Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse‑effect potential

Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L‑DOPA‑induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice‑daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200–500 nM plasma concentrations. In the elevated plus maze eltoprazine increased anxiety‑like behavior. On the other hand, it induced a clear‑cut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test. Regarding adverse effects, eltoprazine was found to produce hypothermia starting from 1 mg/kg. At similar doses it also increased locomotion in the open field. However, eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg). In summary, effects of eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects

The role of metabotropic glutamate receptors group I in learning and memory in rats.

Die Rolle metabotroper Glutamatrezeptoren der Gruppe I in der Ratte wurde in verschiedenen Lern- und Gedächtnismodellen mit Hilfe spezifischer Rezeptorantagonisten getestet. Die verwendeten Modelle bieten den Vorteil, dass nach nur wenigen Trainingseinheiten sowie kurzer Trainingszeit stabile Furchtgedächtnisse geformt werden, und zudem können die verschiedenen Stadien wie Akquisition, Konsolidierung und Expression getrennt untersucht werden. Allen Modellen liegt aversives Lernen zu Grunde, jedoch variieren sie in der unterschiedlichen Beteiligung verschiedener Hirnbereiche sowie in der Expression der Verhaltensantwort. EMQMCM, MTEP sowie (+)-MK-801, verminderten die Akquisition in den beiden kontext-abhängigen Modellen Passive Avoidance und kontext-abhängiger Furchtkonditionierung, jedoch hatte keine dieser genannten Substanzen einen Einfluss auf die Akquisition in auditiver Furchtkonditionierung. Diese wurde lediglich durch Skopolamin vermindert. Jedoch konnte gezeigt werden, dass sowohl MTEP als auch (+)-MK-801 die Akquisition in FPS hemmten, ein wie AFK klassisches Konditionierungsmodell. Dies deutet darauf hin, dass das glutamaterge System bei der Akquisition in AFK möglicherweise nicht involviert ist. Interessanterweise konnte für mGluR1 keine Beteiligung an der Akquisition in FPS nachgewiesen werden, was für eine unterschiedliche Rezeptorbeteiligung beim Erlernen von FPS spricht. In der vorliegenden Arbeit konnte zum ersten Mal gezeigt werden, dass zum einen eine gemeinsame Aktivierung von mGluR1 und mGluR5, sowie NMDAR und mGluR1 und NMDAR und mGluR5, zur Akquisition von Hippokampus-abhängigem PA nötig ist. Dies konnte für die Akquisition in Hippokampus-unabhängigem FPS nicht beobachtet werden. Ein weiterer Unterschied zwischen mGluR1 und mGluR5 war bei der Expression von PA zu beobachten, wobei der Gedächtniswiederabruf nur durch EMQMCM, aber nicht durch MTEP gestört wurde. Im Gegensatz dazu wurde die Expression in AFK durch MTEP gehemmt, wobei EMQMCM keinen Effekt zeigte. Im Unterschied dazu konnte eine Beteiligung von sowohl mGluR1 als auch mGluR5 bei der Expression in KFK gezeigt werden. Zusammenfassend kann man festhalten, dass das glutamaterge System nicht generell an allen Lernprozessen in verschiedenen Verhaltensmodellen der Ratte beteiligt zu sein scheint. Im Hinblick auf mGlu Rezeptoren der Gruppe I zeigte sich eine unterschiedliche Beteiligung an der Akquisition von FPS sowie Expression von PA und AFK. Hingegen scheint die Akquisition in kontext-abhängigen Modellen wie PA und KFK von einer Aktivierung von NMDA als auch von mGlu Rezeptoren der Gruppe I abhängig zu sein.The role of group I metabotropic glutamate receptors in the rat was examined in different models of learning and memory using selective antagonists. The advantage of the used animal models is the formation of a stable, strong fear memories after short time of training. Moreover, these models provide the possibility to investigate different stages of memory formation like acquisition, consolidation and expression. All paradigms are based on aversive conditioning, while they vary in the contribution of different brain structures and different expression of behavioural responses. The mGluR1 antagonist EMQMCM, the mGluR5 antagonist MTEP, as well as (+)MK-801, an NMDA receptor antagonist reduced acquisition in both context-dependent tasks passive avoidance and contextual fear conditioning, while none of the substances had an influence on auditory fear conditioning. Conditioned fear responses in the latter model were only reduced by scopolamine. In contrast, MTEP and (+)MK-801 reduced acquisition of fear conditioning in FPS. These findings suggest, that the glutamatergic system may not be involved in acquisition of auditory fear conditioning. Interestingly, an involvement of mGlur1 in acquisition in FPS could not be demonstrated, which may be due to a different receptor contribution in learning of FPS. For the first time, the present study showed that a combined activation of mGluR1 and mGluR5, as well as NMDAR and mGlur1 and NMDAR and mGluR5 is necessary for the acquisition of hippocampal dependent PA. However, this was not observed in acquisition in FPS, which is independent from the hippocampus. Another difference of mGluR1 and mGluR5 was observed in expression in PA. While MTEP had no effect, EMQMCM blocked expression of PA when given before retrieval. In contrast, expression in AFC was impaired by MTEP, while EMQMCM had no effect. Expression of contextual fear conditioning has been shown to be dependent on both mGluR1 and mGluR5. In summary, the glutamatergic system may not be involved in all forms of learning and memory in the rat. With respect to mGluR group I, a different involvement of the receptor subtypes could be shown in acquisition in FPS and expression in PA and AFC. In contrast, acquisition in context-dependent tasks like PA and CFC may be dependent on the activation of NMDARs and group I mGluRs

Facies Iuris Publici Hungariae

Praeside Johanne Gravio ... Publico examini submissa Die Augusti, loco horisque solitis, a Joh. Andrea Lochnero, Sempr. Hungar

Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication

International audienceBenzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M(1) receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side-effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M(1) receptor were performed. They revealed an inflection point value of BQCA corresponding to 306nM, and potentiation of the agonist response up to 47-fold in presence of 10μM of BQCA. In vivo, brain microdialysis showed a maximal brain level of 270nM, 40min after i.p. administration at 10mg/kg. Based on in vitro data obtained with this dose, it can be concluded that BQCA reaches brain levels which should potentiate the agonist response about 4-fold. Behavioural data confirmed that BQCA used at 10mg/kg attenuated scopolamine-induced memory deficit in a spontaneous alternation task. Moreover, BQCA showed no side effect at 10mg/kg and above in spontaneous locomotion and salivation tests. The profile of BQCA observed in the present study displays a clear advantage over the M(1)-M(3) agonist cevimeline. The present data show the therapeutic potential of the M(1) receptor positive allosteric modulator BQCA for the treatment of memory deficits observed in Alzheimer's disease

Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats

In the present study, we evaluated the effects of subchronic blockade of mGluR5 by 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on learning, anxiety and levodopa-induced dyskinesia in rats. In addition, we excluded the possibility that subchronic treatment produced pharmacokinetic changes using brain microdialysis. MTEP (5 mg/kg) impaired spatial learning in a radial maze task and contextual fear conditioning (CFC) when administered acutely, and the same effect was observed following a 4-day pre-treatment regime. Similarly, MTEP (5 mg/kg) exerted anxiolytic-like effects in CFC when given before the test whether administered after acute or sub-chronic treatment. Similarly, in levodopa-induced dyskinesia, sub-chronic (7 subsequent days) treatment with MTEP (5 mg/kg) resulted in a significant reduction in abnormal involuntary movements (AIMs), comparable to single acute administration. The data indicate that tolerance does not develop to the anxiolytic and antidyskinetic effects of mGluR5 antagonist MTEP at least at the used treatment mode and tested doses. However, at least at the doses tested, also no tolerance to the memory impairing effect of MTEP was observed. Depending on the indication and model, the amnesic effects of MTEP should be taken into account as a potential limitation, also after repetitive treatment

5-Year Clinical and Radiographic Results of the Direct Anterior Approach for Total Hip Arthroplasty Using a Collared Cementless Femoral Short-Stem Prosthesis

The aim of this study was to investigate the radiological and clinical outcome of the direct anterior approach (DAA) in total hip arthroplasty (THA) using a collared cementless femoral short-stem. This retrospective study included 124 patients with 135 THAs operated from 2014 to 2016 using a collared cementless triple tapered hydroxyapatite-coated femoral short-stem (AMIStem H Collared®, Medacta International, Castel San Pietro, Switzerland) implanted with a DAA. Follow-up was performed at three months, 12 months, and five years. Clinical outcome was assessed using the hip osteoarthritis outcome score (HOOS) and radiological analysis was done using conventional radiographs, which included evaluation of the femur morphology based on Dorr classification, of radiolucencies based on the Gruen zone classification and of stem subsidence. The mean age was 67.7 ± 11.3 years and the mean body mass index (BMI) was 27.4 ± 4.4 kg/m2. The stem survival rate at five years was 99.1% with one revision due to recurrent dislocations. Mean HOOS score improved from 40.9 ± 18.3 preoperatively to 81.5 ± 19.7 at three months, 89.3 ± 10.9 at 12 months, and 89.0 ± 14.0 at five years (all with p < 0.001). No significant correlations were found between age, femoral bone morphology, BMI and HOOS, and the appearance of relevant radiolucencies

Therapeutically relevant plasma concentrations of memantine produce significant L-N-methyl-D-aspartate receptor occupation and do not impair learning in rats

Subchronic treatment with memantine using osmotic pumps in male rats was used to verify whether plasma levels significantly blocking L-N-methyl-D-aspartate (NMDA) receptors (and shown previously to be neuroprotective) may impair learning. Treatment with 6.27, 12.5 and 18.8 mg/rat/day provided plasma levels of 1.03±0.08, 5.07±0.68 and 11.68±0.90 μmol/l. Only the lowest plasma level is therapeutically relevant and has previously been shown to be neuroprotective. Significant deficits in a passive avoidance task were only observed at the highest dose. Working memory, tested as spontaneous alternation in the cross maze, was impaired by the middle and highest doses, and these doses also induced hyperlocomotion. Microdialysis experiments with in-vivo recovery (27.4%) showed that infusion of memantine at 6.27 mg/rat/day (ca. 23 mg/kg/day) produced a concentration of 990±105 nmol/l in extracellular fluid. In-vivo NMDA receptor occupancy experiments demonstrated significant, dose-dependent receptor occupancy of 32.7 and 65.7% by memantine at the doses producing 1 and 5 μmol/l plasma levels, respectively. Moreover, acute administration (2.5 mg/kg intraperitoneally) of memantine to mature female rats produced approximately two-fold higher plasma levels than in young male rats. In conclusion, a dose of memantine which produces a plasma level (1 μmol/l) within the therapeutic range, reported previously to be neuroprotective, leads to intracellular brain levels similar to the affinity of memantine for NMDA receptors (receptor binding, patch clamp). This has been also extended by the experiments showing that at this plasma concentration, memantine occupies ca. 30% NMDA receptors in the brain and produces no cognitive impairment

Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity

Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu5 by positive allosteric modulators or stimulation of mGluR2/3 receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu5 receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol—5-yl]-piperidin-1-yl}-methanone), mGluR2/3 agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10 mg/kg i.p.), the typical antipsychotic haloperidol (0.1 and 0.2 mg/kg i.p.), the atypical antipsychotics aripiprazole (1.25–5 mg/kg i.p.) and olanzapine (2.5 and 5 mg/kg i.p.) all reduced amphetamine-induced hyperlocomotion in Sprague–Dawley rats, unlike the mGlu2/3 receptor agonist LY354740 (1–10 mg/kg i.p.). Interestingly, haloperidol (0.1 and 0.2 mg/kg i.p.), aripiprazole (1.25–5 mg/kg i.p.) and olanzapine (1.25–5 mg/kg i.p.), but not ADX47273 (1–10 mg/kg i.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30 mg/kg i.p.), haloperidol (0.1 and 0.2 mg/kg i.p.) and aripiprazole (5 and 10 mg/kg i.p.) reversed apomorphine (0.5 mg/kg s.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1–10 mg/kg i.p.) nor olanzapine (1.25–5 mg/kg i.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740