TY - JOUR
T1 - Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests
T2 - a comparison of SSR180711 and PNU-282987
AU - Andreasen, Jesper T
AU - Redrobe, John P
AU - Nielsen, Elsebet Ø
N1 - Copyright © 2011 Elsevier Inc. All rights reserved.
PY - 2012/1
Y1 - 2012/1
N2 - Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~ 50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED 50 to displace [ 3H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [ 3H]5-HT uptake, SSR180711 inhibited [ 3H]5-HT uptake with an ED 50 of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~ 2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.
AB - Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~ 50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED 50 to displace [ 3H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [ 3H]5-HT uptake, SSR180711 inhibited [ 3H]5-HT uptake with an ED 50 of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~ 2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.
KW - Animals
KW - Antidepressive Agents
KW - Behavior, Animal
KW - Benzamides
KW - Bicyclo Compounds
KW - Bicyclo Compounds, Heterocyclic
KW - Cerebral Cortex
KW - Citalopram
KW - Depression
KW - Disease Models, Animal
KW - Dose-Response Relationship, Drug
KW - Drug Synergism
KW - Drug Therapy, Combination
KW - Female
KW - Mice
KW - Mice, Inbred Strains
KW - Molecular Targeted Therapy
KW - Nicotinic Agonists
KW - Receptors, Nicotinic
KW - Serotonin
KW - Serotonin Plasma Membrane Transport Proteins
KW - Serotonin Uptake Inhibitors
KW - Tissue Distribution
KW - alpha7 Nicotinic Acetylcholine Receptor
U2 - 10.1016/j.pbb.2011.11.004
DO - 10.1016/j.pbb.2011.11.004
M3 - Journal article
C2 - 22108649
SN - 0091-3057
VL - 100
SP - 624
EP - 629
JO - Pharmacology, Biochemistry and Behavior
JF - Pharmacology, Biochemistry and Behavior
IS - 3
ER -