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The article extended the idea of active vibration reduction of beams with symmetric modes to beams with asymmetric modes. In the case of symmetric modes, the symmetric PZT (s-PZT) was used, and the optimization of the problem led to the location of the s-PZT centre at the point with the greatest beam curvature. In the latter case, the asymmetric modes that occur due to the addition of the point mass cause an asymmetric distribution of the bending moment and transversal displacement of a beam. In this case, the optimal approach to the active vibration reduction requires both new asymmetric PZT (a-PZT) and its new particular distribution on the beam. It has been mathematically determined that the a-PZT asymmetry point (a-point), ought to be placed at the point of maximum beam bending moment. The a-PZT asymmetry was found mathematically by minimizing the amplitude of the vibrations. As a result, it was possible to formulate the criterion of the maximum bending moment of the beam. The numerical calculations confirmed theoretical considerations. So, it was shown that in the case of asymmetric vibrations, the a-PZTs reduced vibrations more efficiently than the s-PZT.

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178.

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

An active reduction of transverse vibration of the triangular plate with P-F-F boundary conditions is considered. The cracked plate is idealized research model as partially clamped on one edge with varying clamped length. The active reduction is realised with PZTs. In the paper, assuming the detached base clamped length, the influence of PZTs distribution on the bending moment and the shearing force at the clamped edge is investigated. To realize the purpose two cases are considered. At the former the PZTs are attached at points in which the curvatures of the surface locally take their maximum (MC sub-areas or quasi-optimal ones). At the latter, the PZTs are somewhat shifted. The plate is excited with harmonic plane acoustic wave. The second mode is considered only. The active vibration reduction study with a finite element method (FEM) is carried out. The numerical calculations show that better results are obtained for MC distribution of the PZTs. [ABSTRACT FROM AUTHOR]

Abstract: Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain. The role of CRF in the behavioural activity and modulation of anxiety states in several brain structures has been well documented, but its function in the cerebral cortex still remains unknown. The aim of our study was to investigate the effect of CRF injected bilaterally into rat frontal cortex on the locomotor and exploratory activity and anxiety of rats. We also examined the effect of CRF on extracellularly recorded field potentials in rat frontal cortical slices in vitro. Behavioural experiments showed that CRF in doses of 0.05, 0.1, 0.2μg/1μl/site decreased locomotor and exploratory activity during a 40-min session in the open field test. In the elevated plus-maze test, CRF in a dose of 0.2μg/1μl/site produced a significant anxiolytic-like effect, which was prevented by CRF receptor antagonists (α-helicalCRF(9-41) and NBI 27914). Electrophysiological experiments showed that CRF-induced a transient depression of field potentials in slices partly disinhibited by GABAA and GABAB receptors antagonists. The blockade of NMDA receptors prevented the occurrence of that effect. The obtained results suggest that CRF may have anxiolytic-like effects in the frontal cortex. Moreover, the peptide inhibits locomotor and exploratory activity and depresses excitatory synaptic transmission in a NMDA receptor-dependent manner. [Copyright &y& Elsevier]