Ligands selective for α4β2 but not α3β4 or α7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat

Smith, Janice W.; Mogg, Adrian J.; Tafi, Elisiana; Peacey, Eleanor; Pullar, Ian A.; Szekeres, Philip G.; Tricklebank, Mark D.

doi:10.1007/s00213-006-0596-8

Cited by 93 publications

(101 citation statements)

References 51 publications

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“…In contrast to the CPP assessment, results show that the ␣5 nAChR subunit is not involved in the discriminative stimulus effects of nicotine, because ␣5(Ϫ/Ϫ) mice did not differ from (ϩ/ϩ) counterparts at any dose tested. The ␤2 and ␣4 nAChR are involved in nicotine reward (Tapper et al, 2004;Walters et al, 2006) as well as nicotine discrimination (Shoaib et al, 2002;Smith et al, 2007). Based on our results, the ␣4␤2␣5* nAChR subtype does not play a role in the discriminative stimulus effects of nicotine, but it may be a candidate in mediating nicotine reward.…”

Section: Discussionmentioning

confidence: 67%

Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Jackson

Marks

Vann

et al. 2010

J Pharmacol Exp Ther

142

127

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Incorporation of the ␣5 nicotinic acetylcholine receptor (nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the ␣5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the ␣5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the ␣5 nAChR subunit in nicotine dependence. Using ␣5(Ϫ/Ϫ) mice, the current study aimed to examine the role of ␣5 nAChRs in the initial pharmacological effects of nicotine, nicotine reward using the conditioned place preference model, and the discriminative effects of nicotine using a two-lever drug discrimination model. 86 Rb ϩ efflux and 125 I-epibatidine binding assays were conducted to examine the effect of ␣5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that ␣5(Ϫ/Ϫ) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the ␣5 nAChR is involved in nicotine reward. Alternatively, ␣5(Ϫ/Ϫ) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the ␣5 nAChR subunit resulted in a statistically significant decrease in function in the thalamus and hindbrain, but the decreases noted in spinal cord were not statistically significant. Receptor number was unaltered in all areas tested. Taken together, results of the study suggest that ␣5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence.

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Section: Discussionmentioning

confidence: 67%

Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Jackson

Marks

Vann

et al. 2010

J Pharmacol Exp Ther

142

127

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“…Functional assays with sazetidine-A on native rat nAChRs have therefore been performed to answer this specific question. Dopamine release from rat striatal slices is mediated by the activation of native ␣4␤2* and ␣6␤2* nAChRs (Mogg et al, 2004;Salminen et al, 2004;Grady et al, 2007;Smith et al, 2007). We found that sazetidine-A acts as a potent and efficacious agonist in evoking […”

Section: Resultsmentioning

confidence: 99%

“…HEK293 cell lines stably expressing the nicotinic ␣4␤2 or ␣3␤4 receptors were maintained in Dulbecco's modified Eagle's medium/Nutrient Mix F-12 (3:1; Invitrogen, Carlsbad, CA) supplemented with 5% fetal bovine serum (Invitrogen), 250 g/ml G418 (Geneticin), and 20 mM HEPES (Invitrogen). Membranes from large-scale cell production were prepared as described previously (Smith et al, 2007). In brief, cell pastes were homogenized in 4 volumes of buffer (50 mM Tris-HCl, 150 mM NaCl, and 5 mM KCl, pH 7.4).…”

Section: [ 3 H]epibatidine Binding To ␣4␤2 and ␣3␤4 Nachrs Stably Expmentioning

confidence: 99%

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Zwart

Carbone²,

Moroni³

et al. 2008

Mol Pharmacol

100

129

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Sazetidine-A has been recently proposed to be a "silent desensitizer" of ␣4␤2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes ␣4␤2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to distinguish between the role of activation and desensitization of ␣4␤2 nAChRs in mediating the central nervous system effects of nicotine itself, as well as those of new nicotinic drugs. We were surprised to find that sazetidine-A potently and efficaciously stimulated nAChR-mediated dopamine release from rat striatal slices, which is mediated by ␣4␤2* and ␣6␤2* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant ␣4␤2 nAChRs in more detail. We expressed the two alternative stoichiometries of ␣4␤2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both ␣4(2)␤2(3)and ␣4(3)␤2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of ␣4␤2 nAChR: it was a full agonist on ␣4(2)␤2(3) nAChRs, whereas it had an efficacy of only 6% on ␣4(3)␤2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant ␣4␤2 nAChRs but shows differential efficacy on ␣4␤2 nAChRs subtypes.

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“…Varenicline previously has been characterized as a nicotinic partial agonist at the a4b2 receptor subtype (Rollema et al, 2007(Rollema et al, , 2010 and, depending on experimental conditions, may substitute partially or fully for nicotine in nicotine-trained rats and monkeys (Rollema et al, 2007;Smith et al, 2007;LeSage et al, 2009;Jutkiewicz et al, 2011;Cunningham et al, 2012). The plateau in the dose-effect function for varenicline at an intermediate level of responding on the MA-associated lever in the present experiments, in conjunction with its ability to antagonize the stimulant effects of nicotine in MA-trained rodents (Desai and Bergman, 2010), is consistent with its characterization as a nicotinic partial agonist.…”

Section: Drugmentioning

confidence: 99%

Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

Desai

Bergman

2014

J Pharmacol Exp Ther

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Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included a4b2-selective ligands that may vary in efficacy from relatively high [nicotine, (1) (ED 50 ) values, corresponded more closely with their relative affinities at a4b2 than at a7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the a4b2-selective antagonist dihydro-b-erythroidine hydrobromide (DHbE) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (2)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (.10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through a4b2 nicotinic acetylcholine receptor actions, and 2) nicotinic a4b2 partial agonists, like the nicotinic antagonist DHbE, can reduce MA-like behavioral effects of nicotine.

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Ligands selective for α4β2 but not α3β4 or α7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat

Abstract: Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at beta2 but not at beta4- or at alpha7-containing nicotinic receptors.

Cited by 93 publications

References 51 publications

Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors

Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

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