NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

Rafael Pazinatto Aguiar; Lígia Mendes Soares; Mark Varney; Adrian Newman-Tancredi A; Humberto Milani; Jos Prickaerts; Rúbia Maria Weffort de Oliveira

doi:10.1016/j.neurobiolaging.2022.12.013

NLX-101, a 5-HT_1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

Neurobiol Aging. 2023 Apr:124:52-59. doi: 10.1016/j.neurobiolaging.2022.12.013. Epub 2022 Dec 31.

Authors

Rafael Pazinatto Aguiar¹, Lígia Mendes Soares¹, Mark Varney², Adrian Newman-Tancredi A², Humberto Milani¹, Jos Prickaerts³, Rúbia Maria Weffort de Oliveira⁴

Affiliations

¹ Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil.
² Neurolixis Inc., Park Ridge, NJ, USA.
³ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
⁴ Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil. Electronic address: rmmwoliveira@uem.br.

PMID: 36739621
DOI: 10.1016/j.neurobiolaging.2022.12.013

Abstract

5-HT_1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT_1A receptor-biased agonist, and F13714, a presynaptic 5-HT_1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Unlike younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT_1A as a treatment for cognitive deficits related to aging.

Keywords: 5-HT(1A) receptor; Aged rats; F13714; NLX-101; Neuroplasticity; Pattern separation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor*
Rats
Receptor, Serotonin, 5-HT1A*
Serotonin / metabolism
Serotonin 5-HT1 Receptor Agonists / pharmacology
Serotonin Receptor Agonists

Substances

3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
Receptor, Serotonin, 5-HT1A
Brain-Derived Neurotrophic Factor
Serotonin
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists