as from the phencyclidine model of schizophrenia, that different MAP kinase cascades may be involved in the pathogenesis of schizophrenia, and potentially in other psychiatric disorders, is presented. Knowledge of MAP kinase signaling will aid greatly in our ability t o understand causal changes in disease process and may lead to new therapeutic approaches in controlling or treating schizophrenia.

A review of NMDA receptors and the phencyclidine model of schizophrenia.

Current models of drug-induced psychosis insufficiently describe the symptoms of schizophrenia. Phencyclidine-induced psychosis is a model that more completely reflects the pathophysiology of the disease. By decreasing glutamatergic neurotransmission, phencyclidine decreases gamma-aminobutyric acid release from the nucleus accumbens, striatum, and hippocampus (manifested by MK-801); may inhibit tonic release of dopamine from the nucleus accumbens and striatum, resulting in increased dopamine phasic reactivity; and decreases long-term potentiation. Glutamatergic system dysfunction may be involved, but pharmacologic manipulation has not revealed a clear mechanism of this dysfunction.

Recent advances in the phencyclidine model of schizophrenia

Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology. Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.