α3*Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake

Allelic variation in CHRNA3, the gene encoding the alpha 3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for alpha 3-containing (alpha 3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. alpha 3* 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 Chrna3(tm1.1Hwrt) hypomorphic mice, which express constitutively low levels of alpha 3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg(-1) 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 (0.01-0.18 mg kg(-1) per infusion). Using whole-cell recordings, we found that the alpha 3 beta 4* nAChR-selective antagonist alpha-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the alpha 3 beta 2* nAChR-selective antagonist alpha-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of alpha-conotoxin AuIB (10 mu M) but not alpha-conotoxin MII (10 mu M) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that alpha 3 beta 4* 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.