DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.

BACKGROUND: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. OBJECTIVES: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. RESULTS: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition. CONCLUSIONS: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.

Magnon-Phonon Coupling of Synthetic Antiferromagnets in a Surface Acoustic Wave Cavity Resonator.

We used a surface acoustic wave (SAW) cavity resonator to study the coupling of acoustic magnons in a synthetic antiferromagnet (SAF) and phonons carried by SAWs. The SAF is composed of a CoFeB/Ru/CoFeB trilayer, and the scattering matrix of the SAW resonator is studied to assess the coupling. We find that the spectral line width of the SAW resonator is modulated when the frequency of the excited magnons approaches the SAW resonance frequency. Such a change in the spectral linewidth can be well reproduced using macrospin-like model calculations. From the model analyses, we estimate the magnon-phonon coupling strength to be ∼9.9 MHz at a SAW resonance frequency of 1.8 GHz: the corresponding magnomechanical cooperativity is ∼0.66. As the spectral shape hardly changes in a CoFeB single-layer reference sample, these results show that SAF provides an ideal platform to study magnon-phonon coupling in an SAW cavity resonator.

Acoustic spin Hall effect in strong spin-orbit metals.

We report on the observation of the acoustic spin Hall effect that facilitates lattice motion-induced spin current via spin-orbit interaction (SOI). Under excitation of surface acoustic wave (SAW), we find that a spin current flows orthogonal to the SAW propagation in nonmagnetic metals (NMs). The acoustic spin Hall effect manifests itself in a field-dependent acoustic voltage in NM/ferromagnetic metal bilayers. The acoustic voltage takes a maximum when the NM layer thickness is close to its spin diffusion length, vanishes for NM layers with weak SOI, and increases linearly with the SAW frequency. To account for these results, we find that the spin current must scale with the SOI and the time derivative of the lattice displacement. These results, which imply the strong coupling of electron spins with rotating lattices via the SOI, show the potential of lattice dynamics to supply spin current in strong spin-orbit metals.