Abstract
Background and Purpose Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. Key Results When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-Administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-Administration and CPP without affecting motor functions. Conclusion and Implications Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
| Original language | English |
|---|---|
| Pages (from-to) | 835-849 |
| Number of pages | 15 |
| Journal | British Journal of Pharmacology |
| Volume | 168 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 2013 |
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Keywords
- α4β2 and α6β2 nicotinic Ach receptor subtypes
- 5-hydroxytryptamine3 receptors
- conditioned place preference
- neurotransmitter release
- partial agonist
- rat
- self-Administration
ASJC Scopus subject areas
- Pharmacology
Cite this
CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation. / Sala, Mariaelvina; Braida, Daniela; Pucci, Luca; Manfredi, Irene; Marks, Michael J.; Wageman, Charles R.; Grady, Sharon R.; Loi, Barbara; Fucile, Sergio; Fasoli, Francesca; Zoli, Michele; Tasso, Bruno; Sparatore, Fabio; Clementi, Francesco; Gotti, Cecilia.
In: British Journal of Pharmacology, Vol. 168, No. 4, 02.2013, p. 835-849.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation
AU - Sala, Mariaelvina
AU - Braida, Daniela
AU - Pucci, Luca
AU - Manfredi, Irene
AU - Marks, Michael J.
AU - Wageman, Charles R.
AU - Grady, Sharon R.
AU - Loi, Barbara
AU - Fucile, Sergio
AU - Fasoli, Francesca
AU - Zoli, Michele
AU - Tasso, Bruno
AU - Sparatore, Fabio
AU - Clementi, Francesco
AU - Gotti, Cecilia
PY - 2013/2
Y1 - 2013/2
N2 - Background and Purpose Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. Key Results When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-Administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-Administration and CPP without affecting motor functions. Conclusion and Implications Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
AB - Background and Purpose Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. Key Results When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-Administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-Administration and CPP without affecting motor functions. Conclusion and Implications Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
KW - α4β2 and α6β2 nicotinic Ach receptor subtypes
KW - 5-hydroxytryptamine3 receptors
KW - conditioned place preference
KW - neurotransmitter release
KW - partial agonist
KW - rat
KW - self-Administration
UR - http://www.scopus.com/inward/record.url?scp=84872896597&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872896597&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2012.02204.x
DO - 10.1111/j.1476-5381.2012.02204.x
M3 - Article
C2 - 22957729
AN - SCOPUS:84872896597
VL - 168
SP - 835
EP - 849
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 4
ER -