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’

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

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

Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization

Abstract Rationale Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. Objectives The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. Materials and methods Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. Results Sessions, 63± 8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT) 2C receptors, and the 5-HT 2C antagonists, SB242,084, SB243,213 and S32006, revealed dosedependent and full (≥80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT 2A antagonists, MDL100,907 and SR46349-B, the 5-HT 2B antagonist, SB204,741, and the 5-HT 3 antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT 1A receptors, the 5-HT 1A agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks α 2 -adrenoceptors, but several α 2 -adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H 1 receptors, no substitution was seen with the selective H 1 antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. Conclusion Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT 2C receptors display dosedependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective

S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors : II. Functional and behavioral profile compared with GR218,231 and L741,626

ABSTRACT The selective dopamine D 3 -receptor antagonist S33084 dose dependently attenuated induction of hypothermia by 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT) and PD128,907. S33084 also dose dependently reduced 7-OH-DPAT-induced penile erections (PEs) but had little effect on 7-OH-DPAT-induced yawning and hypophagia, and it did not block contralateral rotation elicited by the preferential D 3 agonist quinpirole in unilateral substantia nigra-lesioned rats. In models of potential antipsychotic activity, S33084 had little effect on conditioned avoidance behavior and the locomotor response to amphetamine and cocaine in rats, and weakly inhibited apomorphineinduced climbing in mice. Moreover, S33084 was inactive in models of potential extrapyramidal activity in rats: induction of catalepsy and prolactin secretion and inhibition of methylphenidate-induced gnawing. Another selective D 3 antagonist, GR218,231, mimicked S33084 in inhibiting 7-OH-DPAT-induced PEs and hypothermia but neither hypophagia nor yawning behavior. Similarly, it was inactive in models of potential antipsychotic and extrapyramidal activity. In distinction to S33084 and GR218,231, the preferential D 2 antagonist L741,626 inhibited all responses elicited by 7-OH-DPAT. Furthermore, it displayed robust activity in models of antipsychotic and, at slightly higher doses, extrapyramidal activity. In summary, S33084 was inactive in models of potential antipsychotic and extrapyramidal activity and failed to modify spontaneous locomotor behavior. Furthermore, it did not affect hypophagia or yawns, but attenuated hypothermia and PEs, elicited by 7-OH-DPAT. This profile was shared by GR218,231, whereas L741,626 was effective in all models. Thus, D 2 -receptors are principally involved in these paradigms, although D 3 -receptors may contribute to induction of hypothermia and PEs. S33084 should comprise a useful tool for further exploration of the pathophysiological significance of D 3 -versus D 2 -receptors. In In this study, we addressed two complementary and interdependent issues. First, we characterized the in vivo actions of S33084 in several models involving dopaminergic activity in rodents, in particular paradigms considered predictive of antipsychotic or extrapyramidal properties. Second, using S33084 together with GR218,231 and L741,626, we examined the role of D 3 -compared with D 2 -receptors in the diverse functional models used. These may be summarized as follows. First, we examined the decrease in core temperatur

Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: A comparison to melatonin and to the 5-HT(2c) antagonist, S32006

C1 - Journal Articles Referee