Allelic variation in CHRNA3, the gene encoding the a3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for a3-containing (a3p) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. a3p nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of a3p nAChRs, self-administer greater quantities of nicotine (0.4mg kg21 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01–0.18mg kg21 per infusion). Using whole-cell recordings, we found that the a3b4p nAChR-selective antagonist a-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the a3b2p nAChR-selective antagonist a-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of a-conotoxin AuIB (10 lM) but not a-conotoxin MII (10 lM) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that a3b4p nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.
- Interpeduncular nucleus