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Neuron Nov 2018The medial prefrontal cortex (mPFC) is important for social behavior, but the mechanisms by which mPFC neurons code real-time social exploration remain largely unknown....
The medial prefrontal cortex (mPFC) is important for social behavior, but the mechanisms by which mPFC neurons code real-time social exploration remain largely unknown. Here we utilized miniScopes to record calcium activities from hundreds of excitatory neurons in the mPFC while mice freely explored restrained social targets in the absence or presence of the psychedelic drug phencyclidine (PCP). We identified distinct and dynamic ON and OFF neural ensembles that displayed opposing activities to code real-time behavioral information. We further illustrated that ON and OFF ensembles tuned to social exploration carried information of salience and novelty for social targets. Finally, we showed that dysfunctions in these ensembles were associated with abnormal social exploration elicited by PCP. Our findings underscore the importance of mPFC ON and OFF neural ensembles for proper exploratory behavior, including social exploration, and pave the way for future studies elucidating neural circuit dysfunctions in psychiatric disorders.
Topics: Action Potentials; Animals; Excitatory Amino Acid Antagonists; Exploratory Behavior; Mice; Mice, Inbred C57BL; Nerve Net; Optogenetics; Phencyclidine; Prefrontal Cortex; Social Behavior
PubMed: 30269987
DOI: 10.1016/j.neuron.2018.08.043 -
Schizophrenia Bulletin Sep 2012Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the... (Review)
Review
Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.
Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Brief Psychiatric Rating Scale; Cerebral Cortex; Disease Models, Animal; Dopamine; Emotions; Glutamic Acid; Humans; Ketamine; Neurosciences; Phencyclidine; Psychoses, Substance-Induced; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Synapses; Translational Research, Biomedical
PubMed: 22899397
DOI: 10.1093/schbul/sbs075 -
PloS One 20161,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy,...
1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.
Topics: Acetamides; Analgesics, Opioid; Animals; Drug Overdose; Humans; Ketamine; Phencyclidine; Phenethylamines; Piperidines; Psychotropic Drugs; Pyridines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin
PubMed: 27314670
DOI: 10.1371/journal.pone.0157021 -
European Neuropsychopharmacology : the... Mar 2019Phencyclidine (PCP) administration is commonly used to model schizophrenia in laboratory animals. While PCP is well-characterized as an antagonist of glutamate-sensitive...
Phencyclidine (PCP) administration is commonly used to model schizophrenia in laboratory animals. While PCP is well-characterized as an antagonist of glutamate-sensitive N-methyl-D-aspartate (NMDA) receptors, its effects on dopamine signaling are not well understood. Here we used whole-cell and cell-attached patch-clamp electrophysiology of substantia nigra dopamine neurons to determine the effects of acute and subchronic PCP exposure on both dopamine D2 autoreceptor-mediated currents and burst firing evoked by glutamate receptor activation. Acute PCP affected D2 autoreceptor-mediated currents through two apparently distinct mechanisms: a low-concentration dopamine transporter (DAT) inhibition and a high-concentration potassium (GIRK) channel inhibition. Subchronic administration of PCP (5 mg/kg, i.p., every 12 h for 7 days) decreased sensitivity to low dopamine concentrations, and also enhanced evoked burst firing of dopamine neurons. These findings suggest the effects of PCP on dopaminergic signaling in the midbrain could enhance burst firing and contribute to the development of schizophreniform behavior.
Topics: Action Potentials; Animals; Dizocilpine Maleate; Dopamine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Drug Administration Schedule; Electric Stimulation; Excitatory Amino Acid Antagonists; In Vitro Techniques; Iontophoresis; Kynurenic Acid; Male; Mice; Patch-Clamp Techniques; Phencyclidine; Receptors, Dopamine D2; Signal Transduction; Substantia Nigra
PubMed: 30686631
DOI: 10.1016/j.euroneuro.2019.01.108 -
Advances in Clinical and Experimental... 2012The study attempted to investigate the anti-anxiety activities of Phencyclidine (1-(1-phenylcyclohexyl) piperidine, PCP, I) and some of its derivatives (M, F, L, B, S,...
OBJECTIVES
The study attempted to investigate the anti-anxiety activities of Phencyclidine (1-(1-phenylcyclohexyl) piperidine, PCP, I) and some of its derivatives (M, F, L, B, S, P) with the elevated-plus maze (EPM) Test.
MATERIAL AND METHODS
Phencyclidine and its derivatives (M, F, L, B, S, P) were administrated intraperitoneally (i.p.) at a dose of 10 mg/kg to male mice. Anxiety-like behaviors were assessed using the elevated-plus maze test.
RESULTS
EPM results revealed an increase in open arms time spent after applying PCP and M, L, P, and B compounds at the administered dosage. Moreover, an increase in the number of open arm entries was observed with M, P, and B compounds. The P, B and S compounds increased the locomotion of animals, too, which might be considered as the side effect to the compounds.
CONCLUSIONS
Considering the elevated-plus maze results, it was concluded that M and L compounds could be considered as a potential anxiolytic with less side effects due to a probable high electron donation of the methoxy group, as well as the hydrophilic properties of hydroxyl groups on these compounds.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Disease Models, Animal; Hydrophobic and Hydrophilic Interactions; Injections, Intraperitoneal; Male; Maze Learning; Mice; Molecular Structure; Motor Activity; Phencyclidine; Structure-Activity Relationship
PubMed: 23214193
DOI: No ID Found -
Drug Development Research Dec 2014Preclinical Research N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but... (Comparative Study)
Comparative Study
Preclinical Research N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but abuse potential of these agents is a concern. The NMDA antagonist phencyclidine has known abuse liability but undefined efficacy as an antidepressant. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA antagonists, this study evaluated the effects of phencyclidine (1.0-10.0 mg/kg) in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects (differential-reinforcement-of-low-rate [DRL] 72 s schedule of food reinforcement; n = 9) and abuse-related drug effects (intracranial self-stimulation [ICSS]; n = 6). Under the DRL 72 s schedule, phencyclidine (10.0 mg/kg) increased reinforcers and decreased responses without shifting the peak location of the interresponse time (IRT) distribution. Ketamine (10.0 mg/kg) also increased reinforcers and decreased responses, but unlike phencyclidine, it produced a rightward shift in the peak location of the IRT distribution. The 10.0 mg/kg phencyclidine dose that decreased DRL 72 s responding also decreased rates of ICSS for 50 min after its administration; however, abuse-related ICSS facilitation was observed at later times (100-300 min) or after a lower phencyclidine dose (3.2 mg/kg). These results suggest that phencyclidine produces weaker antidepressant-like effects, but stronger abuse-related effects than ketamine in these procedures.
Topics: Animals; Antidepressive Agents; Conditioning, Operant; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Phencyclidine; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Self Stimulation; Time Factors
PubMed: 25315690
DOI: 10.1002/ddr.21228 -
Neuropsychobiology 2017The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony,...
BACKGROUND/AIMS
The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats.
METHODS
Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli.
RESULTS
Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components.
CONCLUSIONS
Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders.
Topics: Acoustic Stimulation; Animals; Auditory Cortex; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials, Auditory; Excitatory Amino Acid Antagonists; Male; Phencyclidine; Psychoacoustics; Rats; Rats, Sprague-Dawley; Spectrum Analysis; Time Factors
PubMed: 29065422
DOI: 10.1159/000480511 -
Psychopharmacology Nov 2018Serotonin 5-HT and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis...
BACKGROUND
Serotonin 5-HT and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates.
METHODS
Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.
RESULTS
The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.
CONCLUSION
These findings further support the existence of a functionally relevant crosstalk between 5-HT and mGlu2 receptors in different preclinical models of antipsychotic activity.
Topics: Animals; Antipsychotic Agents; Clozapine; Frontal Lobe; Male; Mice; Mice, Knockout; Phencyclidine; Psychomotor Agitation; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Schizophrenia
PubMed: 30209534
DOI: 10.1007/s00213-018-5015-4 -
Neuropsychopharmacology : Official... Nov 2018GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other...
TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia.
GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABA α2,3 subtype-selective GABA partial agonist and α antagonist, and the neurosteroid, pregnenolone sulfate, a GABA antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-D-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABA agonists may be of benefit to treat CIAS.
Topics: Animals; Cognitive Dysfunction; Dose-Response Relationship, Drug; GABA-A Receptor Agonists; Hallucinogens; Male; Mice; Mice, Inbred C57BL; Phencyclidine; Pyridazines; Reversal Learning; Schizophrenia; Triazoles
PubMed: 30093697
DOI: 10.1038/s41386-018-0160-3 -
Behavioural Pharmacology Aug 2016The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive...
Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice.
The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase (COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. In a novel object recognition procedure, tolcapone counteracted a 24-h-dependent forgetting of a familiar object as well as phencyclidine-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor that does not readily cross the blood-brain barrier, failed to show efficacy at doses up to 30 mg/kg. Tolcapone at a dose of 30 mg/kg also improved novel object recognition performance in transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders.
Topics: Animals; Benzophenones; Blood-Brain Barrier; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cognition Disorders; Dopamine; Dose-Response Relationship, Drug; Male; Memory Disorders; Mice; Mice, Transgenic; Nitriles; Nitrophenols; Phencyclidine; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Recognition, Psychology; Tolcapone
PubMed: 26919286
DOI: 10.1097/FBP.0000000000000208