Affiliations: Department of Pharmaceutical Sciences, College of
Pharmacy, Midwestern University, Glendale, AZ 85308, USA. Tel.: +1 623 572
3589; Fax: +1 623 572 3550; E-mail: harias@midwestern.edu
Abstract: 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.