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Cited by 15Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances

Andreasen, Jesper T., Redrobe, John P., Nielsen, Elsebet Ø., Christensen, Jeppe K., Olsen, Gunnar M., Peters, Dan·2013·Neuropharmacology
DOI 10.1016/j.neuropharm.2013.04.060
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Abstract

As affective and cognitive disturbances frequently co-occur in psychiatric disorders, research into opportunities to simultaneously target both entities is warranted. These disorders are typically treated with monoamine reuptake inhibitors (MRIs), whereas ongoing research suggests that symptoms also improve by nicotinic acetylcholine receptor (nAChR) activation. Preclinical studies have corroborated this and also demonstrated a synergistic antidepressant-like action when nAChR agonists and MRIs are combined. Here, we present the in vitro and in vivo profile of NS9775, a combined full α7 nAChR agonist and triple MRI. NS9775 potently inhibited [(3)H]α-bungarotoxin binding in vitro (Ki: 1.8 nM), and ex vivo (ED₅₀: 3.6 mg/kg), showing negligible activity at α4β2-(Ki: 1720 nM) or α1-containing nAChRs (Ki: 12,200 nM). In α7-expressing oocytes, NS9775 displayed an EC₅₀ value of 280 nM, with a maximal response of 77% relative to a saturating acetylcholine concentration. Furthermore, NS9775 inhibited cortical [(3)H]5-HT, [(3)H]NA and [(3)H]DA uptake equipotently (14-43 nM), and inhibited striatal [(3)H]WIN35,428 binding (ED₅₀: 9.1 mg/kg). Behaviourally in mice, NS9775 (0.3-3.0 mg/kg) reversed scopolamine-induced deficits in a modified Y-maze and MK-801-induced learning deficits in 5-trial inhibitory avoidance. Swim distance in the forced swim test was increased by 30 mg/kg NS9775, and 10 and 30 mg/kg NS9775 reduced digging behaviour in the marble burying paradigm and increased the number of punished crossings in the four plate test. This pro-cognitive, antidepressant-like and anxiolytic-like effect of NS9775 suggests that combining α7 nAChR agonism and triple monoamine reuptake inhibition could be a step in the evolution of pharmacological treatments of affective and/or cognitive disturbances.

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Authors
Andreasen, J. T., Redrobe, J. P., Nielsen, E. Ø., Christensen, J. K., Olsen, G. M., & Peters, D.
Affiliations
  • University of Copenhagen (DK)
  • Lundbeck (Denmark) (DK)
  • NeuroSearch (Denmark) (DK)
  • Danpet (Sweden) (SE)
Corresponding author
Andreasen, Jesper T.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2013-10
Volume
73
Pages
183-191
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2013.04.060
OpenAlex
W2056075112
Cited by
15
References
75
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 4
FWCI
1.04
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
α7 nicotinic acetylcholine receptor agonist, monoamine reuptake inhibitors, antidepressant-like effects, anxiolytic-like effects, cognitive enhancement, emotional disturbance, combination therapy, scopolamine-induced cognitive deficits, forced swim test
MeSH terms
Affective Symptoms, Animals, Avoidance Learning, Behavior, Animal, Brain, Bungarotoxins, Cognition Disorders, Drug Evaluation, Preclinical, Female, Male, Naphthalenes, Punishment, Radioligand Assay, Radionuclide Imaging, Neurotransmitter Uptake Inhibitors, Tritium, Nicotinic Agonists, Maze Learning, Mice

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