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The International Journal of... May 2015Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic...
BACKGROUND
Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals.
METHOD
To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3 mg/kg).
RESULTS
Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus.
CONCLUSION
With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.
Topics: Animals; Behavior, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Hippocampus; Humans; Injections, Intraventricular; Locomotion; Male; Mice; Mice, Inbred C57BL; Microdialysis; Motor Activity; Neuregulin-1; Phencyclidine; Prefrontal Cortex; Prepulse Inhibition; Reflex, Startle; Signal Transduction; Treatment Outcome; gamma-Aminobutyric Acid
PubMed: 26478928
DOI: 10.1093/ijnp/pyu114 -
Psychopharmacology Aug 2016In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle.
BACKGROUND
In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle.
OBJECTIVES
The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water.
MATERIALS AND METHODS
Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions.
RESULTS
Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases.
CONCLUSIONS
Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.
Topics: Administration, Oral; Animals; Cocaine; Dopamine Uptake Inhibitors; Drug-Seeking Behavior; Female; Follicular Phase; Luteal Phase; Macaca mulatta; Male; Menstrual Cycle; Phencyclidine; Reward; Saccharin; Self Administration; Sex Factors; Sweetening Agents
PubMed: 27318989
DOI: 10.1007/s00213-016-4343-5 -
Schizophrenia Bulletin Sep 2012At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently...
At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.
Topics: Antipsychotic Agents; Glutamic Acid; History, 20th Century; History, 21st Century; Humans; Phencyclidine; Psychoses, Substance-Induced; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 22987849
DOI: 10.1093/schbul/sbs100 -
Neurotoxicity Research Oct 2018Nowadays cognitive impairments are a growing unresolved medical issue which may accompany many diseases and therapies, furthermore, numerous researchers investigate...
Nowadays cognitive impairments are a growing unresolved medical issue which may accompany many diseases and therapies, furthermore, numerous researchers investigate various neurobiological aspects of human memory to find possible ways to improve it. Until any other method is discovered, in vivo studies remain the only available tool for memory evaluation. At first, researchers need to choose a model of amnesia which may strongly influence observed results. Thereby a deeper insight into a model itself may increase the quality and reliability of results. The most common method to impair memory in rodents is the pretreatment with drugs that disrupt learning and memory. Taking this into consideration, we compared the activity of agents commonly used for this purpose. We investigated effects of phencyclidine (PCP), a non-competitive NMDA receptor antagonist, and scopolamine (SCOP), an antagonist of muscarinic receptors, on short-term spatial memory and classical fear conditioning in mice. PCP (3 mg/kg) and SCOP (1 mg/kg) were administrated intraperitoneally 30 min before behavioral paradigms. To assess the influence of PCP and SCOP on short-term spatial memory, the Barnes maze test in C57BL/J6 mice was used. Effects on classical conditioning were evaluated using contextual fear conditioning test. Additionally, spontaneous locomotor activity of mice was measured. These two tests were performed in CD-1 mice. Our study reports that both tested agents disturbed short-term spatial memory in the Barnes maze test, however, SCOP revealed a higher activity. Surprisingly, learning in contextual fear conditioning test was impaired only by SCOP. Graphical Abstract ᅟ.
Topics: Amnesia; Analysis of Variance; Animals; Cholinergic Antagonists; Conditioning, Psychological; Disease Models, Animal; Fear; Hallucinogens; Locomotion; Male; Maze Learning; Mice; Mice, Inbred C57BL; Phencyclidine; Reaction Time; Scopolamine
PubMed: 29680979
DOI: 10.1007/s12640-018-9901-7 -
Pharmacology, Biochemistry, and Behavior Jun 2017Adolescence is a phase of development during which many physiological and behavioral changes occur, including increased novelty seeking and risk taking. In humans, this...
Adolescence is a phase of development during which many physiological and behavioral changes occur, including increased novelty seeking and risk taking. In humans, this is reflected in experimentation with drugs. Research demonstrates that drug use that begins during adolescence is more likely to lead to addiction than drug use that begins later in life. Despite this, relatively little is known of the effects of drugs in adolescence, and differences in response between adolescents and adults. PCP and ketamine are popular club drugs, both possessing rewarding properties that could lead to escalating use. Drug sensitization (or reverse tolerance), which refers to an increase in an effect of a drug following repeated use, has been linked with the development of drug cravings that is a hallmark of addiction. The current work investigated the acute response and the development of sensitization to PCP and ketamine in adolescent and adult rats. Periadolescent Sprague-Dawley rats (30days or 38days of age), and young adults (60days of age) received PCP (6mg/kg IP) or ketamine (20mg/kg IP) once every three days, for a total of five drug injections. Adolescents and adults showed a stimulant response to the first injection of either drug, however the response was considerably greater in the youngest adolescents and lowest in the adults. With repeated administration, adults showed a robust escalation in activity that was indicative of the development of sensitization. Adolescents showed a flatter trajectory, with similar high levels of activity following an acute treatment and after five drug treatments. The results demonstrate important distinctions between adolescents and adults in the acute and repeated effects of PCP and ketamine.
Topics: Age Factors; Anesthetics, Dissociative; Animals; Drug Administration Schedule; Hallucinogens; Ketamine; Male; Motor Activity; Movement; Phencyclidine; Rats; Rats, Sprague-Dawley
PubMed: 28442368
DOI: 10.1016/j.pbb.2017.04.007 -
British Journal of Pharmacology Jan 2023Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an...
BACKGROUND AND PURPOSE
Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis.
KEY RESULTS
Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway.
CONCLUSION AND IMPLICATIONS
This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
Topics: Animals; Rats; Male; Phencyclidine; Schizophrenia; Fingolimod Hydrochloride; Brain-Derived Neurotrophic Factor; Rats, Sprague-Dawley; Cognitive Dysfunction; Cytokines; Disease Models, Animal
PubMed: 36106568
DOI: 10.1111/bph.15954 -
Journal of Psychopharmacology (Oxford,... Jul 2020Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural...
Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system - implications for the 3Rs and preclinical drug discovery.
BACKGROUND
Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias.
AIM
To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly utilised to model aspects of schizophrenia.
METHODS
Rats housed in groups of three were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg).
RESULTS
PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage mates and this asociality occured from 60 to 105 min post treatment.
CONCLUSIONS
Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery through improved welfare and increased between-laboratory replicability.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Dissociative Disorders; Locomotion; Male; Phencyclidine; Radio Frequency Identification Device; Rats; Reproducibility of Results; Social Behavior; Time Factors
PubMed: 32438848
DOI: 10.1177/0269881120920455 -
Basic & Clinical Pharmacology &... Nov 2004Studies in rats and primates have demonstrated that repeated phencyclidine treatment can produce enduring cognitive deficits that may resemble the cognitive deficits...
Studies in rats and primates have demonstrated that repeated phencyclidine treatment can produce enduring cognitive deficits that may resemble the cognitive deficits seen in schizophrenia, suggesting that neurodegeneration resulting from NMDA-receptor dysfunction may be a valid model of schizophrenia. The purpose of the present experiments was to expand these findings and to determine if medium and high doses of the NMDA-antagonists phencyclidine and (+)MK-801 could produce permanent behavioural changes in animal tests with face validity for some aspects of the positive and negative symptoms of schizophrenia. Rats were treated with dose regimens of (+)MK-801 and phencyclidine known to produce mild and severe irreversible levels of neurotoxicity, and were tested 7 or 10 days after the last drug administration in the social interaction test and in standard activity cages. The rats did not show any enduring behavioural changes as a result of the treatment. The present study could therefore not provide additional evidence for the face validity of this model of schizophrenia.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Male; Motor Activity; Neurotoxicity Syndromes; Phencyclidine; Rats; Rats, Wistar; Schizophrenia; Social Behavior; Stereotyped Behavior
PubMed: 15546479
DOI: 10.1111/j.1742-7843.2004.pto950507.x -
PloS One 2013In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent...
In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.
Topics: Cyclohexanones; Cyclohexylamines; Drug Evaluation, Preclinical; Humans; Ketamine; Molecular Structure; National Institute of Mental Health (U.S.); Phencyclidine; Radioligand Assay; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Serotonin Plasma Membrane Transport Proteins; United States
PubMed: 23527166
DOI: 10.1371/journal.pone.0059334 -
Canadian Medical Association Journal Aug 1964The discovery of new dysleptic drugs has prompted the present review of these substances which influence neuropsychic activity. It is possible to divide dysleptics into... (Review)
Review
The discovery of new dysleptic drugs has prompted the present review of these substances which influence neuropsychic activity. It is possible to divide dysleptics into two categories: under the first heading fall mescaline, LSD-25, psilocybine, adrenochrome, bufotenine and dimethyltryptamin; the other group includes Ditran, Butoxamine, WH-4849, and AHR-379. The place of Sernyl could not be ascertained and it might well constitute a class by itself. The mescaline type of reaction is mainly characterized by the induction of perceptual distortions without alteration of the state of consciousness, whereas the Ditran type reaction is one of confusion with postexperimental amnesia. Electroencephalographic recordings support this classification: lowering of amplitude, acceleration of rhythm and desynchronization were noted with the first group; and slowing of rhythm and slow waves similar to those seen during the onset of sleep, with the other group.
Topics: Adrenochrome; Anesthetics; Bufotenin; Electroencephalography; Epinephrine; Hallucinogens; Indoles; Lysergic Acid Diethylamide; Mescaline; Norepinephrine; Parasympatholytics; Phencyclidine; Piperidines; Psilocybin; Serotonin; Toxicology; Tryptamines
PubMed: 14184040
DOI: No ID Found