Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

© 2020, The Author(s). Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40–200mg/kg) and ORG24598 (0.63–5mg/kg), the agonists, glycine (40–800mg/kg), and D-serine (10–160mg/kg) and the partial agonists, S18841 (2.5mg/kg s.c.) and D-cycloserine (2.5–40mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20mg/kg), and the glycine modulatory site antagonist, L701,324 (10mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5–10μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10mg/kgs.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired

Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs

© 2020 Elsevier Ltd To date, there are no interventions that impede the inexorable progression of Alzheimer's disease (AD), and currently-available drugs cholinesterase (AChE) inhibitors and the N-Methyl-D-Aspartate receptor antagonist, memantine, offer only modest symptomatic benefit. Moreover, a range of mechanistically-diverse agents (glutamatergic, histaminergic, monoaminergic, cholinergic) have disappointed in clinical trials, alone and/or in association with AChE inhibitors. This includes serotonin (5-HT) receptor-6 antagonists, despite compelling preclinical observations in rodents and primates suggesting a positive influence on cognition. The emphasis has so far been on high selectivity. However, for a multi-factorial disorder like idiopathic AD, 5-HT6 antagonists possessing additional pharmacological actions might be more effective, by analogy to “multi-target” antipsychotics. Based on this notion, drug discovery programmes have coupled 5-HT6 blockade to 5-HT4 agonism and inhibition of AchE. Further, combined 5-HT6/dopamine D3 receptor (D3) antagonists are of especial interest since D3 blockade mirrors 5-HT6 antagonism in exerting broad-based pro-cognitive properties in animals. Moreover, 5-HT6 and dopamine D3 antagonists promote neurocognition and social cognition via both distinctive and convergent actions expressed mainly in frontal cortex, including suppression of mTOR over-activation and reinforcement of cholinergic and glutamatergic transmission. In addition, 5-HT6 blockade affords potential anti-anxiety, anti-depressive and anti-epileptic properties, and antagonising 5-HT6 receptors may be associated with neuroprotective (“disease-modifying”) properties. Finally D3 antagonism may counter psychotic episodes and D3 receptors themselves offer a promising hub for multi-target agents. The present article reviews the status of “R and D” into multi-target 5-HT6 and D3 ligands for improved treatment of AD and other neurodegenerative disorders of aging. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’

Overexpression of 5-HT2C receptors in forebrain leads to elevated anxiety and hypoactivity

The 5-HT2C receptor has been implicated in mood and eating disorders. In general, it is accepted that 5-HT2C receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5-HT2C receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5-HT2C receptor expression, and thus increased 5-HT2C receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5-HT2C receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5-HT2C receptors under the control of the CaMKIIα promoter (C2CR mice) have elevated 5-HT2C receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5-HT2C ligand binding sites in the forebrain. The C2CR mice show increased anxiety-like behaviour in the elevated plus-maze, decreased wheel-running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5-HT2C receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5-HT2C receptors

Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests:A model for reward pathology with effects of agomelatine

A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity

Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats

Item does not contain fulltextRATIONALE: Serotonin is an important modulator of social behaviour. Individual differences in serotonergic signalling are considered to be a marker of personality that is stable throughout lifetime. While a large body of evidence indicates that central serotonin levels are inversely related to aggression and sexual behaviour in adult rats, the relationship between serotonin and social behaviour during peri-adolescence has hardly been explored. OBJECTIVE: To study the effect of acute and constitutive increases in serotonin neurotransmission on social behaviour in peri-adolescent rats. MATERIALS AND METHODS: Social behaviour in peri-adolesent rats (28-35 days old) was studied after genetic ablation of the serotonin transporter, causing constitutively increased extra-neuronal serotonin levels, and after acute treatment with the serotonin reuptake inhibitor fluoxetine or the serotonin releasing agent 3,4-methylenedioxymethamphetamine (MDMA). A distinction was made between social play behaviour that mainly occurs during peri-adolescence, and non-playful social interactions that are abundant during the entire lifespan of rats. RESULTS: In serotonin transporter knockout rats, social play behaviour was markedly reduced, while non-playful aspects of social interaction were unaffected. Acute treatment with fluoxetine or MDMA dose-dependently inhibited social play behaviour. MDMA also suppressed non-playful social interaction but at higher doses than those required to reduce social play. Fluoxetine did not affect non-playful social interaction. CONCLUSIONS: These data show that both acute and constitutive increases in serotonergic neurotransmission reduce social play behaviour in peri-adolescent rats. Together with our previous findings of reduced aggressive and sexual behaviour in adult serotonin transporter knockout rats, these data support the notion that serotonin modulates social behaviour in a trait-like manner

Behavioural Models for the Characterisation of Established and Innovative Antidepressant Agents

To improve the management of depressive states, it is essential to develop preclinical behavioural models for the characterisation of both conventional and new antidepressant agents. This need is illustrated in this article with two very different classes of antidepressant agents, serotonin and/or noradrenaline reuptake inhibitors (SNRIs) and neurokinin NK1 receptor antagonists. Their effects are evaluated in rodent models of (i) the detection of potential antidepressant activity via marble-burying behaviour in mice; (ii) drug discrimination procedures in rats (mechanistic); and (iii) the evaluation of potential activity on co-morbid symptoms, such as anxiety, via the social recognition test in rats and gerbils. It is concluded that behavioural assays offer a palette of techniques for the characterisation of clinically active antidepressants as well as for innovative (acting on new targets) or improved (multi-target) antidepressants. Nevertheless, for antidepressants of the future, as for established antidepressants, feedback from clinical trials are awaited to confirm the predictive value of these models

Inventaire PROSCITEC : outil de valorisation et de gestion de patrimoine

La Région des Hauts-de-France est riche d’une histoire du travail et du savoir-faire dans de nombreux domaines tels que le textile, les transports, l’agroalimentaire, la céramique… De nombreux musées et collections techniques conservent et valorisent ces savoir-faire d’hier et d’aujourd’hui. L’association PROSCITEC, Patrimoines et Mémoires des Métiers, accompagne en Hauts-de-France ces musées sur le chantier de leur inventaire des collections en mettant à leur disposition un outil informatisé conçu spécialement pour répondre à leurs besoins. Dans son objectif de valorisation et de partage des connaissances vers tous les publics, PROSCITEC valorise le contenu de cette base de données par l’intermédiaire d’un site internet dédié, véritable vitrine du patrimoine technique régional.The Hauts-de-France region has a rich history of work and know-how in maby fields such as textiles, transport, food, ceramics… Many museums and technical collections preserve and enhance these know-how of yesterday and today. The PROSCITEC Association, heritages and memories of professions, supports these museums in Hauts de France on the site of their inventory of collections by providing them with a computerized tool specially designed to meet their needs. In its objective of promoting and sharing knowledge with all audiences, PROSCITEC promotes the content of this database through a dedicated website, a true showcase of regional technical heritage

Role des informations contextuelles dans la reactivation et la discrimination des souvenirs : approche des mecanismes de l'evocation mnesique

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

La BDTopo de l’IGN: une nouvelle ligne de production

Dekeyne Christophe. La BDTopo de l’IGN: une nouvelle ligne de production. In: Mappemonde, 1998/1. p. 3