A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances
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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.
In: Neuropharmacology, Vol. 73, 10.2013, p. 183-91.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances
AU - Andreasen, Jesper T
AU - Redrobe, John P
AU - Nielsen, Elsebet Ø
AU - Christensen, Jeppe K
AU - Olsen, Gunnar M
AU - Peters, Dan
N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Affective Symptoms
KW - Animals
KW - Avoidance Learning
KW - Behavior, Animal
KW - Brain
KW - Bungarotoxins
KW - Cognition Disorders
KW - Drug Evaluation, Preclinical
KW - Female
KW - Male
KW - Maze Learning
KW - Mice
KW - Naphthalenes
KW - Neurotransmitter Uptake Inhibitors
KW - Nicotinic Agonists
KW - Punishment
KW - Radioligand Assay
KW - Tritium
U2 - 10.1016/j.neuropharm.2013.04.060
DO - 10.1016/j.neuropharm.2013.04.060
M3 - Journal article
C2 - 23748055
VL - 73
SP - 183
EP - 191
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -
ID: 140627704