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::The purpose of this study was to examine, in healthy volunteers without histories of extensive sedative use, the acute behavioral effects of doses of alprazolam used in clinical applications. Subjects participated in daily sessions over 12 study days. They consumed a standard breakfast, received an oral drug dose (0, ...
journal_title:Behavioural pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1997-02-01 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::The fentanyl derivative mirfentanil has a novel set of behavioral effects in non-humans including low-efficacy opioid actions and non-opioid antinociceptive actions. This study evaluated the rate-decreasing effects of mirfentanil, morphine, naltrexone and ketamine in pigeons both prior to and during a period of chroni...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/00008877-199909000-00012
更新日期:1999-09-01 00:00:00
abstract::This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperito...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000464
更新日期:2019-08-01 00:00:00
abstract::Central nicotinc acetylcholine receptors have been targeted for the development of novel treatments for memory deficits in Alzheimer's disease (AD) and other neurodegenerative disorders. Nicotine itself has been shown to improve memory-related task performance in aged animals and in AD patients. Administration of nico...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/00008877-199911000-00015
更新日期:1999-11-01 00:00:00
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
doi:10.1097/FBP.0b013e3281f19ca0
更新日期:2007-07-01 00:00:00
abstract::Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined wheth...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000363
更新日期:2018-04-01 00:00:00
abstract::The dopamine D3/D2 receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2 agonist bromocriptine, and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has be...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/00008877-199809000-00008
更新日期:1998-09-01 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::This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of μ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (μ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0b013e328349ab6c
更新日期:2011-09-01 00:00:00
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
doi:10.1097/00008877-200006000-00009
更新日期:2000-06-01 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::The behavioural effects of six compounds with N-methyl-D-aspartate (NMDA) antagonist properties were compared on the responding of rats maintained by a differential reinforcement of low rate 15s (DRL-15s) schedule. This schedule requires that responses be temporally spaced in order to be reinforced (timing behaviour)....
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-12-01 00:00:00
abstract::The prefrontal cortex (PFC) plays a critical role in mediating executive functions and orchestrating the way in which we think, decide, and behave. Many studies have shown that PFC neurons not only play a major role in mediating behavioral responses to stress but are also sensitive to stress and undergo remodeling fol...
journal_title:Behavioural pharmacology
pub_type: 杂志文章,评审
doi:10.1097/FBP.0000000000000429
更新日期:2018-10-01 00:00:00
abstract::Glutamate, an excitatory neurotransmitter in the brain, produces excitotoxicity through its agonistic action on postsynaptic N-methyl-D-aspartate receptor, resulting in neurodegeneration. We hypothesized that the administration of low doses of glutamate in cerebral ischemia could attenuate the excitotoxicity in neuron...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000256
更新日期:2016-10-01 00:00:00
abstract::Individuals with attention-deficit/hyperactivity disorder tend to make risker choices during probabilistic-discounting procedures. Thus, how common attention-deficit/hyperactivity disorder medications affect probabilistic discounting is of interest. In general, d-amphetamine increases risk-taking while atomoxetine has...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000500
更新日期:2019-10-01 00:00:00
abstract::The technique of microdialysis was employed to investigate in vivo 5-hydroxytryptamine (5-HT) release in isolation-reared rats compared with socially reared rats. Two methods were employed to stimulate 5-HT release: local KCI injection into the frontal cortex of chloral hydrate anaesthetized rats, and the exposure of ...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-06-01 00:00:00
abstract::Drug-addicted individuals show high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decad...
journal_title:Behavioural pharmacology
pub_type: 杂志文章,评审
doi:10.1097/FBP.0b013e3283305eb4
更新日期:2009-09-01 00:00:00
abstract::The cannabinoid receptor agonist Δ(9)-tetrahydrocannabinol (THC) enhances the antinociceptive effects of µ-opioid receptor agonists, raising the possibility of using a combination of THC and opioids for treating pain. This study examined the effects of noncontingent and contingent administration of THC on intravenous ...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0b013e32835a3907
更新日期:2012-12-01 00:00:00
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
doi:10.1097/FBP.0000000000000342
更新日期:2018-02-01 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::Cocaine addicts very often use different combinations of cocaine and other drugs of abuse such as gamma-hydroxybutyric acid. The objective of the present work was to evaluate the impact of gamma-hydroxybutyric acid administration on the rewarding actions of cocaine, using the conditioned place preference procedure. Co...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/01.fbp.0000190685.84984.ec
更新日期:2006-03-01 00:00:00
abstract::In spite of the current availability of several pharmacological therapies for the treatment of Parkinson's disease, side effects are invariably manifested during long-term treatment. Dyskinesia, wearing-off and on-off are among the most disabling side effects produced by the dopamine precursor L-dihydroxyphenylalanine...
journal_title:Behavioural pharmacology
pub_type: 杂志文章,评审
doi:10.1097/00008877-200609000-00005
更新日期:2006-09-01 00:00:00
abstract::A previous study from this laboratory reported an antiaversive effect of the beta-adrenoceptor blocker propranolol microinjected into the dorsal periaqueductal grey (DPAG) of the rat, that was antagonized by the 5-HT(2) receptor blocker ritanserin. The present results show that microinjection into the DPAG of isamolta...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/00008877-199102000-00010
更新日期:1991-02-01 00:00:00
abstract::Animal models of nicotine dependence are fundamental experimental tools for the understanding of the neurobiological and molecular processes underlying smoking behaviour. Substance use is controlled by four main processes: positive reinforcing effects, aversive effects, discriminative effects and stimulus-conditioned ...
journal_title:Behavioural pharmacology
pub_type: 杂志文章,评审
doi:10.1097/00008877-199911000-00005
更新日期:1999-11-01 00:00:00
abstract::5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of ...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0b013e3282f62d8c
更新日期:2008-03-01 00:00:00
abstract::Contingency management (CM) is associated with decreases in off-target drug and alcohol use during primary target treatment. The primary hypothesis for this trial was that targeting alcohol use or tobacco smoking would yield increased abstinence in the opposite, nontargeted drug. We used a 2 [CM vs. noncontingent cont...
journal_title:Behavioural pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1097/FBP.0000000000000379
更新日期:2018-08-01 00:00:00
abstract::The recent recreational use of synthetic cannabinoid ligands, collectively referred to as 'Spice', has raised concerns about their safety and possible differences in their biological effect(s) from marijuana/Δ-tetrahydrocannabinol (THC). AM2201, a highly efficacious, potent cannabinoid receptor 1 (CB1R) agonist, is a ...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000196
更新日期:2016-04-01 00:00:00
abstract::Cannabinoid receptor (CBR) agonists produce antinociception in conventional preclinical assays of pain-stimulated behavior but are not effective in preclinical assays of pain-depressed behavior. Fatty acid amide hydrolase (FAAH) inhibitors increase physiological levels of the endocannabinoid anandamide, which may conf...
journal_title:Behavioural pharmacology
pub_type: 杂志文章
doi:10.1097/FBP.0000000000000023
更新日期:2014-04-01 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