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Cellular and Molecular Life Sciences :... Apr 2016Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and...
Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.
Topics: Animals; Benzothiepins; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Cells, Cultured; Cognition Disorders; Down-Regulation; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Motor Activity; Neurons; Phencyclidine; Phosphorylation; Protein Tyrosine Phosphatases; RNA Interference; Receptors, N-Methyl-D-Aspartate; Ubiquitination
PubMed: 26450419
DOI: 10.1007/s00018-015-2057-1 -
Journal of Neuroscience Research Jan 2024Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms...
Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.
Topics: Animals; Female; Humans; Male; Mice; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology
PubMed: 37814998
DOI: 10.1002/jnr.25257 -
The International Journal of... May 2014Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the...
Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.
Topics: Animals; Antipsychotic Agents; Benzazepines; Butyric Acid; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Clozapine; Dopamine Antagonists; Epigenesis, Genetic; Exploratory Behavior; Hallucinogens; Haloperidol; Histamine Antagonists; Histone Deacetylases; Histones; Male; Memory Disorders; Mice; Mice, Inbred ICR; Phencyclidine; Phencyclidine Abuse; Prefrontal Cortex; Receptors, Dopamine D1
PubMed: 24345457
DOI: 10.1017/S1461145713001466 -
Brain Research Jan 1991The neuronal localization of glutamate and phencyclidine (PCP) receptors was evaluated in the cerebral cortex and hippocampal formation of rat CNS using quantitative...
The neuronal localization of glutamate and phencyclidine (PCP) receptors was evaluated in the cerebral cortex and hippocampal formation of rat CNS using quantitative autoradiography. Scatchard analysis of [3H]glutamate binding in the cortex (layers I and II and V and VI) showed no difference in the total number of binding sites (Bmax) or apparent affinity (Kd) 1 week, 1 month and 2 months following unilateral ibotenate lesions to nucleus basalis of Meynert (nbM) compared to the non-lesioned side. Quisqualic acid displacement of [3H]glutamate in layers I and II, 1 week following nbM destruction, revealed both high- and low-affinity binding sites (representing the quisqualate (QA) and N-methyl-D-aspartate (NMDA) sites, respectively). Compared to the control side, there was no difference in binding parameters for either of the receptor sites. In similarly lesioned animals, the NMDA receptor was specifically labelled with [3H]glutamate and the associated PCP receptor labelled with [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) in adjacent brain sections. For both receptors, there was no change in the total number of binding sites in the cortex following destruction of nbM. On the other hand, virtually all binding to NMDA and PCP receptors was eliminated following chemical destruction of intrinsic cortical neurons. These results suggest that the NMDA/PCP receptor complex does not exist on the terminals of cortical cholinergic afferents. One week after knife cuts of the glutamatergic entorhinal pathway to the hippocampal formation only an approximate 10% reduction of NMDA and PCP receptors was seen in the dentate gyrus. Conversely, selective destruction of the dentate granule cells using colchicine caused a near identical loss of NMDA and PCP receptors (84% vs 92% respectively). It is concluded from these experiments that glutamate and PCP receptors exist almost exclusively on neurons intrinsic to the hippocampal formation and that no more than 10% of NMDA and PCP receptors exist as autoreceptors on glutamatergic terminals.
Topics: Acetylcholinesterase; Animals; Autoradiography; Binding, Competitive; Carbon Radioisotopes; Cerebral Cortex; Choline O-Acetyltransferase; Functional Laterality; Glutamates; Hippocampus; Kinetics; Male; Phencyclidine; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Tritium
PubMed: 1850317
DOI: 10.1016/0006-8993(91)90373-4 -
The International Journal of... Oct 2014Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman... (Comparative Study)
Comparative Study
Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex.
BACKGROUND
Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits.
METHODS
The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys.
RESULTS
One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance.
CONCLUSIONS
As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia.
Topics: Age Factors; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Chlorocebus aethiops; Cognition; Disease Models, Animal; Disease Susceptibility; Dopamine; Female; Male; Memory, Short-Term; Phencyclidine; Prefrontal Cortex; Schizophrenia; Schizophrenic Psychology; Sex Factors; Spinal Cord; Synapses; Time Factors
PubMed: 25522392
DOI: 10.1093/ijnp/pyu048 -
Journal of Pharmacological Sciences Sep 2021Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in...
Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in the etiology of schizophrenia. Andrographolide is a diterpenoid lactone from Andrographis paniculate, which has shown anti-inflammation and anti-oxidative effects. In this study, we explored whether andrographolide can improve schizophrenia-like behaviors through its inhibition of inflammation and oxidative stress in Phencyclidine (PCP)-induced mouse model of schizophrenia. We found that abnormal behavioral including locomotor activity, forced swimming and novel object recognition were ameliorated following andrographolide administration (5 mg/kg and 10 mg/kg). Andrographolide inhibited PCP-induced production of inflammatory cytokines, decreased p-p65, p-IκBα, p-p38 and p-ERK1/2 in the prefrontal cortex. Andrographolide significantly declined the level of MDA and GSH, as well as elevated the activity of SOD, CAT and GCH-px. In addition, andrographolide increased expression of NRF-2, HO-1 and NQO-1, promoted nuclear translocation of NRF-2 through blocking the interaction between NRF-2 and KEAP1, which may be associated with directly binding to NRF-2. Furthermore, antioxidative effects and anti-schizophrenia-like behaviors of andrographolide were compromised by the application of NRF-2 inhibitor ML385. In conclusion, these results suggested that andrographolide improved oxidative stress and schizophrenia-like behaviors induced by PCP through increasing NRF-2 pathway.
Topics: Andrographis paniculata; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Diterpenes; Epistasis, Genetic; Inflammation; Kelch-Like ECH-Associated Protein 1; Male; Mice, Inbred ICR; NF-E2-Related Factor 2; Oxidative Stress; Phencyclidine; Phytotherapy; Schizophrenia; Signal Transduction; Mice
PubMed: 34294378
DOI: 10.1016/j.jphs.2021.05.007 -
Behavioural Brain Research Apr 2021Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate...
Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), impair reversal learning of rodents. Touchscreen-based pairwise visual discrimination and reversal test is a translational tool to assess reversal learning in rodents. However, to fully exploit this task in testing of novel compounds, it is necessary to perform several reversal learning experiments with trained animals. Firstly, we assessed whether PCP-induced deficits in visual reversal learning in rats would be detectable with a short (5 sessions) reversal learning phase, and whether the short reversal phases could be repeated with novel stimulus pairs. Secondly, we assessed whether the PCP-induced deficits in reversal learning could be seen upon repeated PCP challenges with the same animals. Finally, we tested the effect of a novel compound, a selective α adrenoceptor antagonist, ORM-13070, to reverse PCP-induced cognitive deficits in this model. A 4-day PCP treatment at a dose of 1.5 mg/kg/day impaired early reversal learning in male Lister Hooded rats without inducing non-specific behavioral effects. We repeated the reversal learning experiment four times using different stimulus pairs with the same animals, and the PCP-induced impairment was evident in every single experiment. The α adrenoceptor antagonist ameliorated the PCP-induced cognitive deficits. Our results suggest that repeated PCP challenges in the touchscreen set-up induce schizophrenia-like cognitive deficits in visual reversal learning, improve throughput of the test and provide a protocol for testing novel drugs.
Topics: Animals; Cognitive Dysfunction; Discrimination Learning; Male; Phencyclidine; Photic Stimulation; Rats; Receptors, N-Methyl-D-Aspartate; Reversal Learning
PubMed: 33316322
DOI: 10.1016/j.bbr.2020.113057 -
British Journal of Pharmacology Jul 2020Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates...
BACKGROUND AND PURPOSE
Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit COMT, a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one of the negative symptoms of schizophrenia.
EXPERIMENTAL APPROACH
We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice.
KEY RESULTS
In chronic PCP-treated mice, hispidulin (10 mg·kg , i.p.) attenuated social withdrawal similar to that observed with dopamine D receptor antagonist (SCH-23390, 0.02 mg·kg , i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg , i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser -phosphorylation and D activation in the PFC exits in both models.
CONCLUSIONS AND IMPLICATIONS
Hispidulin attenuated social withdrawal by activating D receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
Topics: Animals; Flavones; Mice; Phencyclidine; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Isolation
PubMed: 32133633
DOI: 10.1111/bph.15043 -
Neurobiology of Disease Jan 2023Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is...
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.
Topics: Mice; Animals; Cannabinoids; Cyclin-Dependent Kinase 5; Psychotic Disorders; Schizophrenia; Phencyclidine; Cannabinoid Receptor Agonists; Disks Large Homolog 4 Protein
PubMed: 36473591
DOI: 10.1016/j.nbd.2022.105942 -
Behavioural Brain Research Feb 2016GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate...
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.
Topics: Animals; Cognition; Disease Models, Animal; Excitatory Amino Acid Antagonists; Ketamine; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Oligopeptides; Phencyclidine; Recognition, Psychology
PubMed: 26632337
DOI: 10.1016/j.bbr.2015.10.060