ABSTRACT
Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases.
Subject(s)
Imidazoles/pharmacology , Microglia/drug effects , Pyridines/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Alzheimer Disease/pathology , Animals , Cell Proliferation/drug effects , Disease Models, Animal , Genome-Wide Association Study , Humans , Imidazoles/metabolism , Mice , Mice, Transgenic , Microglia/physiology , Neurodegenerative Diseases/drug therapy , Neurogenesis , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/physiology , Pyridines/metabolism , Receptors, GABA/genetics , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Tauopathies/drug therapy , tau Proteins/geneticsABSTRACT
Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.
ABSTRACT
BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
Subject(s)
C-Reactive Protein/analysis , Depressive Disorder, Treatment-Resistant/diagnosis , Adult , Biomarkers/blood , Depressive Disorder, Treatment-Resistant/blood , Female , Humans , Male , PhenotypeABSTRACT
The science of neuroimmunopsychiatry has evolved rapidly in the last few years with the hope of tackling the unmet need in mood disorders. This article focuses on an inflammatory pathway, highly conserved in myeloid cells that may play a role in neuroinflammatory disorders including depression. Within the brain tissue, microglia are the myeloid cells that express the P2X7 ion channel that is connected through the NLRP3 inflammasome complex leading to release of IL-1ß and IL-18. We present, in the way of reviewing relevant literature, the preclinical data and scientific rationale supporting the role of the P2X7-NLRP3-IL-1ß pathway in mood disorders. We also highlight recent advances in drug discovery and development of P2X7 small molecule antagonists and P2X7 PET ligands which provide optimism that clinical tools are availableto address critical proof-of-concept experiments in mood disorders.
Subject(s)
Mood Disorders/metabolism , Receptors, Purinergic P2X7/metabolism , Receptors, Purinergic P2X7/physiology , Animals , Depression/drug therapy , Humans , Inflammation/metabolism , Interleukin-1beta/metabolism , Interleukin-1beta/physiology , Microglia , Mood Disorders/physiopathology , Myeloid Cells/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/physiology , Neuroimmunomodulation/physiology , Purinergic P2X Receptor Antagonists/metabolism , Purinergic P2X Receptor Antagonists/therapeutic useABSTRACT
BACKGROUND AND PURPOSE: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent. KEY RESULTS: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg-1 . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg-1 . CONCLUSION AND IMPLICATIONS: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.
Subject(s)
Behavior, Animal/drug effects , Indenes/pharmacology , Nootropic Agents/pharmacology , Receptors, AMPA/drug effects , Sulfonamides/pharmacology , Allosteric Regulation/drug effects , Animals , Avoidance Learning/drug effects , Cognition/drug effects , Dose-Response Relationship, Drug , Electroshock , Humans , Indenes/administration & dosage , Indenes/toxicity , Male , Maze Learning/drug effects , Nootropic Agents/administration & dosage , Nootropic Agents/toxicity , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, AMPA/metabolism , Recognition, Psychology/drug effects , Scopolamine/toxicity , Sulfonamides/administration & dosage , Sulfonamides/toxicityABSTRACT
RATIONALE: We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl-D-aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs. OBJECTIVES: We assessed the effects of antipsychotic drugs to validate the assay (study 1), selective dopamine and serotonin ligands for pharmacological characterisation of the model (study 2) and a number of compounds with efficacy in models of schizophrenia to understand the predictive validity of the model (study 3). METHODS: Adult males (n = 9/group) were pretreated with a test compound, habituated to locomotor activity cages before receiving MK-801 (0.32 mg/kg) and activity recorded for a further 75 or 120 min. In study 1, we tested haloperidol, clozapine, olanzapine, risperidone, ziprasidone, aripiprazole, sertindole and quetiapine. In study 2, we tested SCH23390 (D(1) antagonist), sulpiride (D(2)/D(3) antagonist), raclopride (D(2)/D(3) antagonist), SB-277011 (D(3) antagonist), L-745,870 (D(4) antagonist), WAY100635 (5-HT(1A) antagonist), 8-OH-DPAT (5-HT(1A) agonist), ketanserin (5-HT(2A)/5-HT(2C) antagonist) and SB-242084 (5-HT(2C) antagonist). In study 3, we tested xanomeline (M(1)/M(4) receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABA(A) modulator) and thioperamide (H(3) receptor antagonist). RESULTS: All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D(1), D(2) and 5-HT(2) receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not. CONCLUSIONS: MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M(1)/M(4), mGluR2/3 and GABA(A) receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.
Subject(s)
Antipsychotic Agents/pharmacology , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Motor Activity/drug effects , Animals , Antipsychotic Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Delivery Systems , Hyperkinesis/chemically induced , Hyperkinesis/prevention & control , Male , Mice , Mice, Inbred BALB C , Receptors, GABA-A/metabolism , Receptors, Metabotropic Glutamate/drug effects , Receptors, Metabotropic Glutamate/metabolism , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Time FactorsABSTRACT
PURPOSE: Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs. METHODS: Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions. RESULTS: The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class. DISCUSSION: These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.
Subject(s)
Anticonvulsants/therapeutic use , Neurokinin-1 Receptor Antagonists , Piperidines/therapeutic use , Seizures/drug therapy , Sodium Channels/metabolism , Tetrazoles/therapeutic use , Animals , Anticonvulsants/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Synergism , Electroshock/adverse effects , Male , Rats , Rats, Sprague-Dawley , Seizures/etiologyABSTRACT
Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
Subject(s)
Aminoquinolines/metabolism , Aminoquinolines/pharmacology , Brain/drug effects , Brain/metabolism , Quinolines/metabolism , Quinolines/pharmacology , Receptors, Tachykinin/antagonists & inhibitors , Aminoquinolines/pharmacokinetics , Animals , Behavior, Animal/drug effects , Brain/cytology , Brain/physiology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cloning, Molecular , Dopamine/metabolism , Extracellular Space/drug effects , Extracellular Space/metabolism , Guinea Pigs , Habenula/cytology , Haloperidol/pharmacology , Humans , Inositol Phosphates/metabolism , Male , Microdialysis , Neurokinin B/pharmacology , Neurons/cytology , Neurons/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Peptide Fragments/pharmacology , Peptides/chemistry , Quinolines/pharmacokinetics , Rats , Receptors, Tachykinin/genetics , Receptors, Tachykinin/metabolism , Substance P/analogs & derivatives , Substance P/pharmacologyABSTRACT
The mechanism of action of standard drug treatments for psychiatric disorders remains fundamentally unknown, despite intensive investigation in academia and the pharmaceutical industry. So far, little is known about the effects of psychotropic medications on brain metabolism in either humans or animals. In this study, we investigated the effects of a range of psychotropic drugs on rat brain metabolites. The drugs investigated were haloperidol, clozapine, olanzapine, risperidone, aripiprazole (antipsychotics); valproate, carbamazapine (mood stabilizers) and phenytoin (antiepileptic drug). The relative concentrations of endogenous metabolites were determined using high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy. The results revealed that different classes of psychotropic drugs modulated a range of metabolites, where each drug induced a distinct neurometabolic profile. Some common responses across several drugs or within a class of drug were also observed. Antipsychotic drugs and mood stabilizers, with the exception of olanzapine, consistently increased N-acetylaspartate (NAA) levels in at least one brain area, suggesting a common therapeutic response on increased neuronal viability. Most drugs also altered the levels of several metabolites associated with glucose metabolism, neurotransmission (including glutamate and aspartate) and inositols. The heterogenic pharmacological response reflects the functional and physiological diversity of the therapeutic interventions, including side effects. Further study of these metabolites in preclinical models should facilitate the development of novel drug treatments for psychiatric disorders with improved efficacy and side effect profiles.
Subject(s)
Brain/physiology , Oligodendroglia/physiology , Psychotropic Drugs/pharmacology , Animals , Brain/drug effects , Magnetic Resonance Spectroscopy , Oligodendroglia/drug effects , RatsABSTRACT
A hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Compelling evidence of altered NMDA receptor subunit expression in the schizophrenic brain has not, however, so far emerged. Rats reared in isolation exhibit several characteristics, including disturbed sensory gating, which resemble those seen in schizophrenia. To explore the possibility that NMDA receptor dysfunction may contribute to the behavioral and neurochemical consequences of rearing rats in isolation, we compared NMDA receptor subunit expression in brains of rats which were housed in isolation and which displayed a deficit in prepulse inhibition of the acoustic startle response with that of socially housed controls. An initial microarray analysis revealed a 1.26-fold increase in NR2A transcript in the prefrontal cortex, but not in the nucleus accumbens, of rats reared in isolation compared with those housed socially. In contrast, NR1, NR2B, NR2C, NR2D, NR3A, and NR3B subunit expression was unchanged in either brain area. In a second cohort of animals, in situ hybridization revealed increased NR2A mRNA expression in the medial prefrontal cortex, an observation that was substantiated by increased [(3)H]CGP39653 binding suggesting that NR2A receptor subunit protein expression was also elevated in the medial prefrontal cortex of the same animals. No changes in expression of NR1 or NR2B subunits were observed at both mRNA and protein level. Altered NR2A subunit expression in the medial prefrontal cortex of rats reared in isolation suggests that NMDA receptor dysfunction may contribute to the underlying pathophysiology of this preclinical model of aspects of schizophrenia.
Subject(s)
Gene Expression Regulation/physiology , Prefrontal Cortex/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Social Isolation , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/metabolism , Acoustic Stimulation/adverse effects , Animals , Animals, Newborn , Gene Expression Profiling/methods , Indoles/metabolism , Male , Oligonucleotide Array Sequence Analysis/methods , Protein Binding/physiology , Radioligand Assay/methods , Rats , Receptors, N-Methyl-D-Aspartate/genetics , Reflex, Startle/physiology , Tritium/metabolismABSTRACT
Haloperidol and olanzapine are widely used antipsychotic drugs in the treatment of schizophrenia and other psychotic disorders. Despite extensive research efforts within the biopharmaceutical industry and academia, the exact molecular mechanisms of their action remain largely unknown. Since the response of patients to existing medications can be variable and often includes severe side effects, it is critical to increase our knowledge on their mechanism of action to guide clinical usage and new drug development. In this study, we have employed the label-free liquid chromatography tandem mass spectrometry (LC-MSE) to identify differentially expressed proteins in rat frontal cortex following subchronic treatment with haloperidol or olanzapine. Subcellular fractionation was performed to increased proteomic coverage and provided insight into the subcellular location involved in the mechanism of drug action. LC-MSE profiling identified 531 and 741 annotated proteins in fractions I (cytoplasmic-) and II (membrane enriched-) in two drug treatments. Fifty-nine of these proteins were altered significantly by haloperidol treatment, 74 by olanzapine and 21 were common to both treatments. Pathway analysis revealed that both drugs altered similar classes of proteins associated with cellular assembly/organization, nervous system development/function (particularly presynaptic function) and neurological disorders, which indicate a common mechanism of action. The top affected canonical signaling pathways differed between the two treatments. The haloperidol data set showed a stronger association with Huntington's disease signaling, while olanzapine treatment showed stronger effects on glycolysis/gluconeogenesis. This could either relate to a difference in clinical efficacy or side effect profile of the two compounds. The results were consistent with the findings reported previously by targeted studies, demonstrating the validity of this approach. However, we have also identified many novel proteins which have not been found previously to be associated with these drugs. Further study of these proteins could provide new insights into the etiology of the disease or the mechanism of antipsychotic medications.
Subject(s)
Antipsychotic Agents/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Frontal Lobe/drug effects , Animals , Benzodiazepines/pharmacology , Chromatography, Liquid/methods , Detergents/pharmacology , Haloperidol/pharmacology , Male , Mass Spectrometry/methods , Nervous System/drug effects , Olanzapine , Proteomics/methods , Rats , Rats, Wistar , Synaptic TransmissionABSTRACT
The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.2 channels and the unbound brain concentration required for anticonvulsant efficacy. Furthermore, the data suggest that an unbound concentration equivalent to less than 50% of the Ki is sufficient for anticonvulsant effect. We noted that increasing sodium channel blocking potency was associated with increasing brain tissue binding and lipophilicity. These data suggest that there is a balance between sodium channel blocking potency in vitro and good pharmacokinetic characteristics necessary for anticonvulsant efficacy in vivo. Finally, we examined the sodium channel blocking potency of sodium valproate in relation to its anticonvulsant efficacy in vivo. We found that a higher unbound concentration of the drug in the brain was required for anticonvulsant efficacy than would be expected given its sodium channel blocking potency.
Subject(s)
Anticonvulsants/therapeutic use , Seizures/drug therapy , Sodium Channel Blockers/therapeutic use , Triazines/therapeutic use , Animals , Anticonvulsants/pharmacology , Biophysics , Cell Line, Transformed , Dialysis/methods , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation/methods , Electroshock/adverse effects , Humans , Lamotrigine , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Patch-Clamp Techniques/methods , Rats , Seizures/etiology , Sodium Channel Blockers/pharmacology , Sodium Channels/genetics , Transfection/methods , Triazines/pharmacologyABSTRACT
OBJECTIVES: To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential. MATERIALS AND METHODS: Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations. RESULTS: GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg. CONCLUSIONS: The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration.
Subject(s)
Antipsychotic Agents/pharmacology , Benzazepines/pharmacology , Histamine Antagonists/pharmacology , Pyrazines/pharmacology , Schizophrenia/drug therapy , Administration, Oral , Amphetamine/pharmacology , Animals , Antipsychotic Agents/administration & dosage , Behavior, Animal/drug effects , Benzazepines/administration & dosage , Dose-Response Relationship, Drug , Histamine Antagonists/administration & dosage , Hyperkinesis/chemically induced , Hyperkinesis/prevention & control , Male , Memory/drug effects , Pyrazines/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/drug effects , Recognition, Psychology/drug effects , Schizophrenia/physiopathology , Social Isolation/psychologyABSTRACT
Presented in this unit is a protocol using subchronically administered phencyclidine (PCP) for establishing a behavioral sensitization model of aspects of schizophrenia. This model is validated using haloperidol and risperidone. The end-point of the assay is locomotor hyperactivity, which is induced by PCP challenge following subchronic treatment with this NMDA receptor antagonist. The antipsychotics haloperidol, risperidone, and quetiapine all reduce hyperactivity in a dose-dependent and selective manner. While the effects of other antipsychotics such as clozapine, olanzapine, and ziprasidone are similar to haloperidol, the interpretation of responses to them is often confounded by nonspecific effects during habituation.
Subject(s)
Antipsychotic Agents/pharmacology , Hallucinogens , Hyperkinesis/chemically induced , Phencyclidine , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Hallucinogens/administration & dosage , Hyperkinesis/prevention & control , Male , Phencyclidine/administration & dosage , Rats , Rats, Sprague-Dawley , Schizophrenia/chemically inducedABSTRACT
Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
Subject(s)
Acetamides/pharmacology , Cognition/drug effects , Dopamine Agonists/pharmacology , Motor Activity/drug effects , Pyridines/pharmacology , Receptors, Dopamine D4/agonists , Reward , Acetylcholine/metabolism , Amphetamine/pharmacology , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Routes , Extracellular Fluid/drug effects , Male , Memory Disorders/drug therapy , Methylphenidate/pharmacology , Microdialysis/methods , Pattern Recognition, Visual/drug effects , Photic Stimulation , Rats , Rats, Sprague-DawleyABSTRACT
Chandelier neurons are a subset of parvalbumin containing cortical interneurons characterised by their preferential targeting of the axon initial segments of pyramidal neurons. They have been the focus of recent interest after evidence that the arrays of boutons are reduced in the prefrontal cortex of schizophrenic patients, post mortem. Since one chandelier neuron may innervate the axon initial segments of several hundred pyramidal neurons, it is hypothesized that their special connectivity might facilitate synchronisation of cortical outputs and play a key role in working memory. Disruption in their function is therefore thought to play a potentially important role in cortically associated symptoms of schizophrenia. Using the isolation rearing animal model of schizophrenia, we examined immunolabelling for GABA-transporter 1, a marker of chandelier cartridges. We show that the numbers of arrays of chandelier axons are reduced by 36% in the ventral prelimbic cortex of isolation-reared rats, compared with their socially-housed litter mates. This mimics findings in the PFC of schizophrenic patients where GAT-1-positive cartridges are reduced by 40% and is the first study to demonstrate changes in chandelier cartridges in an animal model of schizophrenia.
Subject(s)
Axons/pathology , GABA Plasma Membrane Transport Proteins/metabolism , Interneurons/pathology , Prefrontal Cortex/pathology , Social Isolation/psychology , gamma-Aminobutyric Acid/metabolism , Animals , Axons/metabolism , Behavior, Animal/physiology , Cell Differentiation/physiology , Disease Models, Animal , Environment, Controlled , Immunohistochemistry , Interneurons/metabolism , Male , Neural Inhibition/physiology , Prefrontal Cortex/growth & development , Prefrontal Cortex/metabolism , Rats , Schizophrenia/metabolism , Schizophrenia/pathology , Schizophrenia/physiopathology , Sensory Deprivation/physiologyABSTRACT
The ability of a noncompetitive antagonist of the N-methyl-D-aspartate receptor, MK-801, to stimulate locomotor activity (LMA) in mice was compared across CD-1, MF1, NIH Swiss (NIHS), C57BL6/J and BALB/C strains with the aim of identifying the most suitable strain for a putative model of schizophrenia. Animals were habituated to novel LMA cages for 1 h before receiving either saline or MK-801 (0.1, 0.32, or 0.5 mg/kg; i.p.) and activity recorded for 2 h. At the end of the test, blood and brain samples were taken and the total concentrations of MK-801 determined. Mice strains differed in habituation; C57BL6/J mice were the most active, whereas BALB/C mice were the least active and slowest to habituate. Robust strain-dependent differences in sensitivity to MK-801 were found, but not to saline. NIHS, C57BL6/J and BALB/C were more active in response to MK-801, exhibiting more rapid, robust and long-lasting increases in LMA than CD-1 or MF1 mice. Total concentrations of MK-801 in the brain did not differ across the strains. We found no correlation between the LMA stimulated by novelty and MK-801. NIHS, C57BL6/J and BALB/C appeared significantly more sensitive to MK-801 than CD-1 and MF1 and can be strains of choice in evaluating the effect of antipsychotic compounds in this model.
Subject(s)
Dizocilpine Maleate , Exploratory Behavior/drug effects , Motor Activity/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Brain/metabolism , Disease Models, Animal , Dizocilpine Maleate/blood , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Male , Mice , Schizophrenia/chemically induced , Species SpecificityABSTRACT
In a putative model of acute phencyclidine (PCP)-induced psychosis we evaluated effects of the drug on locomotor activity (LMA) and immediate early gene (IEG) induction in the rat using two routes of drug administration, intraperitoneal (i.p.) and subcutaneous (s.c.). Adult male rats received saline or PCP (1.0-5.0 mg/kg) either i.p or s.c. and were assessed for LMA for 60 min. At the end of the LMA testing animals were culled and blood and brain samples were collected for PCP concentration analysis. Separate cohorts of animals received 5.0 mg/kg PCP (i.p. or s.c.) and were used to investigate (1) the pharmacokinetics of PCP or (2) induction of IEG (Arc, c-fos, BDNF, junB, Krox-20, sgk-1, NURR1, fra-2, Krox-24, and egr-3) mRNA expression in the prefrontal cortex (PFC). Administration of PCP resulted in locomotor hyperactivity which was more robust and longer-lasting in animals dosed s.c. compared to i.p.-treated-animals. Differences in hyperlocomotion were paralleled by higher concentrations of PCP in the blood and in the brain of s.c.-treated animals compared to i.p.-treated animals. The differences in the concentration of PCP between the two routes of administration were detected 30 min after dosing and persisted for up to 4 h. Administration of PCP via the s.c. route resulted in induction of more IEGs and consistently larger magnitudes of induction than that via the i.p. route. Therefore, we have outlined the dosing conditions to induce rapid and robust effect of acute PCP on behaviour, gene induction, and pharmacokinetic profile, to allow investigation of this as a potential animal model of acute psychosis.
Subject(s)
Behavior, Animal/drug effects , Gene Expression Regulation/drug effects , Motor Activity/drug effects , Phencyclidine/administration & dosage , Phencyclidine/pharmacokinetics , Psychoses, Substance-Induced/etiology , Schizophrenia/chemically induced , Animals , Behavior, Animal/physiology , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Genes, Immediate-Early/drug effects , Genes, Immediate-Early/genetics , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Motor Activity/physiology , Phencyclidine/blood , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transcriptional ActivationSubject(s)
Brain-Derived Neurotrophic Factor/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Enzyme Inhibitors/pharmacology , Hippocampus/metabolism , Phencyclidine/pharmacology , Animals , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Phencyclidine/administration & dosage , RatsABSTRACT
Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (the prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in psychiatric disorders such as schizophrenia. Ketamine, a non-competitive N-methyl-D-aspartate antagonist has been shown to induce schizophrenia-like behavioural changes in humans and PPI deficits in rats, which can be reversed by antipsychotics. Thus, ketamine-induced PPI deficits in rats may provide a translational model of schizophrenia. The aim of this study was to investigate the effects of antipsychotic drugs and drugs known to alter the glutamate system upon ketamine-induced PPI deficits in rats. Rats were habituated to the PPI procedure [randomized trials of either pulse alone (110 dB/50 ms) or prepulse + pulse (80 dB/10 ms)]. Animals were assigned to pre-treatments based on the level of PPI on the last habituation test and balanced across startle chambers. Ketamine (1-10 mg/kg s.c; 15 min ptt) increased startle amplitude and induced PPI deficits at 6 and 10 mg/kg. PPI deficits induced by ketamine at 6 mg/kg were not attenuated by clozapine (2.5-10 mg/kg s.c.; 60 min ptt), risperidone (0.1-1 mg/kg i.p.; 60 min ptt), haloperidol (0.1-1 mg/kg i.p.; 60 min ptt), lamotrigine (3-30 mg/kg p.o.; 60 min ptt), or SB-271046-A (5-20 mg/kg p.o.; 2 hour ptt) nor potentiated by 2-methyl-6-(phenylethynyl)-pyridine (3-10 mg/kg i.p.; 30 min ptt). These results suggest that under these test conditions ketamine-induced PPI deficits in rats is relatively insensitive and does not represent a translational model for drug discovery in schizophrenia.