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Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at ?2*nicotinic acetylcholine receptors.

ABSTRACT: Nicotine dose-dependently activates or preferentially desensitizes ?2 subunit containing nicotinic ACh receptors (?2*nAChRs). Genetic and pharmacological manipulations assessed effects of stimulation versus inhibition of ?2*nAChRs on nicotine-associated anxiety-like phenotype.Using a range of doses of nicotine in ?2*nAChR subunit null mutant mice (?2KO; backcrossed to C57BL/6J) and their wild-type (WT) littermates, administration of the selective ?2*nAChR agonist, 5I-A85380, and the selective ?2*nAChR antagonist dihydro-?-erythroidine (DH?E), we determined the behavioural effects of stimulation and inhibition of ?2*nAChRs in the light-dark and elevated plus maze (EPM) assays.Low-dose i.p. nicotine (0.05?mg·kg(-) 1) supported anxiolysis-like behaviour independent of genotype whereas the highest dose (0.5?mg·kg(-1) ) promoted anxiogenic-like phenotype in WT mice, but was blunted in ?2KO mice for the measure of latency. Administration of 5I-A85380 had similar dose-dependent effects in C57BL/6J WT mice; 0.001?mg·kg(-1) 5I-A85380 reduced anxiety on an EPM, whereas 0.032?mg·kg(-1) 5I-A85380 promoted anxiogenic-like behaviour in both the light-dark and EPM assays. DH?E pretreatment blocked anxiogenic-like effects of 0.5?mg·kg(-1) nicotine. Similarly to DH?E, pretreatment with low-dose 0.05?mg·kg(-1) nicotine did not accumulate with 0.5?mg·kg(-1) nicotine, but rather blocked anxiogenic-like effects of high-dose nicotine in the light-dark and EPM assays.These studies provide direct evidence that low-dose nicotine inhibits nAChRs and demonstrate that inhibition or stimulation of ?2*nAChRs supports the corresponding anxiolytic-like or anxiogenic-like effects of nicotine. Inhibition of ?2*nAChRs may relieve anxiety in smokers and non-smokers alike.

SUBMITTER: Anderson SM

PROVIDER: S-EPMC4439881 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at β2*nicotinic acetylcholine receptors.

Anderson S M SM Brunzell D H DH

British journal of pharmacology 20150324 11

<h4>Background and purpose</h4>Nicotine dose-dependently activates or preferentially desensitizes β2 subunit containing nicotinic ACh receptors (β2*nAChRs). Genetic and pharmacological manipulations assessed effects of stimulation versus inhibition of β2*nAChRs on nicotine-associated anxiety-like phenotype.<h4>Experimental approach</h4>Using a range of doses of nicotine in β2*nAChR subunit null mutant mice (β2KO; backcrossed to C57BL/6J) and their wild-type (WT) littermates, administration of th ...[more]

PMID: 25625469

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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.

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Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at ?2*nicotinic acetylcholine receptors.

Publications

Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at β2*nicotinic acetylcholine receptors.

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