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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 -
Molecular Brain Oct 2014The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the...
BACKGROUND
The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental.
RESULTS
To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice.
CONCLUSIONS
The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo.
Topics: Animals; Behavior, Animal; Brain; Dysbindin; Dystrophin-Associated Proteins; Gene Expression Regulation; Humans; Methamphetamine; Mice, Inbred C57BL; Mice, Transgenic; Phencyclidine
PubMed: 25298178
DOI: 10.1186/s13041-014-0074-x -
Behavioural Pharmacology Aug 2019Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in...
Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in relation to drug exposure, and no studies have explored alterations in acoustic features over time. The goal of this study was to examine nicotine- and phencyclidine-induced alterations of bandwidth, duration, and frequency of 50 kHz vocalizations. The minimum and maximum frequency, bandwidth, and duration of calls were examined after 7 days of daily subcutaneous administration of phencyclidine (2.0 mg/kg) and nicotine (0.2 and 0.4 mg/kg) in male Sprague-Dawley rats. Bandwidth was significantly decreased in rats treated with both nicotine (0.2 and 0.4 mg/kg) and phencyclidine. Maximum frequency was lowest on the first day of exposure compared with all other days and was not altered by drug exposure. Call duration was not affected by time or drug exposure. These findings suggest the importance of studying alterations in acoustic features in time, especially those induced by drug exposure.
Topics: Acoustics; Animals; Male; Nicotine; Phencyclidine; Rats; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal
PubMed: 30801260
DOI: 10.1097/FBP.0000000000000463 -
The Journal of Neuroscience : the... May 1996Rats learned to lever-press when such behavior was reinforced by microinjections of phencyclidine (PCP) directly into the ventromedial (shell) region of nucleus...
Rats learned to lever-press when such behavior was reinforced by microinjections of phencyclidine (PCP) directly into the ventromedial (shell) region of nucleus accumbens, indicating that the drug has direct rewarding actions in that region. Separate groups of rats learned to lever-press when reinforced with microinjections of dizoclipine (MK-801) or 3-((+/-)2-carboxypiperazin-4yl)propyl-1-phosphate (CPP), drugs known to block NMDA receptor function but not dopamine uptake, into the same region. Each drug was ineffective or markedly less effective when injected at a slightly more dorsal and lateral site in the core of nucleus accumbens. Self-administration of PCP, MK-801, or CPP directly into nucleus accumbens was not altered by co-infusion of a dose of the dopamine antagonist sulpiride that effectively blocked intracranial self-administration of the dopamine uptake inhibitor nomifensine, suggesting that the rewarding actions of the NMDA receptor antagonists are not dopamine-dependent. Rats also developed lever-pressing habits when PCP, MK-801, and CPP were each microinjected directly into frontal cortex, a region previously associated with the rewarding actions of cocaine but not nomifensine. Thus nucleus accumbens and frontal cortex are each potential substrates for the rewarding properties of PCP and related drugs, and the ability of these drugs to disrupt NMDA receptor function seems sufficient to account for their rewarding actions. When considered with independent evidence, the present results suggest a model of drug reward within which the critical event is inhibition of medium spiny neurons in nucleus accumbens.
Topics: Animals; Dopamine; Frontal Lobe; Male; Microinjections; Nucleus Accumbens; Phencyclidine; Rats; Rats, Inbred Strains; Reward; Self Administration
PubMed: 8622141
DOI: 10.1523/JNEUROSCI.16-09-03112.1996 -
Journal of Neurophysiology Aug 2017-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants....
-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture. This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.
Topics: Animals; Chlorocebus aethiops; Cortical Synchronization; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Gamma Rhythm; Globus Pallidus; Ketamine; Microelectrodes; Motor Cortex; Neural Pathways; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Signal Processing, Computer-Assisted
PubMed: 28468999
DOI: 10.1152/jn.00765.2016 -
Neuropharmacology Mar 2012Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive...
PURPOSE
Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort.
METHODS
Monkeys were trained to perform reversal learning and object retrieval procedures before twice daily administration of PCP (0.3 mg/kg intra-muscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice daily administration of saline (control) or asenapine (50, 100, or 150 μg/kg, intra-muscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite.
RESULTS
On average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2-4 weeks of dosing. In week 4, the improvement with asenapine 150 μg/kg (p = 0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 μg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50-150 μg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit.
CONCLUSIONS
In this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder.
Topics: Animals; Antipsychotic Agents; Biogenic Monoamines; Chlorocebus aethiops; Cognition Disorders; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Male; Phencyclidine; Psychomotor Performance; Reversal Learning; Treatment Outcome
PubMed: 21875607
DOI: 10.1016/j.neuropharm.2011.08.026 -
British Journal of Pharmacology Jun 1983The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids...
The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone-anaesthetized cats and rats. Both ketamine and phencyclidine selectively blocked excitation by N-methyl-aspartate (NMA) with little effect on excitation by quisqualate and kainate. Ketamine reduced responses to L-aspartate somewhat more than those of L-glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other. On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root-evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation. Intravenous ketamine, 2.5-20 mg/kg, and phencyclidine, 0.2-0.5 mg/kg, also selectively blocked excitation of neurones by NMA. Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or gamma-aminobutyricacid (GABA). The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.
Topics: Acetylcholine; Animals; Aspartic Acid; Cats; Female; In Vitro Techniques; Ketamine; Male; N-Methylaspartate; Neurons; Phencyclidine; Rats; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Synapses
PubMed: 6317114
DOI: 10.1111/j.1476-5381.1983.tb11031.x -
Schizophrenia Bulletin Sep 2012The history of the chemical synthesis and animal/human pharmacology of phencyclidine is documented. From its early use as a general anesthetic, chemical model of...
The history of the chemical synthesis and animal/human pharmacology of phencyclidine is documented. From its early use as a general anesthetic, chemical model of schizophrenia, and drug of abuse, phencyclidine has had a checkered history. Research with this agent and its chemical derivatives like ketamine have provided a solid foundation for just a beginning to understanding the neuropathology of schizophrenia.
Topics: Anesthetics; Animals; Disease Models, Animal; History, 20th Century; History, 21st Century; Humans; Illicit Drugs; Neuropharmacology; Phencyclidine; Psychoses, Substance-Induced; Schizophrenia
PubMed: 22390879
DOI: 10.1093/schbul/sbs011 -
Neuron Apr 2016The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple...
The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca(2+)-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca(2+)-dependent K(+) channels (Kcnn2 and Kcnn3), voltage-gated Ca(2+) channels (Cacna1g and Cacna1h), or Ca(2+)/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca(2+) ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca(2+)-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.
Topics: Animals; Calcium; Calcium Channels, T-Type; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Computer Simulation; Dizocilpine Maleate; Electroencephalography; Electromyography; Excitatory Amino Acid Antagonists; Membrane Potentials; Mice; Mice, Knockout; Phencyclidine; Plasma Membrane Calcium-Transporting ATPases; Receptors, N-Methyl-D-Aspartate; Sleep; Sleep, REM; Small-Conductance Calcium-Activated Potassium Channels; Time Factors
PubMed: 26996081
DOI: 10.1016/j.neuron.2016.02.032 -
The International Journal of... Sep 2022Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal...
BACKGROUND
Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.
METHODS
We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.
RESULTS
Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.
CONCLUSIONS
ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.
Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Guanidines; Isoquinolines; Male; Memory Disorders; Methamphetamine; Mice; Mice, Knockout; Phencyclidine; Rats; Rats, Transgenic; Receptors, Serotonin; Scopolamine; Serotonin; Serotonin Antagonists
PubMed: 35882205
DOI: 10.1093/ijnp/pyac041