当前位置： SCI文献检索 > NEUROPHARMACOLOGY期刊下所有文献 > Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs.

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

Abstract：

: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'.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Millan MJ,Dekeyne A,Gobert A,Brocco M,Mannoury la Cour C,Ortuno JC,Watson D,Fone KCF

doi

10.1016/j.neuropharm.2020.108099

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

108099

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(20)30167-2

journal_volume

177

pub_type

杂志文章,评审

相关文献

NEUROPHARMACOLOGY文献大全
  • Metabotropic glutamate autoreceptors of the mGlu(5) subtype positively modulate neuronal glutamate release in the rat forebrain in vitro.

    abstract：:In the present study we have examined the role of presynaptic group I metabotropic glutamate (mGlu) receptors in the control of neuronal glutamate release using rat forebrain slices pre-loaded with [(3)H]D-aspartate. We have also addressed the question of which group I mGlu receptor subtype, mGlu(1) or mGlu(5), mediat...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(99)00223-3

    authors： Thomas LS,Jane DE,Harris JR,Croucher MJ

    更新日期：2000-07-10 00:00:00

  • Is there a role for neurotrophic factors and their receptors in augmenting the neuroprotective effect of (-)-epigallocatechin-3-gallate treatment of sciatic nerve crush injury?

    abstract：:This study analyzed and compared the effects of EGCG treatment on the expression of NTFs and NTF receptors expression in the sciatic nerve and the L3-L6 spinal cord segments at the early phase of regeneration following sciatic nerve crush injury. Analysis of BDNF, GDNF and NT3 neurotropic factors and Trk-B, Trk-C and ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2015.10.029

    authors： Renno WM,Khan KM,Benov L

    更新日期：2016-03-01 00:00:00

  • The drug MK-801 attenuates the development, but not the expression, of long-term potentiation and stimulus train-induced bursting in hippocampal slices.

    abstract：:Recent studies have demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a use-dependent blocker of N-methyl-D-aspartate (NMDA)-activated membrane channels, attenuates the development of long-term potentiation in vitro and kindling in vivo. Both of these phenomena are manifestat...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(89)90076-2

    authors： Swartzwelder HS,Ferrari C,Anderson WW,Wilson WA

    更新日期：1989-05-01 00:00:00

  • Modulation of neurotransmitter release by P2X and P2Y receptors in the rat spinal cord.

    abstract：:In this study, the P2 receptor-mediated modulation of [3H]glutamate and [3H]noradrenaline release were examined in rat spinal cord slices. Adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and 2-methylthioadenosine 5'-diphosphate (2-MeSADP) decreased the electrical stimulation-evoked [3H]glutamate efflu...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2007.10.013

    authors： Heinrich A,Kittel A,Csölle C,Sylvester Vizi E,Sperlágh B

    更新日期：2008-02-01 00:00:00

  • Desensitization of 5-HT1A autoreceptors by chronic administration of 8-OH-DPAT.

    abstract：:The function of 5-HT1A autoreceptors was examined by measuring the ability of the 5-HT1A receptor agonist 8-OH-DPAT to reduce 5-HT release in the striatum using in vivo microdialysis. 8-OH-DPAT reduced the release of 5-HT in the striatum. Chronic treatment with 8-OH-DPAT (1.0 mg/kg s.c.) for 7 days, but not 1 day, att...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(92)90110-b

    authors： Kreiss DS,Lucki I

    更新日期：1992-10-01 00:00:00

  • Oxytocin and a C-terminal derivative (Z-prolyl-D-leucine) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain.

    abstract：:The effects of oxytocin (OXT) and of dipeptides derived from the C-terminal portion of oxytocin (Z-prolyl-leucine and Z-prolyl-D-leucine) on the development of acute and chronic tolerance to, and dependence on morphine were tested in the mouse. Oxytocin and the dipeptides attenuated the development of acute and chroni...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(85)90026-7

    authors： Kovács GL,Horváth Z,Sarnyai Z,Faludi M,Telegdy G

    更新日期：1985-05-01 00:00:00

  • Fractional occupancy of synaptic binding sites and the molecular plasticity of inhibitory synapses.

    abstract：:The postsynaptic density (PSD) at inhibitory synapses is a complex molecular assembly that serves as a platform for the interaction of neurotransmitter receptors, scaffold and adapter proteins, cytoskeletal elements and signalling molecules. The stability of the PSD depends on a multiplicity of interactions linking in...

    journal_title：Neuropharmacology

    pub_type： 杂志文章,评审

    doi：10.1016/j.neuropharm.2019.01.008

    authors： Specht CG

    更新日期：2020-06-01 00:00:00

  • Changes in alpha- and beta-receptor densities in rat brain as a result of treatment with monoamine oxidase inhibiting antidepressants.

    abstract：:The effects of chronic administration of the nonselective monoamine oxidase (MAO) inhibitor, phenelzine, and two selective inhibitors, clorgyline, and pargyline on adrenergic receptor binding and MAO activity were studied in the rat brain. Chronic but not acute administration of both phenelzine and the MAO-A inhibitor...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(82)90091-0

    authors： Cohen RM,Campbell IC,Dauphin M,Tallman JF,Murphy DL

    更新日期：1982-04-01 00:00:00

  • Effects of chronic treatment with haloperidol on [3H]PK 11195 binding in the rat brain and peripheral tissues.

    abstract：:The effects of chronic treatment with haloperidol on [3H]PK 11195 binding and labelling of the peripheral-type benzodiazepine receptor (PBR) in the rat brain and peripheral tissues were investigated using an in vitro receptor binding technique. The intraperitoneal injection with haloperidol (0.3 or 1.0 mg/kg) for 21 d...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(96)00040-8

    authors： Kurumaji A,Kaneko K,Toru M

    更新日期：1996-01-01 00:00:00

  • Differential effects of adolescent and adult-initiated voluntary exercise on context and cued fear conditioning.

    abstract：:Adolescence is a critical period for postnatal brain maturation and a time during which there is increased susceptibility to developing emotional and cognitive-related disorders. Exercise during adulthood has been shown to increase hippocampal plasticity and enhance cognition. However, the impact of exercise initiated...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2018.05.007

    authors： O'Leary JD,Hoban AE,Cryan JF,O'Leary OF,Nolan YM

    更新日期：2019-02-01 00:00:00

  • Tetrodotoxin-sensitivity of nicotine-evoked dopamine release from rat striatum.

    abstract：:Recent observations from synaptosome preparations have questioned the tetrodotoxin (TTX) insensitivity of nicotine-evoked release in the striatum, a characteristic previously considered diagnostic of presynaptically located nicotinic acetylcholine receptors (nAChRs). Therefore, we have undertaken a comparison of nicot...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(96)00117-7

    authors： Marshall D,Soliakov L,Redfern P,Wonnacott S

    更新日期：1996-01-01 00:00:00

  • Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors.

    abstract：:Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2011.02.002

    authors： Azmitia EC,Singh JS,Whitaker-Azmitia PM

    更新日期：2011-06-01 00:00:00

  • Glycine transporters type 1 inhibitor promotes brain preconditioning against NMDA-induced excitotoxicity.

    abstract：:Brain preconditioning is a protective mechanism, which can be activated by sub-lethal stimulation of the NMDA receptors (NMDAR) and be used to achieve neuroprotection against stroke and neurodegenerative diseases models. Inhibitors of glycine transporters type 1 modulate glutamatergic neurotransmission through NMDAR, ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2014.10.003

    authors： Pinto MC,Lima IV,da Costa FL,Rosa DV,Mendes-Goulart VA,Resende RR,Romano-Silva MA,de Oliveira AC,Gomez MV,Gomez RS

    更新日期：2015-02-01 00:00:00

  • Behavioral and convulsant effects of the (S) enantiomer of the group I metabotropic glutamate receptor agonist 3,5-DHPG in mice.

    abstract：:The purpose of the present studies was to investigate the behavioral and convulsant effects produced by the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Administered i.c.v. to mice, (S)-3,5-DHPG produced a behavioral syndrome consisting of scratching and/or facial grooming, tr...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2005.01.017

    authors： Barton ME,Shannon HE

    更新日期：2005-05-01 00:00:00

  • Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior.

    abstract：:The lateral habenula (LHb) is critical for modulation of negative reinforcement, punishment and aversive responses. In light of the success of deep-brain-stimulation (DBS) in the treatment of neurological disorders, we explored the use of LHb DBS as a method of intervention in cocaine self-administration, extinction, ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2010.06.008

    authors： Friedman A,Lax E,Dikshtein Y,Abraham L,Flaumenhaft Y,Sudai E,Ben-Tzion M,Ami-Ad L,Yaka R,Yadid G

    更新日期：2010-11-01 00:00:00

  • Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition.

    abstract：:The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1-30mg/kg, i.p.), a balanced serotonergic-noradrenergic reuptake inhibitor (SNRI), was equiefficacious and...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2006.08.005

    authors： Jones CK,Eastwood BJ,Need AB,Shannon HE

    更新日期：2006-12-01 00:00:00

  • Ciclopirox prevents peroxynitrite toxicity in astrocytes by maintaining their mitochondrial function: a novel mechanism for cytoprotection by ciclopirox.

    abstract：:Previously we have reported that astrocytes deprived of glucose were highly vulnerable to peroxynitrite (Choi and Kim, J. Neurosci. Res. 54 (1998) 870; Neurosci. Lett. 256 (1988) 109; Ju et al., J. Neurochem. 74 (2000) 1989). Here we report that ciclopirox, which is clinically used as an anti-fungal agent, completely ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(02)00081-3

    authors： Choi JJ,Kong MY,Lee SJ,Kim HC,Ko KH,Kim WK

    更新日期：2002-09-01 00:00:00

  • Behavioral syndrome induced by allylnitrile, crotononitrile or 2-pentenenitrile in rats.

    abstract：:A single oral administration of allylnitrile, crotononitrile or 2-pentenenitrile in rats induced behavioral abnormalities, such as head-twitching, head weaving, hindlimb abduction, backward pedaling and pivoting. The head-twitching, which was most consistently observed, was suppressed by serotonin (5-HT) antagonists, ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(91)90123-s

    authors： Tanii H,Hayashi M,Hashimoto K

    更新日期：1991-08-01 00:00:00

  • From unilateral to bilateral parkinsonism: Effects of lateralization on dyskinesias and associated molecular mechanisms.

    abstract：:The mechanisms underlying lateralization and progression of motor symptoms from unilateral to bilateral in Parkinson's disease (PD) remain to be elucidated. In addition, the molecular mechanisms involved in levodopa-induced dyskinesias (LIDs) depending on lateralization and disease progression from unilaterally to bil...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2015.06.004

    authors： Marin C,Bonastre M,Mengod G,Cortés R,Rodríguez-Oroz MC

    更新日期：2015-10-01 00:00:00

  • Blood pressure and heart rate responses to microinjection of vasopressin into the nucleus tractus solitarius region of the rat.

    abstract：:The nucleus tractus solitarius (NTS) region in the rat has been shown to receive arginine vasopressin (AVP) and oxytocin (OT) neurophysin-containing neuronal projections from the suprachiasmatic (SNC) and paraventricular nucleus (PVN). Thus, vasopressin and oxytocin might have central influences on the circulation. Th...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/0028-3908(82)90012-0

    authors： Matsuguchi H,Sharabi FM,Gordon FJ,Johnson AK,Schmid PG

    更新日期：1982-07-01 00:00:00

  • Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens.

    abstract：:A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin(2C) receptor (5-HT(2C)R) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT(2C)R located in the medial prefrontal cor...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2008.10.005

    authors： Leggio GM,Cathala A,Moison D,Cunningham KA,Piazza PV,Spampinato U

    更新日期：2009-02-01 00:00:00

  • The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism.

    abstract：:Neuronal nicotinic acetylcholine receptors (nAChR) have been suggested to play a role in a variety of modulatory and regulatory processes, including neuroprotection. Here we have characterized the neuroprotective effects of nicotine against an excitotoxic insult in primary hippocampal cultures. Exposure of hippocampal...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(00)00127-1

    authors： Dajas-Bailador FA,Lima PA,Wonnacott S

    更新日期：2000-10-01 00:00:00

  • Olvanil: a non-pungent TRPV1 activator has anti-emetic properties in the ferret.

    abstract：:Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2009.10.002

    authors： Chu KM,Ngan MP,Wai MK,Yeung CK,Andrews PL,Percie du Sert N,Rudd JA

    更新日期：2010-02-01 00:00:00

  • Presynaptic alpha 2- and postsynaptic beta-adrenoceptor sensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs.

    abstract：:The effect of chronic (4 weeks) treatment of rats with the antidepressant drugs desipramine, maprotiline, chlorimipramine, zimelidine or iprindol on the sensitivity of presynaptic alpha 2- and postsynaptic beta-adrenoceptors in neocortical slices was investigated. Acute (1 day) treatment with the antidepressants did n...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/s0028-3908(84)80002-7

    authors： Schoffelmeer AN,Hoorneman EM,Sminia P,Mulder AH

    更新日期：1984-02-01 00:00:00

  • Pregnenolone sulfate enhances survival of adult-generated hippocampal granule cells via sustained presynaptic potentiation.

    abstract：:Synaptic input activity affects the neurogenesis in adult hippocampal dentate gyrus (DG), while the input activity is potentiated by neurosteroid pregnenolone sulfate (PREGS). This study focused on exploring the effects of PREGS on the survival of newborn neurons in the DG of adult male mice. Proliferating cells were ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2010.11.017

    authors： Yang R,Zhou R,Chen L,Cai W,Tomimoto H,Sokabe M,Chen L

    更新日期：2011-02-01 00:00:00

  • Overexpression of miRNA-137 in the brain suppresses seizure activity and neuronal excitability: A new potential therapeutic strategy for epilepsy.

    abstract：:miRNA-137 is an extremely abundant miRNA in the central nervous system and is thought to be closely related to synaptic plasticity. Here, we report a previously unrecognized role of miRNA-137 in epilepsy. The expression of miRNA-137 was decreased both in patients with temporal lobe epilepsy (TLE) and in two different ...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2018.06.010

    authors： Wang W,Guo Y,He L,Chen C,Luo J,Ma Y,Li J,Yang Y,Yang Q,Du C,Zhang Y,Li Z,Xu X,Tian X,Wang X

    更新日期：2018-08-01 00:00:00

  • Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments.

    abstract：:Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we stu...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2011.02.009

    authors： Guilloux JP,David DJ,Xia L,Nguyen HT,Rainer Q,Guiard BP,Repérant C,Deltheil T,Toth M,Hen R,Gardier AM

    更新日期：2011-09-01 00:00:00

  • miR-132/212 is induced by stress and its dysregulation triggers anxiety-related behavior.

    abstract：:miR-132 and miR-212 are structurally-related microRNAs that are expressed from the same non-coding transcript. Accumulating evidence has shown that the dysregulation of these microRNAs contributes to aberrant neuronal plasticity and gene expression in the mammalian brain. Consistent with this, altered expression of mi...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2018.10.020

    authors： Aten S,Page CE,Kalidindi A,Wheaton K,Niraula A,Godbout JP,Hoyt KR,Obrietan K

    更新日期：2019-01-01 00:00:00

  • Behavioural phenotype of histamine H4 receptor knockout mice: Focus on central neuronal functions.

    abstract：:The functional expression of H4 receptors (H4R) within neurons of the central nervous system has been recently reported, but their role is poorly understood. The present study aims to elucidate the role of neuronal H4R by providing the first description of the behavioural phenotype of H4R-deficient (H4R knockout, H4R-...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2016.11.023

    authors： Sanna MD,Ghelardini C,Thurmond RL,Masini E,Galeotti N

    更新日期：2017-03-01 00:00:00

  • mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving.

    abstract：:Many studies have demonstrated that negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGlu5) reduce cocaine and methamphetamine seeking in extinction-reinstatement animal models of addiction. Less is known about effects of mGlu5 NAMs in abstinence models, particularly for methamphetamine. We u...

    journal_title：Neuropharmacology

    pub_type： 杂志文章

    doi：10.1016/j.neuropharm.2021.108452

    authors： Murray CH,Christian DT,Milovanovic M,Loweth JA,Hwang EK,Caccamise AJ,Funke JR,Wolf ME

    更新日期：2021-01-12 00:00:00