Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models.


: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.


Behav Pharmacol


Behavioural pharmacology


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 G




Has Abstract


2015-06-01 00:00:00












  • Opioid drugs and timeout from avoidance.

    abstract::The effects of µ agonists fentanyl, methadone and morphine and kappa agonist U50,488 on behavior maintained by negative reinforcement were determined. Rats were trained on concurrent schedules in which pressing one lever postponed shock on a Sidman avoidance schedule and pressing the other lever produced signaled peri...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Galizio M,Robinson EG,Ordronneau C

    更新日期:1994-04-01 00:00:00

  • Diphenyl diselenide improves scopolamine-induced memory impairment in mice.

    abstract::This study was conducted to evaluate the effects of exposure to diphenyl diselenide (PhSe)2 on cognitive impairment induced by scopolamine, a muscarinic antagonist, using the Y-maze and Morris water maze tests in mice. One hour before the tests, mice were treated with (PhSe)2 (50 mg/kg, oral) and 30 min later memory i...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Souza AC,Brüning CA,Leite MR,Zeni G,Nogueira CW

    更新日期:2010-09-01 00:00:00

  • Haloperidol blocks the acquisition but not the retrieval of a conditioned sensitization to apomorphine.

    abstract::The dopamine agonist apomorphine (apo) elicits stereotyped pecking bouts in pigeons, a response which increases with successive apo injections. The present study sought, first, to confirm the hypothesis that this sensitization arises through a Pavlovian conditioning driven by both external and internal cues; and, seco...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Acerbo MJ,Godoy AM,Delius JD

    更新日期:2003-12-01 00:00:00

  • Behavioral effects in adult rats of chronic prepubertal treatment with the cannabinoid receptor agonist WIN 55,212-2.

    abstract::Human and animal studies provide evidence for vulnerable periods of brain development for deleterious effects of cannabinoids. We have recently shown that pubertal chronic cannabinoid treatment leads to long-lasting behavioral deficits, whereas a comparable treatment in adult rats did not affect the animals' behavior....

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Schneider M,Drews E,Koch M

    更新日期:2005-09-01 00:00:00

  • Modification of the discriminative stimulus effects of 8-OH-DPAT, buspirone and the beta-adrenoreceptor antagonist pindolol after chronic administration of the 5-HT(1A) agonist 8-OH-DPAT in the pigeon.

    abstract::The involvement of adrenoreceptor blocking drugs with the 5-HT(1A)-mediated discriminative stimulus was studied in pigeons trained to discriminate the 5-HT(1A) receptor agonist 8-OH-DPAT (0.3mg/kg) from saline. Cumulative dose-response curves were determined for 8-OH-DPAT, the beta-adrenergic antagonist pindolol, the ...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Zhang L,Barrett JE

    更新日期:1991-11-01 00:00:00

  • Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia.

    abstract::Neonatal ventral hippocampal lesions in the rat result in post-pubertal onset of behavioural abnormalities, modelling some aspects of schizophrenia. We further assessed the behavioural effects of neonatal lesions in rats in a variety of cognitive tasks and in the prepulse inhibition (PPI) of startle response paradigm....

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Le Pen G,Grottick AJ,Higgins GA,Martin JR,Jenck F,Moreau JL

    更新日期:2000-06-01 00:00:00

  • Feeding-produced subchronic high plasma levels of uric acid improve behavioral dysfunction in 6-hydroxydopamine-induced mouse model of Parkinson's disease.

    abstract::The development of Parkinson's disease (PD) involves the degeneration of dopaminergic neurons caused by oxidative stress. Accumulating clinical evidence indicates that high blood levels of uric acid (UA), an intrinsic antioxidative substance, are associated with reduced risk of PD. However, this hypothesis has not bee...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Nakashima A,Yamauchi A,Matsumoto J,Dohgu S,Takata F,Koga M,Fukae J,Tsuboi Y,Kataoka Y

    更新日期:2019-02-01 00:00:00

  • Spatial learning deficit after NMDA receptor blockade and state-dependency.

    abstract::The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) (0.08 and 0.12 mg/kg, i.p.) was used to examine whether spatial memory is learned state-dependently. Rats pre-treated with drug or saline were trained for 9 days in an eight-arm radial maze, in which four arms were baited. On the ...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Kretschmer BD,Fink S

    更新日期:1999-07-01 00:00:00

  • Adenosine receptor antagonists improve short-term object-recognition ability of spontaneously hypertensive rats: a rodent model of attention-deficit hyperactivity disorder.

    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


    authors: Pires VA,Pamplona FA,Pandolfo P,Fernandes D,Prediger RD,Takahashi RN

    更新日期:2009-03-01 00:00:00

  • Environmental influences on behavioural sensitization to the dopamine agonist quinpirole.

    abstract::A runway was used to measure locomotor responses to quinpirole (200µg/kg), in rats. The locomotor stimulant effect of quinpirole increased progressively over successive trials at 3-day intervals. Animals administered quinpirole in the home cage were also sensitized, but to a lesser degree than animals tested in the ru...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Willner P,Papp M,Cheeta S,Muscat R

    更新日期:1992-02-01 00:00:00

  • Neuroprotective effects of coenzyme Q10 on paraquat-induced Parkinson's disease in experimental animals.

    abstract::Parkinson's disease (PD) affects ∼1-2% of the elderly population. Development of a neuroprotective therapy that may be initiated early in the course of the disease to retard/prevent disease progression is highly desirable. This study aimed to investigate prophylactic treatment with coenzyme Q10 (CoQ10) before paraquat...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Attia HN,Maklad YA

    更新日期:2018-02-01 00:00:00

  • Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands.

    abstract::The interoceptive stimulus induced by clozapine (5 mg/kg, i.p.) has been characterized in an operant drug discrimination procedure in the rat using a wide range of receptor subtype-selective agonists and antagonists. Only the muscarinic receptor antagonist scopolamine generalized fully to clozapine (>80%). Partial gen...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Goudie AJ,Smith JA,Taylor A,Taylor MA,Tricklebank MD

    更新日期:1998-12-01 00:00:00

  • The role of N-methyl-D-aspartate receptors and metabotropic glutamate receptor 5 in the prepulse inhibition paradigms for studying schizophrenia: pharmacology, neurodevelopment, and genetics.

    abstract::Treatments for the positive and negative symptoms of schizophrenia have been explored for decades, but no completely successful therapy has been found as yet. Metabotropic glutamate receptor 5 (mGluR5), which potentiates N-methyl-D-aspartate receptors in brain regions implicated in schizophrenia, has become a novel dr...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章,评审


    authors: Wu Z,Yang Z,Zhang M,Bao X,Han F,Li L

    更新日期:2018-02-01 00:00:00

  • Behaviour in the novel environment predicts responsiveness to d-amphetamine in the rat: a multivariate approach.

    abstract::The behaviour of rats in a novel environment was studied using a rapid time-sampling observation procedure followed by a principal component analysis (PCA) of the data. This approach revealed that novel environment behaviour can be described by two factors or principal components. The first factor comprised rearing, s...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Exner M,Clark D

    更新日期:1993-02-01 00:00:00

  • Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297.

    abstract::A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related inc...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Reavill C,B Bond,Overend P,Hunter AJ

    更新日期:1993-04-01 00:00:00

  • The dopamine D2 antagonist eticlopride accelerates extinction and delays reacquisition of food self-administration in rats.

    abstract::Dopamine receptors are implicated in the reinforcing effects of food and drug reinforcement. The purpose of this study was to evaluate whether blocking D2 dopamine receptors during extinction (secondary reinforcement) would affect reacquisition of responding for food pellets (primary reinforcement). Food-restricted ra...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Koerber J,Goodman D,Barnes JL,Grimm JW

    更新日期:2013-12-01 00:00:00

  • Infralimbic cortex activation and motivated arousal induce histamine release.

    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


    authors: Riveros ME,Forray MI,Torrealba F

    更新日期:2015-06-01 00:00:00

  • Salvianolic acid B improves motor function after cerebral ischemia in rats.

    abstract::In a previous short-term study, salvianolic acid B was reported to have a protective effect on cerebral ischemia. Here, we investigated whether salvianolic acid B improves the recovery of motor function after cerebral ischemia in a 14-day investigation. Cerebral ischemia was induced by middle cerebral artery occlusion...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Tang M,Feng W,Zhang Y,Zhong J,Zhang J

    更新日期:2006-09-01 00:00:00

  • Chronic intracerebroventricular infusion of lipopolysaccharide: effects of ibuprofen treatment and behavioural and histopathological correlates.

    abstract::Twenty male Wistar rats were trained under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement. When responding showed no trends, each subject was subcutaneously implanted with an Alzet osmotic mini-pump, connected to a chronic indwelling cannula extending into the lateral ventricle of the brain. T...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Richardson RL,Kim EM,Gardiner T,O'Hare E

    更新日期:2005-11-01 00:00:00

  • Effects of chronic scopolamine administration on spatial working memory and hippocampal receptors related to learning.

    abstract::Scopolamine has been used in neuropsychopharmacology as a standard drug that leads to symptoms mimicking cognitive deficits seen during the aging process in healthy humans and animals. Scopolamine is known to be a nonselective muscarinic receptor blocker, but its chronic effect on the expression of certain hippocampal...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Doguc DK,Delibas N,Vural H,Altuntas I,Sutcu R,Sonmez Y

    更新日期:2012-12-01 00:00:00

  • Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease.

    abstract::Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of ...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: McFarland K,Price DL,Bonhaus DW

    更新日期:2011-10-01 00:00:00

  • The effects of home-cage access to a sweet solution on the discriminative stimulus effects of cocaine.

    abstract::This study assessed whether access to a sweet solution in the home cage could change sensitivity to cocaine, using a drug discrimination procedure. Rats were trained to discriminate 10 mg/kg cocaine from saline. After acquisition, rats were tested with a cumulative dose-response procedure (0-18 mg/kg) for 12 consecuti...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Kohut SJ,Riley AL

    更新日期:2010-05-01 00:00:00

  • The effects of chronic administration of ceronapril on the partial reinforcement extinction effect and latent inhibition in rats.

    abstract::Previous experiments showed that acute administration of the angiotensin converting enzyme (ACE) inhibitor, ceronapril, shares with neuroleptic drugs an ability to enhance latent inhibition (LI), which consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. Expe...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Weiner I,Tarrasch R,Hasson O,Forian R,Smith AD,Rawlins JN,Feldon J

    更新日期:1994-06-01 00:00:00

  • Behavioral effects of dipropyltryptamine in rats: evidence for 5-HT1A and 5-HT2A agonist activity.

    abstract::These studies investigated the role of serotonin-1A (5-HT1A) and 5-HT2A receptors in the behavioral effects of dipropyltryptamine (DPT). Eight rats discriminated 0.56 mg/kg 2,5-dimethoxy-4-methylamphetamine (DOM) from saline and responded under a fixed ratio 5 schedule of food presentation; 12 other rats were used for...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Li JX,Rice KC,France CP

    更新日期:2007-07-01 00:00:00

  • Impairment of working memory by neuronal degeneration with NMDA in rat hippocampal CA-1.

    abstract::Rats were trained on a three-panel runway task prior to injections of N-methyl-D-aspartate (NMDA; 40nmoles/µl/side) into the dorsal hippocampus. One week after the treatment, animals did not show any change in the number of errors on the first runway trial (reference memory), with one correct white and two incorrect b...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Sugimachi K,Izawa K,Nakamura K,Kimura-Iwasaki K,Yamaguchi M,Nakagawa H,Oshino N

    更新日期:1992-08-01 00:00:00

  • Dissociation of effects of chronic diazepam treatment and withdrawal on hippocampal dialysate 5-HT and mCPP-induced anxiety in rats.

    abstract::Acute (10mg/kg, i.p.) and chronic (10mg/kg/day, i.p. for 10 days) diazepam treatments decreased hippocampal dialysate 5-HT (but not 5-HIAA) concentrations in freely moving rats, suggesting decreased availability of 5-HT to receptors. Twenty-four hours after the last chronic diazepam injection, hippocampal dialysate 5-...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Gibson EL,Barnfield AM,Curzon G

    更新日期:1996-03-01 00:00:00

  • Conditioned hyperkinesia induced by cocaine in mice is dose-dependent but not correlated with the unconditioned response or the contextually-sensitized response.

    abstract::The aims of the study were to test whether drug dose is positively related to the magnitude of the conditioned response following sensitization to the behavioural effects of cocaine and to investigate the relationship between the conditioned response and cocaine-induced sensitization. Male mice (C57BL/6J) were first i...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Michel A,Tirelli E

    更新日期:2002-02-01 00:00:00

  • LY294002, an inhibitor of phosphoinositide 3-kinase given into rat hippocampus impairs acquisition, consolidation and retrieval of memory for one-trial step-down inhibitory avoidance.

    abstract::Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the CA1 region of the dorsal hippocampus. Once recovered from surgery, animals were submitted to one session of step-down inhibitory avoidance training (3.0 s, 0.4 mA footshock). Animals received a 0.5-microl infusion of saline, or of LY2940...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Barros DM,Mello e Souza T,de Souza MM,Choi H,DeDavid e Silva T,Lenz G,Medina JH,Izquierdo I

    更新日期:2001-12-01 00:00:00

  • Potential new therapies against a toxic relationship: neuroinflammation and Parkinson's disease.

    abstract::Parkinson's disease (PD) is a neurodegenerative disorder classically associated with motor symptoms, but several nonmotor disturbances appear decades before the clinical diagnosis of the disease. A variety of hypotheses exist to explain the onset of PD, and neuroinflammation is one of the most investigated processes. ...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章,评审


    authors: Rodrigues LS,Fagotti J,D S Targa A,D Noseda AC,L Ilkiwa J,Chuproski AP,W C Dorieux F,D Dos Santos P,M S Lima M

    更新日期:2019-12-01 00:00:00

  • Dissociation of the effects of amphetamine and quinpirole on dopamine release in the nucleus accumbens following behavioural sensitization: an ex vivo voltammetric study.

    abstract::Behavioural sensitization to the locomotor stimulant effect of (+)-amphetamine or quinpirole was induced in rats by intermittent drug administration. Once established, endogenous dopamine release (DA) was measured in slices containing nucleus accumbens using fast cyclic voltammetry. DA release induced by single pulse ...

    journal_title:Behavioural pharmacology

    pub_type: 杂志文章


    authors: Muscat R,Patel J,Trout SJ,Wieczorek W,Kruk ZL

    更新日期:1993-01-01 00:00:00