Varenicline binds to the a4b2 nicotinic acetylcholine receptor (nAChR) with simultaneous partial agonist and antagonist activities
¨ACTIVITY 1: Partial agonist
–Varenicline binds to the receptor, partially stimulating dopamine release
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¨ACTIVITY 2: Antagonist
–Because varenicline is bound to the receptor, it prevents the binding of nicotine
Activation of the central nervous mesolimbic dopamine system is believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking
CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.
Key Point:
The efficacy of varenicline in smoking cessation is believed to be a result of varenicline’s partial agonist activity at the 42 nicotinic acetylcholine receptor (i.e., agonist activity to a lesser degree than nicotine), while simultaneously preventing nicotine binding (i.e., antagonist activity).

Background:
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline acts as a partial agonist at 42 nicotinic acetylcholine receptors. In the absence of nicotine, varenicline’s agonist activity is at a significantly lower level than nicotine, but sufficient to activate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. In the presence of nicotine, which competes for the same human 42 nicotinic acetylcholine receptor binding site, varenicline prevented nicotine from activating the 42 nicotinic acetylcholine receptor, since it has higher affinity for this site. This prevented full stimulation of the central nervous mesolimbic dopamine system.

Reference:
1.CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.