Dataset Information

AT-1001: a high affinity and selective ?3?4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.

ABSTRACT: Genomic and pharmacologic data have suggested the involvement of the ?3?4 subtype of nicotinic acetylcholine receptors (nAChRs) in drug seeking to nicotine and other drugs of abuse. In order to better examine this receptor subtype, we have identified and characterized the first high affinity and selective ?3?4 nAChR antagonist, AT-1001, both in vitro and in vivo. This is the first reported compound with a Ki below 10 nM at ?3?4 nAChR and >90-fold selectivity over the other major subtypes, the ?4?2 and ?7 nAChR. AT-1001 competes with epibatidine, allowing for [³H]epibatidine binding to be used for structure-activity studies, however, both receptor binding and ligand-induced Ca²? flux are not strictly competitive because increasing ligand concentration produces an apparent decrease in receptor number and maximal Ca²? fluorescence. AT-1001 also potently and reversibly blocks epibatidine-induced inward currents in HEK cells transfected with ?3?4 nAChR. Importantly, AT-1001 potently and dose-dependently blocks nicotine self-administration in rats, without affecting food responding. When tested in a nucleus accumbens (NAcs) synaptosomal preparation, AT-1001 inhibits nicotine-induced [³H]dopamine release poorly and at significantly higher concentrations compared with mecamylamine and conotoxin MII. These results suggest that its inhibition of nicotine self-administration in rats is not directly due to a decrease in dopamine release from the NAc, and most likely involves an indirect pathway requiring ?3?4 nAChR. In conclusion, our studies provide further evidence for the involvement of ?3?4 nAChR in nicotine self-administration. These findings suggest the utility of this receptor as a target for smoking cessation medications, and highlight the potential of AT-1001 and congeners as clinically useful compounds.

SUBMITTER: Toll L

PROVIDER: S-EPMC3327842 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.

Toll Lawrence L Zaveri Nurulain T NT Polgar Willma E WE Jiang Faming F Khroyan Taline V TV Zhou Wei W Xie Xinmin Simon XS Stauber Gregory B GB Costello Matthew R MR Leslie Frances M FM

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20120125 6

Genomic and pharmacologic data have suggested the involvement of the α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) in drug seeking to nicotine and other drugs of abuse. In order to better examine this receptor subtype, we have identified and characterized the first high affinity and selective α3β4 nAChR antagonist, AT-1001, both in vitro and in vivo. This is the first reported compound with a Ki below 10 nM at α3β4 nAChR and >90-fold selectivity over the other major subtypes, the α4 ...[more]

PMID: 22278092

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Project description:Abstract Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [3H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain. Keeley et al. present a multimodal study assessing changes in nicotinic receptor subtype expression and resting-state functional connectivity in adolescents and adults after chronic nicotine administration. Following exposure, differences in receptor density and resting-state functional connectivity were found in adolescents but not adults, particularly in the cortical, striatal and thalamic regions. Graphical Abstract Graphical abstract

Dataset Information

AT-1001: a high affinity and selective ?3?4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.

Publications

AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.

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