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Biomedical subjects

Guy A Higgins

Publications and source records attributed to Guy A Higgins.

At least 19 recordsLinked to original sources
PubMed2006

Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Accumulation of amyloid beta-peptide (Abeta) is considered a key step in the etiology of Alzheimer's disease. Abeta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several gamma-secretase inhibitors have been shown to reduce plasma and brain Abeta, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of gamma-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the gamma-secretase inhibitor N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Abeta(40) in young (preplaque) transgenic CRND8 mice (ED(50) approximately 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Abeta(40) by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Abeta levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel gamma-secretase inhibitors.

Administration, Oral↗
PubMed2006

The effects of the 5-HT(2C) receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists.

RATIONALE: The 5-HT(2C) receptor modulates mesolimbic dopamine (DA) function and the expression of DA-dependent behaviors, including stimulant-induced hyperactivity. The 5-HT(2C) receptor may also be involved in drug-induced locomotion that is 5-HT-dependent. OBJECTIVES: This study investigated the effects of the 5-HT(2C) receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB242084) on hyperlocomotion induced by psychomotor stimulants with selective, or mixed, actions on serotonergic and/or dopaminergic systems. MATERIALS AND METHODS: Male Sprague-Dawley rats were treated in the presence or absence of SB242084 with releasers/reuptake inhibitors of DA (amphetamine and methylphenidate), 5-HT (fenfluramine and citalopram), or both 5-HT and DA (MDMA and cocaine). In addition, the effects of SB242084 combined with nicotine, morphine, or the 5-HT(1A/1B) receptor agonist RU24969 were examined. Locomotor activity was recorded for 2 h. RESULTS: SB242084 potentiated hyperactivity induced by MDMA (2.5-5 mg/kg), amphetamine (0.5 mg/kg), fenfluramine (5 mg/kg), cocaine (10 mg/kg), and methylphenidate (5 mg/kg). SB242084 modestly potentiated nicotine-induced (0.2-0.4 mg/kg) and morphine-induced (2.5 mg/kg) hyperactivity. SB242084 failed to influence hyperactivity induced by RU24969 (0.5-1 mg/kg) or citalopram (10-20mg/kg). CONCLUSION: SB242084 potentiated the locomotor stimulant effects of both indirect DA and 5-HT agonists. This potentiation may reflect two distinct mechanisms. The first involves direct enhancement of DA activity as shown by potentiation of the effects of amphetamine and methylphenidate. The second mechanism reflects an unmasking of stimulatory 5-HT receptors activated by 5-HT releasers (possibly 5-HT(1B/2A)) through blockade of inhibitory 5-HT(2C) receptors. The failure of SB242084 to potentiate the effect of citalopram might reflect differences between changes in synaptic levels of 5-HT produced by release compared to reuptake inhibition.

Aminopyridines↗
PubMed2006

Enhancing effects of nicotine and impairing effects of scopolamine on distinct aspects of performance in computerized attention and working memory tasks in marmoset monkeys.

With the CAmbridge Neuropsychological Test Automated Battery (CANTAB), computerized neuropsychological tasks can be presented on a touch-sensitive computer screen, and this system has been used to assess cognitive processes in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque and common marmoset. Recently, we reported that the common marmoset, a small-bodied primate, can be trained to a high and stable level of performance on the CANTAB five-choice serial reaction time (5-CSRT) task of attention, and a novel task of working memory, the concurrent delayed match-to-position (CDMP) task. Here, in order to increase understanding of the specific cognitive demands of these tasks and the importance of acetylcholine to their performance, the effects of systemic delivery of the muscarinic receptor antagonist scopolamine and the nicotinic receptor agonist nicotine were studied. In the 5-CSRT task, nicotine enhanced performance in terms of increased sustained attention, whilst scopolamine led to increased omissions despite a high level of orientation to the correct stimulus location. In the CDMP task, scopolamine impaired performance at two stages of the task that differ moderately in terms of memory retention load but both of which are likely to require working memory, including interference-coping, abilities. Nicotine tended to enhance performance at the long-delay stage specifically but only against a background of relatively low baseline performance. These data are consistent with a dissociation of the roles of muscarinic and nicotinic cholinergic receptors in the regulation of both sustained attention and working memory in primates.

Acetylcholine↗
PubMed2005

2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs as adenosine A2A antagonists: the successful reduction of hERG activity. Part 2.

The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.

Adenosine A2 Receptor Antagonists↗
PubMed2005

Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat.

RATIONALE: We previously reported that the NR2B subunit-selective N-methyl-D-aspartate (NMDA) antagonist Ro 63-1908 produced a marked deficit in response control in the five-choice serial reaction time task (5-CSRTT). OBJECTIVES: The present studies were designed to investigate this further by studying the NR2B NMDA antagonists, ifenprodil, traxoprodil (CP101,606), Ro 25-6981 as well as Ro 63-1908 in this test. METHODS: Following training in the 5-CSRTT, separate groups of rats were either tested under (1) standard test conditions [5 s inter-trial interval (ITI), 0.5 s stimulus duration, 100 trials], (2) high (3 s ITI) and low (10 s ITI) event rate of stimulus presentation and (3) a 250-trial protocol in aged 2-year-old rats. In a final study, the effects of traxoprodil were investigated in an operant delayed match to position (DMTP) task, a test of working memory, and compared to dizocilpine and Ro 63-1908. RESULTS: Similar to Ro 63-1908, both traxoprodil (1-10 mg/kg) and Ro 25-6981 (3--30 mg/kg) increased premature responding but also increased response speed with no error trade-off. Conversely, ifenprodil (1--10 mg/kg) slowed response speed and increased omissions with no effect on premature responding. Tested under a variable ITI, Ro 63--1908 (1 mg/kg) increased premature responding at all ITIs, but this change was proportional to controls. At short ITI (3 s), Ro 63-1908 reliably improved performance both in terms of response speed and accuracy (percent correct). In a 250-trial protocol in aged rats, both Ro 63-1908 (0.1-0.3 mg/kg) and, particularly, traxoprodil (1--3 mg/kg) improved performance-increasing response speed and increasing the number of rewards earned during test. Finally, traxoprodil (1--10 mg/kg) improved accuracy and increased response speed in the DMTP task. CONCLUSIONS: The present studies support the view that selective NR2B NMDA antagonists promote impulsive-type responding in the 5-CSRTT; however, under certain test conditions, drugs of this class-notably traxoprodil-may also improve task performance.

Animals↗
PubMed2005

Age-progressing cognitive impairments and neuropathology in transgenic CRND8 mice.

Patients with Alzheimer's disease suffer from progressive cognitive impairments and show distinct post-mortem neuropathology, including beta-amyloid plaques. Transgenic (Tg) CRND8 mice carry a mutated human amyloid precursor protein gene and show age-related increases in beta-amyloid production and plaque deposition. It was previously reported that during the early stages of plaque deposition, Tg CRND8 mice demonstrated Morris maze impairments. However, it is unknown if Tg mice would be impaired at an earlier age prior to plaque deposition or more impaired at a later age with more extensive plaque deposition. In the current study, we describe Tg CRND8 age-progressing beta-amyloid neuropathology and cognitive abilities in greater detail. At all ages, Tg mice showed normal short-term memory in the Y-maze. Pre-plaque Tg and age-matched Non-Tg mice did not differ in learning the spatial Morris water maze. However, both early and late plaque Tg mice showed impairments during acquisition. In addition, although early plaque Tg mice performed well in the probe trial, late plaque Tg mice demonstrated impaired probe trial performance. Therefore compared to their Non-Tg littermates, Tg CRND8 mice demonstrate cognitive impairments that progressed with age and seemed to coincide with the onset of beta-amyloid plaque deposition.

Age Factors↗
PubMed2005

The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.

RATIONALE: Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders. OBJECTIVES: This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety. METHODS: The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects. RESULTS: The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg. CONCLUSION: Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.

Analgesics↗
PubMed2004

The opioid receptor like-1 receptor agonist Ro 64-6198 (1S,3aS-8-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one) produces a discriminative stimulus in rats distinct from that of a mu, kappa, and delta opioid receptor agonist cue.

Male Wistar rats were trained to discriminate either the opioid receptor like (ORL)-1 receptor agonist Ro 64-6198 (1S,3aS-8-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one) or morphine from saline using a two-choice, food reinforced, operant procedure. Acquisition of Ro 64-6198 discrimination was relatively slow (mean trials to criterion 113 +/- 6), and a final 4 mg/kg dose (initial training dose 2 mg/kg) was required to establish appropriate stimulus control. In comparison, a separate group of rats attained a morphine (2 mg/kg) discrimination in 44 +/- 4 trials. In tests of substitution, Ro 64-6198 produced a dose-related generalization to its own cue (ED(50) of 1.1 mg/kg i.p.), yet only weakly generalized to the morphine cue (19% at 10 mg/kg i.p.). In contrast, morphine generalized completely to the morphine cue (ED(50) of 0.7 mg/kg s.c.), yet only partially generalized to the Ro 64-6198 cue (40% at 6 mg/kg s.c.). The kappa opioid receptor agonist U50,488 [trans-3,4-dichloro-N-methyl-N(2-[1-pyrrolidinyl]cyclohexyl) benzeneacetamide methanesulfonate] (0.3-6 mg/kg s.c.) and the delta opioid receptor agonist SNC-80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (0.3-6 mg/kg i.p.) failed to evoke significant generalization to either cue. The mu opioid receptor agonists codeine (0.3-20 mg/kg) and buprenorphine (0.01-1 mg/kg) completely generalized to the morphine cue, but only buprenorphine partially generalized to the Ro 64-6198 cue. Naloxone pretreatment completely blocked the morphine cue (ED(50) of 0.005 mg/kg s.c.), yet only weakly attenuated the Ro 64-6198 cue at 0.3 mg/kg. Finally, the selective ORL-1 antagonist J-113397 [1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one] completely blocked the Ro 64-6198 cue at a dose (30 mg/kg i.p.) that had no effect against the morphine cue. The present studies demonstrate that rats may be trained to discriminate Ro 64-6198 from saline, and the pharmacological characteristics of this cue are most consistent with ORL-1 receptor activation.

Animals↗
PubMed2004

Pharmacological and genetic evidence indicates that combined inhibition of NR2A and NR2B subunit containing NMDA receptors is required to disrupt prepulse inhibition.

RATIONALE: Glutamate signalling through the N-methyl-D-aspartate (NMDA) receptor is of critical importance for normal central nervous system (CNS) function, as indicated by the marked behavioural disturbances produced by non-subtype selective NMDA antagonists such as dizocilpine (MK-801). OBJECTIVE: The present studies were designed to investigate the involvement of the two major NMDA receptor subunits in the central nervous system, i.e. NR2A and NR2B, on sensorimotor gating in mice. METHODS: These experiments utilised the non-subtype-selective NMDA antagonist dizocilpine, a line of NR2A-KO mice and the selective NR2B antagonist Ro 63-1908, in the study of pre-pulse inhibition of the startle response (PPI). RESULTS: The non-selective NMDA receptor antagonist dizocilpine (0.1-1 mg/kg, IP) robustly disrupted PPI in wild-type mice. Conversely, selective genetic or pharmacological inhibition of either the NMDA NR2A or NR2B receptor subunit containing receptors, respectively, had no effect on PPI. Thus, NR2A KO mice showed normal PPI compared with wild-type littermate controls, and administration of Ro 63-1908 (1-10 mg/kg IP) to wild-type mice did not affect PPI. However, selective inhibition of NR2A and NR2B by administration of Ro 63-1908 to NR2A KO mice significantly disrupted PPI. CONCLUSIONS: These data imply that concomitant inhibition of both NR2A and NR2B subunit-containing NMDA receptors is necessary to disrupt PPI, suggesting that inhibition of NR2A and NR2B-containing NMDA receptors is required to elicit behaviours suggestive of psychomimetic effects in man.

Animals↗
PubMed2004

Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic beta-amyloid (Abeta) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other gamma-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by gamma-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of gamma-secretase inhibition, the gamma-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited Abeta production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4(-)CD8(-)CD44(+)CD25(+) precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak gamma-secretase inhibitor. These studies show that inhibition of gamma-secretase has the expected benefit of reducing Abeta in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.

Administration, Oral↗
PubMed2004

Performance of the marmoset monkey on computerized tasks of attention and working memory.

The CAmbridge Neuropsychological Test Automated Battery (CANTAB) is a computerised battery of neuropsychological tests presented as stimuli on a touch-sensitive computer screen that has been used to assess a wide range of cognitive functions in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque. The common marmoset is a small-bodied, tractable simian primate that breeds well under laboratory conditions. This primate has been quite extensively studied in terms of its abilities and limitations with respect to appetitive cognitive conditioning. However, the CANTAB versions of sustained/divided attention and working memory tasks have to-date not been studied in the marmoset. Here we describe adult marmoset performance on the CANTAB five-choice serial reaction time task, a delayed match-to-position task, and a task derived from the CANTAB visuo-spatial paired associates learning task that constituted two, concurrent delayed match-to-position tasks. The acquisition and stable longitudinal performance of these tasks provide strong evidence that the marmoset, in addition to the macaque, can be the species of choice for CANTAB-based drug and lesion studies of cognitive function, using tasks similar to those deployed in the study of human cognition and diagnosis of neuropsychiatric disorders.

Animals↗
PubMed2004

Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent.

Atrophy of the medial temporal lobes, including the glutamatergic cortical-hippocampal circuitry, is an early event in Alzheimer's disease (AD) and probably contributes to the characteristic short-term mnemonic decline. Pharmacological strategies directly targeted to ameliorating this functional decline may represent a novel approach for the symptomatic treatment of AD. Presynaptic group II metabotropic glutamate receptors (i.e. mGlu2 and mGlu3) exert a powerful modulatory influence on the function of these pathways, in particular the perforant pathway. Using a combination of mGlu2 receptor knockout mice and the group II agonist LY354740, we show that activation of mGlu2 receptors produces a cognitive impairment, i.e. a delay-dependent deficit in delayed matching and non-matching to position, and impaired spatial learning in a Morris water maze. Conversely, a group II antagonist, LY341495, improved acquisition of spatial learning. LY354740 potently reduced field excitatory postsynaptic potentials in hippocampal slices from wild type but not mGlu2 receptor knockout mice. Taken together, these results suggest that activation of mGlu2 receptors evokes a powerful inhibitory effect on hippocampal synaptic transmission and mGlu2 agonists produce a cognitive deficit consistent with this change. Conversely, mGlu2 receptor antagonists may improve certain aspects of cognition and thus represent a novel approach for the symptomatic treatment of AD.

Amino Acids↗
PubMed2004

Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration.

Previously, we have shown that systemic administration of the 5-HT(2C) receptor agonist Ro60-0175 reduces cocaine-induced locomotor activity and cocaine self-administration. Ro60-0175 also alters the activity of midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), a region where 5-HT(2C) receptors are expressed. The present experiments investigated whether microinjections of Ro60-0175 into the VTA would alter the locomotor stimulant effect of cocaine and cocaine self-administration. In the tests for locomotor activity injection of 3 and 10, but not 1 microg, Ro60-0175 into the VTA reduced the locomotor stimulation resulting from injection of 10 mg/kg cocaine. In tests of cocaine self-administration, rats were trained to lever press for intravenous infusions of 0.25 mg cocaine delivered on either a fixed ratio 5 (FR5) or a progressive ratio schedule. Intra-VTA injection of Ro60-0175 at doses of 3 and 10 microg reduced responding for cocaine on both schedules without significantly altering the latency to initiate responding or the rate of responding. A subsequent experiment determined that the suppressant effect of intra-VTA Ro60-0175 (3 microg) on responding for cocaine was prevented by pretreatment with the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg). In a final experiment, intra-VTA injection of Ro60-0175 reduced responding for food reinforcement on the same progressive ratio schedule as used for cocaine self-administration. These results demonstrate that stimulation of 5-HT(2C) receptors in the VTA is sufficient to attenuate the stimulant and reinforcing effects of cocaine. These effects complement electrophysiological and neurochemical findings, and indicate that 5-HT(2C) receptors localized within the VTA modulate the activity of mesolimbic DA neurons.

Aminopyridines↗
PubMed2003

Serotonin and drug reward: focus on 5-HT2C receptors.

Pharmacological manipulation of the 5-hydroxytryptamine (5-HT; serotonin) system has long been associated with a regulation of feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related behaviours, particularly drug reward. The second part of this article considers what we believe to be strong emerging pharmacological and genetic evidence that many of these effects are mediated through 5-HT(2C) receptor signalling mechanisms. Finally, we consider the potential for selective 5-HT(2C) agonists as therapies for substance abuse disorders and the medical implications for different 5-HT(2C) receptor isoforms generated by RNA editing.

Animals↗
PubMed2003

PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation.

Transgenic mice, expressing mutant beta-amyloid precursor proteins (betaAPPs), have lead to a better understanding of the pathophysiological processes in Alzheimer's disease (AD). In many of these models, however, the temporal development of cognitive decline and the relationship to Abeta deposition and inflammation are unclear. We now report a novel transgenic mouse line, PS2APP (PS2N141I x APPswe), which develops a severe cerebral amyloidosis in discrete brain regions, and present a cross-sectional analysis of these mice at 4, 8, 12, and 16 months of age. Each age cohort was investigated for changes in behavior, electrophysiology of synapse efficacy, ELISA-determined Abeta load, histopathology, and in immunoelectron microscopy. Cognitive deficits were first observed at 8 months when Abeta deposits and inflammation were restricted to discrete brain regions, namely the subiculum and frontolateral (motor and orbital) cortex. As early as 5 months, electron microscopy revealed the presence, in these regions, of pre-plaque, immunogold-labeled extracellular fibrillar Abeta. At the same age, increased levels of insoluble Abeta were detected by ELISA, with Abeta1-40 levels exceeding those of Abeta1-42. Further cognitive decline occurred in an age-related manner, and this was accompanied by the spread of amyloidosis to ultimately affect not only neo- and limbic cortices, but also thalamic and pontine nuclei. Dentate gyrus post-tetanic potentiation was significantly attenuated at 17 months, and there were also significant differences in paired-pulse parameters. This systematic cross-sectional study of the behavioral and pathological changes in the PS2APP mouse indicates that it develops age-related cognitive decline associated with severe amyloidosis and inflammation in discrete brain regions and therefore is suitable for testing a range of potential symptomatic and disease-modifying therapies for AD.

Age Factors↗
PubMed2003

The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism.

In the present series of studies, we have investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors on motor and 'impulsive'-type behaviours elicited by the non-competitive N-methyl- d-aspartate (NMDA) antagonist dizocilpine. The selective 5-HT(2A) receptor antagonist M100,907 (0.5 mg/kg) attenuated the hyperlocomotion and stereotypy produced by dizocilpine (0.1-0.3 mg/kg). The selective 5-HT(2B) receptor antagonist SB215,505 (3 mg/kg) and the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg) had no effect against either measure, except that SB242,084 produced a small potentiation of the hyperactivity response. Dizocilpine (0.03 mg/kg) increased premature responding in rats performing the 5-choice serial reaction time task (5-CSRTT), and increased response frequency consequently reducing the mean inter-response time (IRT) and efficiency of responding in a DRL24 task. M100,907 (0.5 mg/kg) attenuated each of these effects, as well as the increased premature responding produced by the NMDA NR2B selective antagonist Ro 63-1908 (1 mg/kg) in the 5-CSRTT. In contrast SB242,084 (0.5 mg/kg) did not attenuate the dizocilpine-induced premature responding or increased responding in the DRL24 task. Rather, SB242,084 (0.05-0.5 mg/kg) produced qualitatively similar effects to dizocilpine, increasing premature responding and reducing IRT. The results suggest that 5-HT(2A) receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction. The 5-HT(2C) receptor antagonist SB242,084 failed to exert equivalent effects, rather a trend toward exacerbation of the behavioural changes produced by dizocilpine was apparent.

Aminopyridines↗