The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, like ketamine, elicit rapid-acting antidepressant activity in the rat chronic mild stress model via cortical mechanisms.
Mariusz Papp, Piotr Gruca, Ewa Litwa, Magdalena Lason, Adrian Newman-Tancredi, Ronan Depoortère
Journal of Psychopharmacology July 1, 2024 DOI: 10.1177/02698811241254832 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Interventions | NLX-101 NLX-204 ketamine WAY-100 635 |
| Dose | 16 µg (NLX-204 and NLX-101), 10 µg (ketamine), 2 µg (WAY-100,635), 0.16 mg/kg i.p. (systemic NLX-204 and NLX-101) |
| Topics | Depression Ketamine Esketamine Serotonin |
| Keywords | Serotonin 5-ht1a receptors Biased agonist Chronic mild stress Antidepressants Neuroscience research Psychiatric treatment Serotonin receptors Drug development |
| Citations | 15 |
| Key findings | NLX-101 and NLX-204 produce rapid antidepressant-like effects in rats through activation of prefrontal cortex 5-HT1A receptors, sharing a common neuroanatomical site with ketamine. |
Abstract
The highly selective 5-HT1A serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM). Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT1A receptor activation in the RAAD activity of NLX compounds. In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT1A antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT1A receptors. These data indicate that 5-HT1A receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine's primary mechanism of action) but also by activating 5-HT1A receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine's troublesome side effects.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 4
- Trends in research on novel antidepressant treatments. Frontiers in Pharmacology 2025
- Biased agonism in psychopharmacology: an opportunity to improve efficacy and safety of treatments. CNS Spectrums August 12, 2025
- The antidepressant-like activity of ketamine in the rat chronic mild stress model requires activation of cortical 5-HT 1A receptors. Behavioural Pharmacology June 1, 2025
- Negative allosteric modulation of α5-GABA A receptors engages dynamic cortical glutamatergic and GABAergic mechanisms underlying adaptive behavior in mice. bioRxiv : the preprint server for biology January 16, 2026
Cites 6
- Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions Proceedings of the National Academy of Sciences June 8, 2015
- Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine Current Neuropharmacology March 10, 2016
- The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models Psychopharmacology June 13, 2023
- The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology & Therapeutics October 2018
- Role of 5-HT1A Receptor Stimulation in the Medial Prefrontal Cortex in the Sustained Antidepressant Effects of Ketamine The International Journal of Neuropsychopharmacology December 22, 2017
and 1 more in the library