Rapid antidepressant effects of 5-HT1A Receptor biased agonists

Major depressive disorder (MDD), is a common and severe mood disorder. Globally, ~ 300 million people of all ages suffer from MDD (WHO 2021), which is the leading cause of disability in 2021. Approximately one third of the patients have inappropriate responses or no response at all to treatment. Even though some response is present, all available antidepressant drugs need to be administered for weeks or months to produce a meaningful clinical improvement. Therefore, finding novel and rapid-acting antidepressant treatments is a global priority. In this regard, the finding that ketamine –a dissociative anesthetic- had a rapid and sustained antidepressant effect in depressed people and the subsequent approval of intranasal esketamine for treatment-resistant depression (TRD) has changed the view of depression therapy from monoaminergic to glutamatergic drugs. It is postulated that ketamine's antidepressant activity results from its inhibition of the γ-aminobutyric acid (GABA) interneurons and the consequent disinhibition of cortical glutamatergic systems. Because selective activation of postsynaptic 5-HT1A receptors induces a rapid antidepressant response, it was thought that novel serotonin 5-HT1A receptor biased agonists could be one of such possible approaches. In the present work, we have studied the behavioral, biochemical and molecular aspects involved in the antidepressant-like effects of NLX-101 (formerly known as F15599). The results show that NLX-101 (0.16 mg/kg) reduced the immobility in the forced swim test when measured 30 min (albeit not 24 h and 7 days) after drug administration. Systemic administration of NLX-101 increased the extracellular concentration of dopamine and glutamate in the medial prefrontal cortex (mPFC). No changes were observed in the prefrontal output of noradrenaline and serotonin (5-HT). NLX-101 also produced a rapid increase in the synthesis of phospho-mTOR 30 min after drug administration. Altogether, our results suggest that NLX-101 has a rapid antidepressant-like response ...