Abstract：
:Given the repeated failure of amyloid-based approaches in Alzheimer's disease, there is increasing interest in tau-based therapeutics. Although methylthioninium (MT) treatment was found to be beneficial in tau transgenic models, the brain concentrations required to inhibit tau aggregation in vivo are unknown. The comparative efficacy of methylthioninium chloride (MTC) and leucomethylthioninium salts (LMTX; 5-75 mg/kg; oral administration for 3-8 weeks) was assessed in two novel transgenic tau mouse lines. Behavioural (spatial water maze, RotaRod motor performance) and histopathological (tau load per brain region) proxies were applied. Both MTC and LMTX dose-dependently rescued the learning impairment and restored behavioural flexibility in a spatial problem-solving water maze task in Line 1 (minimum effective dose: 35 mg MT/kg for MTC, 9 mg MT/kg for LMTX) and corrected motor learning in Line 66 (effective doses: 4 mg MT/kg). Simultaneously, both drugs reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in Line 1 and in a more widespread manner in Line 66. MT levels in the brain followed a sigmoidal concentration-response relationship over a 10-fold range (0.13-1.38 μmol/l). These data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.
journal_name
Behav Pharmacoljournal_title
Behavioural pharmacologyauthors
Melis V,Magbagbeolu M,Rickard JE,Horsley D,Davidson K,Harrington KA,Goatman K,Goatman EA,Deiana S,Close SP,Zabke C,Stamer K,Dietze S,Schwab K,Storey JM,Harrington CR,Wischik CM,Theuring F,Riedel Gdoi
10.1097/FBP.0000000000000133subject
Has Abstractpub_date
2015-06-01 00:00:00pages
353-68issue
4eissn
0955-8810issn
1473-5849journal_volume
26pub_type
杂志文章abstract：:Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has...
journal_title：Behavioural pharmacology
pub_type： 杂志文章,评审
doi：10.1097/FBP.0b013e3282df3cde
更新日期：2007-09-01 00:00:00
abstract：:A-68930 [1R, 3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCI] is a novel, potent and selective dopamine D1 receptor agonist. Previous reports have shown that the selective D1 partial agonist, SK & F 38393, reduced food consumption in rats and mice. The aim of this study was to undertake a microstructural analys...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-04-01 00:00:00
abstract：:In the present study, we focused on γ-aminobutyric acid (GABA) signaling through the γ-aminobutyric acid transporter (GAT) in the developing rat cerebral cortex. Tiagabine was used as a GAT inhibitor. The offspring received injections from birth until postnatal day 21 intraperitoneally. Physical development and neurol...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0b013e328365422f
更新日期：2013-10-01 00:00:00
abstract：:Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other g...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/00008877-199410000-00006
更新日期：1994-10-01 00:00:00
abstract：:We report here that local hippocampal WIN-55,212-2 implants release this cannabinoid agonist for extended periods, the release is restricted to the implanted brain region and is behaviorally active. Radiolabeled WIN-55,212-2 was implanted bilaterally into the CA3 region of the dorsal hippocampus by means of fused sili...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0b013e3282d9e9f9
更新日期：2007-09-01 00:00:00
abstract：:Appetitive behaviours occur in a state of behavioural and physiological activation that allows the optimal performance of these goal-directed behaviours. Here, we tested the hypothesis that histamine neurons under the command of the infralimbic cortex are important to provide behavioural activation. Extracellular hist...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0000000000000129
更新日期：2015-06-01 00:00:00
abstract：:The effects of the competitive NMDA antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) and 3-(2-carboxypiperazin-4-yl) propyl-l-phosphonic acid (CPP), were compared to those of the noncompetitive NMDA antagonists, phencyclidine (PCP) and (+)-5-methyl-10, 11-dihydro-5H-dibenzo (a,d) cyclohe...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-01-01 00:00:00
abstract：:There is clinical and experimental evidence that treatment with immunosuppressive and antiproliferative drugs such as the calcineurin inhibitor cyclosporine A (CsA) is associated with mental health problems and neuropsychological disturbances in patients. However, it remains unclear whether and to what extent cognitiv...
journal_title：Behavioural pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1097/FBP.0000000000000281
更新日期：2017-06-01 00:00:00
abstract：:Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the control of motor activity. However, there are few studies investigating this interaction in other brain regions and its role in additional functions. In the...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/01.fbp.0000166825.62130.9a
更新日期：2005-07-01 00:00:00
abstract：:Neuropsychiatric disorders, such as addiction, are associated with cognitive impairment, including learning and memory deficits. Previous research has demonstrated that the chronic use of methamphetamine (METH) induces long-term cognitive impairment and cannabidiol (CBD), as a neuroprotectant, can reverse spatial memo...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0000000000000544
更新日期：2020-06-01 00:00:00
abstract：:Drug addiction is a progressive, relapsing disease comprised of interlocking stages of disordered motivation. Numerous animal models describing various stages of the addiction process have been developed over the past few decades, providing considerable advantages for the modeling of drug addiction compared with other...
journal_title：Behavioural pharmacology
pub_type： 杂志文章,评审
doi：10.1097/FBP.0b013e3283644d15
更新日期：2013-09-01 00:00:00
abstract：:Different approaches to measuring stimulus generalization in drug discrimination experiments are compared. The main issue, with implications for interpreting partial generalization, has been whether it is preferable to use graded or quantal indices. The first step is to determine whether discriminative drug effects ar...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-11-01 00:00:00
abstract：:The psychomotor/cognitive performance, subject-rated, and observer-rated effects of single oral doses of the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) and the imidazopyridine hypnotic zolpidem (5, 10, and 20 mg/70 kg) were compared in 11 volunteers, in a double-blind, placebo-controlled, crosso...
journal_title：Behavioural pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1097/00008877-199711000-00014
更新日期：1997-11-01 00:00:00
abstract：:Over the last 15 years, genetically modified mice have added important data to our knowledge on psychiatric diseases including anxiety. This has produced many behavioural publications, partially by non-behaviourists, in which differences between mutants and normal wild-type animals were described. The popularity of th...
journal_title：Behavioural pharmacology
pub_type： 杂志文章,评审
doi：10.1097/FBP.0b013e32830c3658
更新日期：2008-09-01 00:00:00
abstract：:The stimulus control by morphine under a fixed-interval (FI) 180-s schedule of reinforcement was examined in five pigeons trained to discriminate 5.0mg/kg of i.m. morphine from saline. After training, dose-response relationships were determined for morphine, d-amphetamine, pentobarbital, fentanyl, and MK-801. At low d...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-10-01 00:00:00
abstract：:Effects of the dopamine D(1) antagonist SCH 39166 were compared with those of the D(2) antagonist eticlopride in squirrel monkeys responding under a second-order fixed-interval schedule of i.v. self-administration of cocaine. Dose-response curves were determined for a range of doses of self-administered cocaine (0.01-...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/00008877-199000140-00009
更新日期：1990-01-01 00:00:00
abstract：:Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. The purpose of the present study was to determine whether PCP can induce similar behavioural effects in rats and whether these effects can be alleviated by neuroleptic drug treatment. Rats were t...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-01-01 00:00:00
abstract：:There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, γ-aminobutyric acid type A (GABA(A)) receptor function is positively modulated by progesterone metabolites....
journal_title：Behavioural pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1097/FBP.0b013e328349fc02
更新日期：2011-09-01 00:00:00
abstract：:An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An underst...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0000000000000064
更新日期：2014-09-01 00:00:00
abstract：:Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate i...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/00008877-200505000-00004
更新日期：2005-05-01 00:00:00
abstract：:Pigeons were trained to discriminate 5mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18s (mult FR40 FI18), mult FR10 FI18s, mult FR10 FI180s and mult FR90 FI10s. After respond...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
abstract：:Previous data indicate that ethanol intoxication (3 g/kg, intragastric) on postnatal day (PD) 7 and 8 increases ethanol acceptance, but on PD 10 and 11 generates an aversion in infant rats. We investigated the participation of the opioid system in these effects. Subcutaneous administration of naloxone (1 or 10 mg/kg) ...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0b013e3282f00754
更新日期：2007-11-01 00:00:00
abstract：:Current concepts of basal ganglia function have evolved from the essentially motoric, to include a range of extramotoric functions that involve not only dopaminergic but also cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic mechanisms. We consider these mechanisms and their efferent systems, including sp...
journal_title：Behavioural pharmacology
pub_type： 杂志文章,评审
doi：10.1097/FBP.0000000000000118
更新日期：2015-02-01 00:00:00
abstract：:Sex-dependent differences have been consistently described in cannabinoid addiction research. In particular, we recently reported that female Lister Hooded rats display greater self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) and stronger reinstatement of cannabinoid-seeking behavior than ...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0000000000000395
更新日期：2018-09-01 00:00:00
abstract：:Sensorimotor gating disruptions are seen in various psychiatric illnesses with putatively different pathologies, including schizophrenia and bipolar disorder. Interestingly, mice lacking the dopamine (DA) transporter (DAT) gene display markedly increased levels of DA, deficits in sensorimotor gating, and hyperactivity...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0b013e32830dc110
更新日期：2008-09-01 00:00:00
abstract：:The strain of spontaneously hypertensive rats (SHR) is considered a genetic model for the study of attention-deficit hyperactivity disorder (ADHD), as it displays hyperactivity, impulsivity and poorly sustained attention. Recently, we have shown the involvement of adenosinergic neuromodulation in the SHR's short-term ...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：10.1097/FBP.0b013e32832a80bf
更新日期：2009-03-01 00:00:00
abstract：:Rats were trained on one of two multiple random-interval schedules of reinforcement, which contained both ascending and descending reinforcement density sequences. The design of the schedules made it possible to determine whether performance changes in a particular component depended on the reinforcement density in th...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-01-01 00:00:00
abstract：:This study was designed to compare the reinforcing efficacy of PCP (phencyclidine:phenylcyclohexyl-piperidine) and the PCP-derivatives BTCP (N-[1-(2-benzo(b)thiophenyl) cyclohexyl]piperidine) and TCP (N-[1-(2-thienyl)cyclohexyl]-piperidine) to that of cocaine, using a progressive ratio schedule of reinforcement (PR). ...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-04-01 00:00:00
abstract：:In previous studies, it was shown that apomorphine-induced stereotyped behaviour could be conditioned when apomorphine was repeatedly paired with sensory stimuli (CS). Since in these experiments, the sum of various sensory stimuli were applied, it seemed of interest to use each sensory stimulus separately in order to ...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-01-01 00:00:00
abstract：:Changes in extracellular concentrations of dopamine (DA) were measured in vivo in the nucleus accumbens of the rat during intravenous self-administration of either cocaine (0.25, 0.5, 1.0mg/infusion) or d-amphetamine (0.05, 0.1, 0.2mg/infusion). Drug intake was limited to 12 self-administered infusions per session for...
journal_title：Behavioural pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
