Molecular interaction of bupropion with nicotinic acetylcholine receptors

This minireview focuses on the anti-nicotinic properties of bupropion (BP) at the molecular and cellular levels. The main pharmacological mechanism is based on the fact that BP induces the release as well as inhibits the reuptake of neurotransmitters such as a dopamine (DA) and norepinephrine (NE). Additional mechanisms of action have been also determined. For example, BP is a noncompetitive antagonist (NCA) of several nicotinic acetylcholine receptors (AChRs). Based on this evidence, the clinical activity of BP is currently considered to be mediated by its stimulatory action on the DA and NE systems as well as its inhibitory action on AChRs. More specifically, BP inhibits presynaptic α4β2-containing AChRs in GABAergic neurons of the ventral tegmental area and α3β4-containing AChRs in the habenulo-intrerpeduncular pathway. This inhibition finally decreases the addictive effects mediated by nicotine. Based on studies on muscle AChRs at the molecular level, a sequential mechanism is hypothesized to explain the inhibitory action of BP on neuronal AChRs: (1) BP first binds to AChRs in the resting state, decreasing the probability of ion channel opening, (2) the remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process, and (3), BP interacts with a binding domain located between the serine (position 6') and valine (position 13') rings that is shared with other NCAs including, phencyclidine, tricyclic antidepressants, and serotonin selective reuptake inhibitors. This new evidence paves the way for further investigations using AChRs as targets for the action of safer antidepressants and novel anti-addictive compounds.