Potential antidepressant-like effects of the biased 5HT1A receptor agonist NLX101 in rats

Abstract

In recent years, major depressive disorder has been studied from many pathophysiolog-ical perspectives and has been concluded as a multifactorial disease with complex inter-actions between multiple signaling systems. The serotoninergic and noradrenergic sys-tems are implicated in the depression symptoms. In general, antidepressants are created to improve serotoninergic system; however, leading to changes in homeostasis mecha-nisms. Well known fact that classical antidepressants work only partially and with a de-layed onset has triggered the emergence of novel antidepressant agents with supposedly more precise mechanisms of action and less unwanted side effects. They increase sero-tonin levels in raphe nucleus that can lead to activation of autoreceptors and consequent decrease of serotonin in frontal cortex. A lot of attention has gained serotonin 1A hetero-receptor and its associated mechanisms. NLX101 is a novel serotonin 1A receptor biased agonist that exhibits antidepressant characteristics in animal models. It has shown a func-tional selectivity for specific G-protein alpha subunits and downstream pathways. Here, we reveal that systemic single dose administration of NLX101 shows antidepressant-like activity in Forced Swim Test, stimulates glutamate and dopamine release in prefrontal cortex dialysate, and increases phosphorylated protein, m-TOR, Glu1A, expression in prefrontal cortex. Overall, NLX101 shows rapid, but not sustained antidepressant-like ac-tion at low doses.