| First Author | Elayouby KS | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 8 | Pages | 1779-1787 |
| PubMed ID | 33380469 | Mgi Jnum | J:303777 |
| Mgi Id | MGI:6508725 | Doi | 10.1523/JNEUROSCI.0127-19.2020 |
| Citation | Elayouby KS, et al. (2021) alpha3* Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake. J Neurosci 41(8):1779-1787 |
| abstractText | Allelic variation in CHRNA3, the gene encoding the alpha3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for alpha3-containing (alpha3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. alpha3* 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 alpha3* 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 alpha3beta4* nAChR-selective antagonist alpha-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the alpha3beta2* nAChR-selective antagonist alpha-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of alpha-conotoxin AuIB (10 mum) but not alpha-conotoxin MII (10 mum) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that alpha3beta4* 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.SIGNIFICANCE STATEMENT Allelic variation in CHRNA3, which encodes the alpha3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that Chrna3 hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of Chrna3 gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. alpha-Conotoxin AuIB, a potent antagonist of the alpha3beta4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that alpha3beta4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine. |
