Journal Article

DZNE-2022-00458

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Biased 5-HT1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment

van Hagen, B. T. J. ; van Goethem, N. P. ; Nelissen, E. ; Paes, D. ; Koymans, K. ; Hoof, S.DZNE* ; Schreiber, R. ; Varney, M. ; Newman-Tancredi, A. ; Prickaerts, J.

2022
Elsevier San Diego, Calif.

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Please use a persistent id in citations: doi:10.1016/j.mcn.2022.103719

Abstract: Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Keyword(s): Aminopyridines: pharmacology (MeSH) ; Animals (MeSH) ; Autoreceptors: physiology (MeSH) ; Hippocampus: drug effects (MeSH) ; Hippocampus: physiology (MeSH) ; Male (MeSH) ; Neuronal Plasticity: drug effects (MeSH) ; Neuronal Plasticity: physiology (MeSH) ; Pattern Recognition, Physiological: drug effects (MeSH) ; Pattern Recognition, Physiological: physiology (MeSH) ; Piperidines: pharmacology (MeSH) ; Pyrimidines: pharmacology (MeSH) ; Rats (MeSH) ; Rats, Wistar (MeSH) ; Receptor, Serotonin, 5-HT1A: physiology (MeSH) ; Recognition, Psychology: drug effects (MeSH) ; Recognition, Psychology: physiology (MeSH) ; Serotonin 5-HT1 Receptor Agonists: pharmacology (MeSH) ; Serotonin 5-HT1 Receptor Agonists: therapeutic use (MeSH)

Note: (CC BY)

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Contributing Institute(s):

1. Autoimmune Enzephalopathies (AG Prüß)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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