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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 -
Pharmacology, Biochemistry, and Behavior Mar 2020Valbenazine, a vesicular monoamine transporter 2 (VMAT2, SLC18A2) inhibitor, is a newly approved treatment for tardive dyskinesia. VMAT2 is present in the membrane of...
Effects of NBI-98782, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor, on neurotransmitter efflux and phencyclidine-induced locomotor activity: Relevance to tardive dyskinesia and antipsychotic action.
Valbenazine, a vesicular monoamine transporter 2 (VMAT2, SLC18A2) inhibitor, is a newly approved treatment for tardive dyskinesia. VMAT2 is present in the membrane of secretory vesicles and transports dopamine (DA), norepinephrine (NE), serotonin (5-HT), histamine, glutamate (Glu), and GABA into vesicles for presynaptic release. We utilized microdialysis in awake, freely moving mice to determine the effect of NBI-98782, the active metabolite of valbenazine, alone, or in combination with several antipsychotic drugs (APDs), to influence neurotransmitter efflux in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR), hippocampus and nucleus accumbens (NAC); we also compared it with tetrabenazine, the prototypical VMAT2 inhibitor. Acute NBI-98782 and tetrabenazine decreased mPFC, dSTR, hippocampus, and NAC DA, 5-HT, and NE efflux, while increasing that of DOPAC, HVA, and 5-HIAA. Sub-chronic NBI-98782 (7 days) decreased baseline DA and 5-HT efflux in both mPFC and dSTR. NBI-98782 elicited similar effects on neurotransmitter efflux in sub-chronic NBI-98782-treated mice but also enhanced ACh and GABA; the decrease in DA efflux in mPFC and dSTR was not significant in the sc-treated animals. NBI-98782 suppressed clozapine-, olanzapine- and risperidone-induced DA efflux in both mPFC and dSTR, and ACh efflux in mPFC. NBI-98782 suppressed the haloperidol-induced DA efflux in dSTR, with minimal effect on GABA efflux. NBI-98782 attenuated PCP-induced DA, 5-HT, NE and Glu efflux, and AMPH-induced DA and NE efflux, in both mPFC and dSTR, as well as PCP- and AMPH-induced hyperlocomotion, suggesting possible beneficial antipsychotic effects.
Topics: Animals; Antipsychotic Agents; Dopamine; Hippocampus; Locomotion; Male; Mice; Mice, Inbred C57BL; Microdialysis; Nucleus Accumbens; Phencyclidine; Prefrontal Cortex; Serotonin; Synaptic Transmission; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 32084491
DOI: 10.1016/j.pbb.2020.172872 -
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,... Oct 2014Both acute and sub-chronic phencyclidine administration produce behavioural and pathophysiological changes that resemble some features of schizophrenia. The present...
Both acute and sub-chronic phencyclidine administration produce behavioural and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if acute and sub-chronic phencyclidine treatment in male rats produces deficits in sociability and social novelty preference, which may reflect aspects of the negative symptomatology observed in schizophrenia. Rats were treated with phencyclidine acutely (2 or 5 mg/kg) or subchronically (2 or 5 mg/kg bi-daily for one week followed by a one week wash-out period) or vehicle. Social affiliative behaviour was assessed using the sociability and preference for social novelty paradigm where social interaction time was measured in (a) a chamber containing an unfamiliar conspecific vs an empty chamber (sociability), or (b) a chamber containing an unfamiliar conspecific vs a chamber containing a familiar conspecific (preference for social novelty). Results showed that acute administration of phencyclidine produced a reduction in measures of sociability but had no effect on preference for social novelty while sub-chronic administration of phencyclidine had no effect on sociability or social novelty. This study provides further evidence for the usefulness of phencyclidine models in modelling the symptomatology of schizophrenia.
Topics: Animals; Choice Behavior; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Hallucinogens; Male; Phencyclidine; Rats; Schizophrenic Psychology; Social Behavior
PubMed: 25122039
DOI: 10.1177/0269881114544778 -
Psychopharmacology Mar 2020A high number of synthetic dissociative drugs continue to be available through online stores, leading to their misuse. Recent inclusions in this category are 4-MeO-PCP...
4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels.
RATIONALE
A high number of synthetic dissociative drugs continue to be available through online stores, leading to their misuse. Recent inclusions in this category are 4-MeO-PCP and 3-MeO-PCMo, analogs of phencyclidine. Although the dissociative effects of these drugs and their recreational use have been reported, no studies have investigated their abuse potential.
OBJECTIVES
To examine their rewarding and reinforcing effects and explore the mechanistic correlations.
METHODS
We used conditioned place preference (CPP), self-administration, and locomotor sensitization tests to assess the rewarding and reinforcing effects of the drugs. We explored their mechanism of action by pretreating dopamine receptor (DR) D1 antagonist SCH23390 and DRD2 antagonist haloperidol during CPP test and investigated the effects of 4-MeO-PCP and 3-MeO-PCMo on dopamine-related proteins in the ventral tegmental area and nucleus accumbens. We also measured the levels of dopamine, phosphorylated cyclic-AMP response element-binding (p-CREB) protein, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens. Additionally, we examined the effects of both drugs on brain wave activity using electroencephalography.
RESULTS
While both 4-MeO-PCP and 3-MeO-PCMo induced CPP and self-administration, only 4-MeO-PCP elicited locomotor sensitization. SCH23390 and haloperidol inhibited the acquisition of drug CPP. 4-MeO-PCP and 3-MeO-PCMo altered the levels of tyrosine hydroxylase, DRD1, DRD2, and dopamine, as well as that of p-CREB, deltaFosB, and BDNF. All drugs increased the delta and gamma wave activity, whereas pretreatment with SCH23390 and haloperidol inhibited it.
CONCLUSION
Our results indicate that 4-MeO-PCP and 3-MeO-PCMo induce rewarding and reinforcing effects that are probably mediated by the mesolimbic dopamine system, suggesting an abuse liability in humans.
Topics: Animals; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Designer Drugs; Dopamine; Illicit Drugs; Male; Mice; Mice, Inbred C57BL; Morpholines; Nucleus Accumbens; Phencyclidine; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Reward; Self Administration; Signal Transduction
PubMed: 31828394
DOI: 10.1007/s00213-019-05412-y -
Neuropharmacology Nov 2018Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related... (Review)
Review
Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
Topics: Animals; Hallucinogens; Humans; Ketamine; Neuronal Plasticity; Receptors, N-Methyl-D-Aspartate
PubMed: 29885421
DOI: 10.1016/j.neuropharm.2018.06.008 -
Psychopharmacology Nov 2015Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive... (Review)
Review
RATIONALE
Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals.
OBJECTIVES
The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks.
METHODS
Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination.
RESULTS
Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation.
CONCLUSIONS
The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.
Topics: Animals; Attention; Cognition Disorders; Disease Models, Animal; Male; Phencyclidine; Rats; Reversal Learning; Schizophrenia
PubMed: 26070547
DOI: 10.1007/s00213-015-3954-6 -
Drug Testing and Analysis Jul 2020The new psychoactive substance (NPS) 3-HO-PCP, a phencyclidine (PCP) analog, was detected in a law enforcement seizure and in forensic samples in Denmark. Compared with... (Comparative Study)
Comparative Study
In vitro and in vivo metabolism and detection of 3-HO-PCP, a synthetic phencyclidine, in human samples and pooled human hepatocytes using high resolution mass spectrometry.
The new psychoactive substance (NPS) 3-HO-PCP, a phencyclidine (PCP) analog, was detected in a law enforcement seizure and in forensic samples in Denmark. Compared with PCP, 3-HO-PCP is known to be a more potent dissociative NPS, but no toxicokinetic investigations of 3-HO-PCP are yet available. Therefore, 3-HO-PCP was quantified in in vivo samples, and the following were investigated: plasma protein binding, in vitro and in vivo metabolites, and metabolic targets. All samples were separated by liquid chromatography and analyzed by mass spectrometry. The unbound fraction in plasma was determined as 0.72 ± 0.09. After in vitro incubation with pooled human hepatocytes, four metabolites were identified: a piperidine-hydroxyl-and piperidine ring opened N-dealkyl-COOH metabolite, and O-glucuronidated- and O-sulfate-conjugated metabolites. In vivo, depending on the sample and sample preparation, fewer metabolites were detected, as the O-sulfate-conjugated metabolite was not detected. The N-dealkylated-COOH metabolite was the main metabolite in the deconjugated urine sample. in vivo analytical targets in blood and brain samples were 3-HO-PCP and the O-glucuronidated metabolite, with 3-HO-PCP having the highest relative signal intensity. The drug levels of 3-HO-PCP quantified in blood were 0.013 and 0.095 mg/kg in a living and a deceased subject, respectively. The 3-HO-PCP concentrations in deconjugated urine in a sample from a living subject and in post-mortem brain were 7.8 and 0.16 mg/kg, respectively. The post mortem results showed a 1.5-fold higher concentration of 3-HO-PCP in the brain tissue than in the post mortem blood sample.
Topics: Chromatography, Liquid; Hallucinogens; Hepatocytes; Humans; Mass Spectrometry; Phencyclidine; Substance Abuse Detection; Tissue Distribution
PubMed: 32311838
DOI: 10.1002/dta.2807 -
Pediatric Neurology Feb 2020Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that works by binding to the phencyclidine-binding site, thereby blocking influx of cations through the... (Review)
Review
Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that works by binding to the phencyclidine-binding site, thereby blocking influx of cations through the NMDA receptor channel. The use of ketamine to treat refractory status epilepticus in adults and older children is well documented. Maturational changes in neonatal NMDA and γ-aminobutyric acid receptor expression and function make NMDA receptor antagonists, like ketamine, attractive potential therapeutic agents for treatment of refractory seizures in the newborn. However, descriptions of its use in this age group are limited to two case reports. Concerns regarding potential ketamine-mediated neurotoxicity in the immature brain require further investigation.
Topics: Drug Resistant Epilepsy; Excitatory Amino Acid Antagonists; Humans; Infant, Newborn; Infant, Newborn, Diseases; Ketamine; Status Epilepticus
PubMed: 31601453
DOI: 10.1016/j.pediatrneurol.2019.09.003 -
Genes, Brain, and Behavior Apr 2022Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual...
Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2 rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.
Topics: Animals; Disease Models, Animal; Guanylate Kinases; Haploinsufficiency; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Phencyclidine; Rats; Schizophrenia; Social Behavior; Tumor Suppressor Proteins
PubMed: 35075790
DOI: 10.1111/gbb.12797