Cholinergic signaling via the
nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as
cocaine and
opioids. In mouse studies, nonselective nAChR antagonist
mecamylamine blocks
cocaine-induced conditioned place preference (
CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist
methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to
cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of
cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR
ligands,
AT-1001 and
AT-1012, on the acquisition of
cocaine-induced
CPP and behavioral sensitization in mice. At 5-30mg/kg,
cocaine produced robust
CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with
AT-1001 (1-10mg/kg) or
AT-1012 (3-10mg/kg) blocked
CPP induced by 5mg/kg
cocaine, but not by 30mg/kg
cocaine. Lower doses of
AT-1001 (0.3-1mg/kg) and
AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg
cocaine. But
AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg
cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of
cocaine, and that selective α3β4 nAChR
ligands can attenuate
cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist
AT-1001 has also been shown to block
nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of
cocaine addiction as well as for
cocaine-
nicotine comorbid addiction.