Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697.
J Neurosci. 2021 Feb 24;41(8):1779-1787. doi: 10.1523/JNEUROSCI.0127-19.2020. Epub 2020 Dec 30.
Allelic variation in , the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* 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 hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg 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 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg per infusion). Using whole-cell recordings, we found that the α3β4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3β2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 μm) but not α-conotoxin MII (10 μm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3β4* 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 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers. Allelic variation in , which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3β4 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 α3β4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.
基因编码的α3 型烟碱型乙酰胆碱受体(nAChR)亚单位的等位基因变异增加了对烟草依赖和与吸烟相关疾病的易感性，但人们对包含α3 亚单位(α3*)的 nAChR 在调节尼古丁相关行为或生理作用中的作用知之甚少。α3* nAChR 由中脑被盖（mHb）神经元密集表达，这些神经元几乎只投射到脚间核（IPn），已知它们调节尼古丁回避行为。我们发现，表达组成型低水平α3* nAChR 的基因敲低小鼠比其野生型同窝仔自我给予更多的尼古丁（0.4mg/kg 输注）。将慢病毒载体微注射到 mHb 或 IPn 中表达短发夹 RNA 以敲低基因转录本，可显著增加大鼠的尼古丁自我给药行为（0.01-0.18mg/kg 输注）。使用全细胞膜片钳记录，我们发现α3β4* nAChR 选择性拮抗剂α-芋螺毒素 AuIB 几乎完全消除了 mHb 神经元中尼古丁诱导的电流。相比之下，α3β2* nAChR 选择性拮抗剂α-芋螺毒素 MII 仅部分减弱了这些电流。最后，将α-芋螺毒素 AuIB（10μm）而非α-芋螺毒素 MII（10μm）微注射到大鼠的 IPn 中，增加了尼古丁自我给药行为。这些数据表明，α3β4* nAChR 调节尼古丁对 mHb-IPn 回路的刺激作用，从而调节尼古丁回避行为。这些发现为理解基因如何增加人类吸烟者对烟草的依赖和与吸烟相关疾病的风险提供了机制上的见解。
