10 results on '"Gartlon JE"'
Search Results
2. Further neurochemical and behavioural investigation of Brattleboro rats as a putative model of schizophrenia
- Author
-
Cilia, J., primary, Gartlon, JE, additional, Shilliam, C., additional, Dawson, LA, additional, Moore, SH, additional, and Jones, DNC, additional
- Published
- 2009
- Full Text
- View/download PDF
3. Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition.
- Author
-
Ellard JM, Madin A, Philps O, Hopkin M, Henderson S, Birch L, O'Connor D, Arai T, Takase K, Morgan L, Reynolds D, Talma S, Howley E, Powney B, Payne AH, Hall A, Gartlon JE, Dawson LA, Castro L, and Atkinson PJ
- Subjects
- Allosteric Regulation drug effects, Animals, Antipsychotic Agents metabolism, Antipsychotic Agents pharmacology, Astrocytes cytology, Astrocytes drug effects, Astrocytes metabolism, Cognition drug effects, Disease Models, Animal, Drug Evaluation, Preclinical, Half-Life, Humans, Microsomes metabolism, Rats, Receptor, Metabotropic Glutamate 5 metabolism, Structure-Activity Relationship, Triazoles metabolism, Triazoles pharmacology, Antipsychotic Agents chemistry, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors, Triazoles chemistry
- Abstract
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
4. The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.
- Author
-
Johnson DJ, Forbes IT, Watson SP, Garzya V, Stevenson GI, Walker GR, Mudhar HS, Flynn ST, Wyman PA, Smith PW, Murkitt GS, Lucas AJ, Mookherjee CR, Watson JM, Gartlon JE, Bradford AM, and Brown F
- Subjects
- Animals, Benzoxazoles chemistry, Benzoxazoles therapeutic use, Brain metabolism, Indoles chemistry, Indoles therapeutic use, Muscarinic Agonists chemistry, Muscarinic Agonists therapeutic use, Nootropic Agents chemistry, Nootropic Agents therapeutic use, Oxindoles, Rats, Benzoxazoles pharmacokinetics, Indoles pharmacokinetics, Memory Disorders drug therapy, Muscarinic Agonists pharmacokinetics, Nootropic Agents pharmacokinetics, Receptor, Muscarinic M1 metabolism
- Abstract
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
5. Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice.
- Author
-
Woolley ML, Carter HJ, Gartlon JE, Watson JM, and Dawson LA
- Subjects
- Animals, Hyperkinesis chemically induced, Hyperkinesis drug therapy, Mice, Mice, Knockout, Muscarinic Agonists therapeutic use, Pyridines therapeutic use, Substrate Specificity, Thiadiazoles therapeutic use, Amphetamine toxicity, Muscarinic Agonists pharmacology, Pyridines pharmacology, Receptor, Muscarinic M1 deficiency, Receptor, Muscarinic M1 genetics, Receptor, Muscarinic M4 deficiency, Receptor, Muscarinic M4 genetics, Thiadiazoles pharmacology
- Abstract
The muscarinic acetylcholine receptor (mAChR) agonist, xanomeline, attenuates amphetamine-induced activity in WT mice. This effect is abolished in mice lacking the M(4) muscarinic acetylcholine receptor (M(4) mAChR KO) and partially attenuated in mice lacking M(1) muscarinic acetylcholine receptor (M(1) mAChR KO). Collectively, these data suggest that the efficacy exhibited by xanomeline in the mouse amphetamine-induced hyperactivity model, is mediated predominantly by M(4) muscarinic acetylcholine receptors, and that M(1) muscarinic acetylcholine receptors may play a more minor role. This supports the hypothesis that activation of M(4), and to a lesser extent M(1) muscarinic acetylcholine receptors, may represent a potential target for the treatment of psychosis seen in schizophrenia.
- Published
- 2009
- Full Text
- View/download PDF
6. Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040.
- Author
-
Southam E, Cilia J, Gartlon JE, Woolley ML, Lacroix LP, Jennings CA, Cluderay JE, Reavill C, Rourke C, Wilson DM, Dawson LA, Medhurst AD, and Jones DN
- Subjects
- 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 psychology, Antipsychotic Agents pharmacology, Benzazepines pharmacology, Histamine Antagonists pharmacology, Pyrazines pharmacology, Schizophrenia drug therapy
- Abstract
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.
- Published
- 2009
- Full Text
- View/download PDF
7. Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.
- Author
-
Woolley ML, Waters KA, Gartlon JE, Lacroix LP, Jennings C, Shaughnessy F, Ong A, Pemberton DJ, Harries MH, Southam E, Jones DN, and Dawson LA
- Subjects
- Acetylcholine metabolism, Amygdala physiology, Animals, Attention drug effects, Brain-Derived Neurotrophic Factor biosynthesis, Conditioning, Operant drug effects, Cues, Dopamine metabolism, Fear drug effects, Fear psychology, Hippocampus drug effects, Hippocampus metabolism, In Situ Hybridization, Male, Muscarinic Antagonists pharmacology, Norepinephrine metabolism, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, RNA, Messenger biosynthesis, Rats, Scopolamine antagonists & inhibitors, Scopolamine pharmacology, Cognition drug effects, Nootropic Agents pharmacology, Oxadiazoles pharmacology, Piperidines pharmacology, Receptors, AMPA drug effects, Recognition, Psychology drug effects
- Abstract
Rationale: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment., Objectives: The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration., Results: CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05)., Conclusions: Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
- Published
- 2009
- Full Text
- View/download PDF
8. Sub-chronic phencyclidine administration increases brain-derived neurotrophic factor in the RAT hippocampus.
- Author
-
Harte MK, Cahir M, Reynolds GP, Gartlon JE, and Jones DN
- Subjects
- Animals, Drug Administration Schedule, Enzyme Inhibitors administration & dosage, Phencyclidine administration & dosage, Rats, Brain-Derived Neurotrophic Factor drug effects, Brain-Derived Neurotrophic Factor metabolism, Enzyme Inhibitors pharmacology, Hippocampus metabolism, Phencyclidine pharmacology
- Published
- 2007
- Full Text
- View/download PDF
9. Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain.
- Author
-
Southam E, Lloyd A, Jennings CA, Cluderay JE, Cilia J, Gartlon JE, and Jones DN
- Subjects
- Animals, Immunohistochemistry, Male, Prosencephalon metabolism, Proto-Oncogene Proteins c-fos biosynthesis, Rats, Rats, Sprague-Dawley, Time Factors, Nitriles pharmacology, Prosencephalon drug effects, Proto-Oncogene Proteins c-fos drug effects, Receptors, Dopamine D3 antagonists & inhibitors, Tetrahydroisoquinolines pharmacology
- Abstract
SB-277011-A is a dopamine D(3) receptor antagonist that exhibits over 100-fold selectivity over dopamine D(2) receptors and a broad spectrum of other receptor, ion channels, and enzymes. We employed c-Fos immunohistochemistry to characterise the functional neuroanatomical effects of acute administration of SB-277011-A and observed a time-dependent increase in the density of c-Fos-like positive nuclei in rat forebrain with maximal effects observed 2 h post-dose. The relative influence of the different brain regions on the overall effect of SB-277011-A was ranked by partial least squares discriminant analysis loadings plot which indicated that sites within the nucleus accumbens exerted the greatest influence on the separation of the vehicle and SB-277011-A treatment groups. At the 2 h time-point, c-Fos-like expression was shown to be significantly elevated (p<0.05) in the core and shell of the nucleus accumbens, at both rostral and caudal levels, and in the lateral septum. No significant changes were detected in the caudate nucleus (lateral or medial) or in the cingulate, infralimbic prefrontal, or somatosensory cortices. The capacity of SB-277011-A to trigger immediate early gene expression in these limbic regions of rat brain adds to a growing consensus of the potential utility of dopamine D(3) receptor antagonism in psychiatric disorders including schizophrenia and drug dependency.
- Published
- 2007
- Full Text
- View/download PDF
10. Urotensin-II, a neuropeptide ligand for GPR14, induces c-fos in the rat brain.
- Author
-
Gartlon JE, Ashmeade T, Duxon M, Hagan JJ, and Jones DN
- Subjects
- Animals, Dose-Response Relationship, Drug, Gene Expression drug effects, Gene Expression genetics, Gyrus Cinguli drug effects, Gyrus Cinguli physiology, Injections, Intraventricular, Male, Midline Thalamic Nuclei drug effects, Midline Thalamic Nuclei physiology, Neuropeptides chemistry, Periaqueductal Gray drug effects, Periaqueductal Gray physiology, Proto-Oncogene Proteins c-fos immunology, Rats, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled physiology, United Kingdom, Urotensins chemistry, Ligands, Neuropeptides pharmacology, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-fos metabolism, Receptors, G-Protein-Coupled drug effects, Urotensins pharmacology
- Abstract
The vasoactive peptide urotensin-II and its receptor, GPR14 (now known as UT receptor), are localised in the mammalian central nervous system. Accordingly, various centrally mediated effects of urotensin-II on behaviour, neuroendocrine hormones and neurochemistry have been described. To investigate neuroanatomical substrates for the central actions of urotensin-II, expression of the immediate early gene c-fos was examined following intracerebroventricular administration to rats. Urotensin-II increased Fos expression in the cingulate cortex and periaqueductal grey, suggesting important central roles for urotensin-II and its receptor., (Copyright 2004 Elsevier B.V.)
- Published
- 2004
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.