The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT receptor expressing interneurons: An in vitro study in rat hippocampus slices.

The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT receptor agonism, 5-HT receptor partial agonism, 5-HT, 5-HT, 5-HT receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods.

A small molecule activator of Na 1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo.

Na 1.1 (SCN1A) channels primarily located in gamma-aminobutyric acid (GABA)ergic fast-spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast-spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability.

Sonic hedgehog is a regulator of extracellular glutamate levels and epilepsy.

Sonic hedgehog (Shh), both as a mitogen and as a morphogen, plays an important role in cell proliferation and differentiation during early development. Here, we show that Shh inhibits glutamate transporter activities in neurons, rapidly enhances extracellular glutamate levels, and affects the development of epilepsy. Shh is quickly released in response to epileptic, but not physiological, stimuli.

Identification and electrophysiological evaluation of 2-methylbenzamide derivatives as Nav1.1 modulators.

Voltage-gated sodium channels (Nav) are crucial to the initiation and propagation of action potentials (APs) in electrically excitable cells, and during the past decades they have received considerable attention due to their therapeutic potential. Here, we report for the first time the synthesis and the electrophysiological evaluation of 16 ligands based on a 2-methylbenzamide scaffold that have been identified as Nav1.1 modulators.

Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.

Vortioxetine, a novel antidepressant with multimodal action, is a serotonin (5-HT)3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter (SERT) inhibitor. Vortioxetine has been shown to improve cognitive performance in several preclinical rat models and in patients with major depressive disorder. Here we investigated the mechanistic basis for these effects by studying the effect of vortioxetine on synaptic transmission, long-term potentiation (LTP), a cellular correlate of learning and memory, and theta oscillations in the rat hippocampus and frontal cortex.