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Effect of a nicotine vaccine on nicotine binding to ?2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

ABSTRACT: Nicotine promotes smoking partly by binding to ?2-containing nicotinic acetylcholine receptors (?2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of ?2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty. Developing nicotine vaccines could improve treatments. The authors used [123I]5-I-A-85380 single photon emission computed tomography (SPECT) to evaluate the effect of 3'-AmNic-rEPA on the amount of nicotine that binds to ?2*-nAChRs in smokers' brain cortical and subcortical regions.Eleven smokers who smoked an average of 19 cigarettes per day, had smoked for 10 years on average, and met criteria for nicotine dependence were given SPECT scans on two days: before and after immunization with 4-400 ?g of 3'-AmNic-rEPA. On scan days, three 30-minute baseline emission scans were followed by intravenous administration of nicotine (1.5 mg/70 kg body weight) and up to nine 30-minute emission scans.?2*-nAChR availability was quantified as VT/fP (total distribution volume divided by free plasma concentration), and nicotine binding was derived by the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding. Nicotine bound to ?2*-nAChRs correlated positively with nicotine injected before but not after vaccination. The daily number of cigarettes and desire for a cigarette decreased after vaccination.This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ?2*-nAChRs and disrupt the relationship between administered nicotine and nicotine available to occupy ?2*-nAChRs.

SUBMITTER: Esterlis I

PROVIDER: S-EPMC3738000 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Effect of a nicotine vaccine on nicotine binding to β2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

Esterlis Irina I Hannestad Jonas O JO Perkins Evgenia E Bois Frederic F D'Souza D Cyril DC Tyndale Rachel F RF Seibyl John P JP Hatsukami Dorothy M DM Cosgrove Kelly P KP O'Malley Stephanie S SS

The American journal of psychiatry 20130401 4

<h4>Objective</h4>Nicotine promotes smoking partly by binding to β2-containing nicotinic acetylcholine receptors (β2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of β2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty. Developing nicotine vaccines could improve treatments. The authors used [123I]5-I-A-85380 single photon emission computed tomography (SPECT) to evaluate the effect of 3'-AmNic-r ...[more]

PMID: 23429725

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Project description:Allelic variation in CHRNA3, 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 Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of α3* 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 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 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 α3 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. 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.

Dataset Information

Effect of a nicotine vaccine on nicotine binding to ?2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

Publications

Effect of a nicotine vaccine on nicotine binding to β2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

Similar Datasets

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