The role of nicotinic receptor α7 subunits in nicotine discrimination

Stolerman, I. P.; Chamberlain, Sarah; Bizarro, Lisiane; Fernandes, Cathy; Schalkwyk, Leonard C.

doi:10.1016/j.neuropharm.2003.10.002

Cited by 55 publications

(49 citation statements)

References 34 publications

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“…a7À/À nicotinenaive mice do not display different IV self-administration of nicotine (model of acute reinforcement) than WT, 145 and a7-KO mice did not show weakened responses to nicotine in a drug discrimination experiment nor difference from WT in sensitivity to the locomotor depressant effects of nicotine. 152,153 The development of nicotine tolerance did not differ between a7-KO and WT mice. 154 Somatic withdrawal signs (after intraperitoneal injection of nAChR antagonist to induce nicotinic withdrawal) are reduced in chrna7 KO mice relative to WT littermates.…”

Section: Chrna7mentioning

confidence: 87%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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Section: Chrna7mentioning

confidence: 87%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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“…It was previously reported that the nicotine cue is blocked by antagonists of the ␤2-subunit of the nAChR (Shoaib et al, 2000) but not by selective ␣7 nAChR antagonists (Brioni et al, 1996). In addition, transgenic mice that lack the ␤2-subunit of the nAChR fail, or hardly learn to detect, the nicotine cue (Shoaib et al, 2002), whereas ␣7 nAChR knockout mice acquire discrimination of nicotine at a rate similar to wild-type mice (Stolerman et al, 2004). It has been argued that the discriminative stimulus effect of nicotine is closely related to its positive reinforcing stimulus effect (for discussion, see Merlo Pich et al, 1999;Stolerman et al, 1999) and that testing the extent of generalization to the nicotine cue offers an opportunity to assess whether such a compound has nicotine-like abuse potential.…”

Section: Discussionmentioning

confidence: 98%

The Novel α7 Nicotinic Acetylcholine Receptor AgonistN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide Improves Working and Recognition Memory in Rodents

Boess¹,

Vry²,

Erb³

et al. 2007

J Pharmacol Exp Ther

136

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The relative contribution of ␣4␤2, ␣7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the ␣7 nAChR agonist. ABBF bound to ␣7 nAChR in rat brain membranes (K i ϭ 62 nM) and to recombinant human 5-hydroxytryptamine (5-HT) 3 receptors (K i ϭ 60 nM). ABBF was a potent agonist at the recombinant rat and human ␣7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT 3 receptor and ␣3␤4, ␣4␤2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3-1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the ␣7 nAChR antagonist methyllycaconitine at 10 g, indicating that it is mediated by ␣7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the ␣7 nAChR and that selective ␣7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that ␣7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.Nicotine enhances cognitive functions, such as attention, learning, consolidation, and retention, in both animals and humans, through activation of brain nicotinic acetylcholine receptors (nAChRs) (Levin et al., 1999(Levin et al., , 2006. These ligandgated ion channels are homopentamers formed by five identical subunits (␣7 nAChR) or heteropentamers of multiple ␣ and ␤ subunits. Various isoforms of these subunits have been identified (␣2-␣10; ␤2-␤4; for reviews, see Paterson and Nordberg, 2000;Gotti et al., 2006). The most common nAChRs found in the brain are the ␣7 subtype with a low affinity for nicotine and the ␣4␤2 subtype with a high affinity for nicotine. Evidence from neuroanatomical, electrophysiological, and behavioral studies support a role for both of these receptor subtypes in processes of learning and memory.

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“…The generation of mice carrying an α7 null mutation provided a new tool for investigating the role of this subunit in the CNS (Orr-Urtreger et al, 1997). So far, few phenotypes have been associated with this mutation in both basal conditions (Franceschini et al, 2000;Morley and Rodriguez-Sierra, 2004;Paylor et al, 1998;Stolerman et al, 2004) and in the presence of nicotine (Franceschini et al, 2002;Stolerman et al, 2004). To date, nicotine withdrawal-enhanced nociception is the only nicotine-related phenotype shown to be affected in α7 −/− mice (Grabus et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the α7 nicotinic acetylcholine receptor subunit

et al. 2007

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Withdrawal symptoms are a major deterrent when people try to quit smoking. The α7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, and has been suspected to play a major role in nicotine addiction. We studied the influence of α7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the α 7 nAChR subunit (α7 −/−). For withdrawal experiments, animals were implanted with osmotic minipumps delivering nicotine for 13 days. A single intraperitoneal injection of the nAChR antagonists mecamylamine (MEC) or methyllycaconitine (MLA) was used to precipitate withdrawal. In wild type mice, both MEC and MLA precipitated somatic signs of withdrawal such as increased grooming, scratching and shaking. In α7 −/− mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed α7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in α7 −/− mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in α7 −/− mice using a battery of anxiety-related tests. The behavior of α7 −/− mice was indistinguishable from that of control mice. Our results point to the α7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior.

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The role of nicotinic receptor α7 subunits in nicotine discrimination

Cited by 55 publications

References 34 publications

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

The Novel α7 Nicotinic Acetylcholine Receptor AgonistN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide Improves Working and Recognition Memory in Rodents

Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the α7 nicotinic acetylcholine receptor subunit

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