The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion

Shoaib, Mohammed; Gommans, Jan; Morley, A. P.; Stolerman, I. P.; Grailhe, Régis; Changeux, Jean‐Pierre

doi:10.1016/s0028-3908(01)00194-0

Cited by 108 publications

(91 citation statements)

References 26 publications

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“…The b2-subunit plays a major role in nicotine discriminative stimulus and taste aversion effects and these properties may affect psychological aspects of ND. 139 Sensitivity to nicotine's stimulus properties is substantially impaired in b2-KO mice (compared with WT), in two experimental models: drug discrimination and conditioned taste aversion. The effect is specific to nicotine, as no difference between WT and KO is detected with regard to morphine-involved discrimination tests.…”

Section: Chrnb2mentioning

confidence: 99%

“…The effect is specific to nicotine, as no difference between WT and KO is detected with regard to morphine-involved discrimination tests. 139 Mice lacking the b2-subunit do not exhibit nicotine CPP (conditioned place preference), a measure of nicotine reward. 140 The effect of nicotine on acoustic startle response sensitivity was assessed in WT compared with b2-KO mice and a significant reduction in startle amplitude after nicotine administration was detected in the KO mice.…”

Section: Chrnb2mentioning

confidence: 99%

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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: Chrnb2mentioning

confidence: 99%

Section: Chrnb2mentioning

confidence: 99%

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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“…β2 KO mice do not show nicotine CPA whereas WT mice do [77]. Finally, mice trained in the nicotine CTA procedure learn to avoid flavored water that is paired with nicotine [53]; a study investigating CTA in β2 KO mice has shown that KO mice have reduced CTA relative to WT mice [152]. Overall, research using several behavioral procedures has consistently demonstrated that the effects of nicotine on avoidance learning, which models the effects of nicotine on affect and cognition in humans, are mediated by β2-containing nAChRs.…”

Section: The β2 Nachr Subunitmentioning

confidence: 99%

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Portugal

Gould

2008

Behavioural Brain Research

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Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

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“…The principal combinations that predominate in the brain are ␣4␤2 and ␣7 subunits (13,14). Mice lacking the ␤2 subunits show abnormal passive avoidance (15) and impaired nicotine self-administration (16) and drug discrimination (17) and exhibit a reduced nociceptive response to nicotine (18) and decreased visual acuity (19). On the other hand, general spatial memory tested in the water-maze task is not affected (9).…”

mentioning

confidence: 99%

Executive and social behaviors under nicotinic receptor regulation

Granon

Fauré

Changeux

2003

Proc. Natl. Acad. Sci. U.S.A.

154

164

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Nicotine enhances several cognitive and psychomotor behaviors, and nicotinic antagonists cause impairments in tasks requiring cognitive effort. To explore the contribution of nicotinic receptors to complex cognitive functions, we developed an automated method to investigate sequential locomotor behavior in the mouse and an analysis of social behavior. We show that, in the ␤2 ؊/؊ mutant, the high-order spatiotemporal organization of locomotor behavior, together with conflict resolution and social interaction, is selectively dissociated from low-level, more automatic motor behaviors. Such deficits in executive functions resemble the rigid and asocial behavior found in some psychopathological disorders such as autism and attention deficit hyperactivity disorder. N icotine and nicotinic agonists enhance cognitive and psychomotor behaviors in various species (1-5). Conversely, nicotinic antagonists (6, 7) and loss of nicotinic acetylcholine receptors (nAChRs) under various pathological conditions impair cognitive performance (8-10). These pharmacological actions of nicotine are mediated by a variety of nAChR subtypes with different distribution patterns in the brain (11,12). To unravel their respective contribution to brain functions, mice lacking defined nAChR subunits have been generated (for a review see ref. 13).Brain nAChRs are pentameric oligomers composed of protein subunits arranged in various combinations of ␣ (2-9) and ␤ (2-4). The principal combinations that predominate in the brain are ␣4␤2 and ␣7 subunits (13,14). Mice lacking the ␤2 subunits show abnormal passive avoidance (15) and impaired nicotine self-administration (16) and drug discrimination (17) and exhibit a reduced nociceptive response to nicotine (18) and decreased visual acuity (19). On the other hand, general spatial memory tested in the water-maze task is not affected (9).The aim of this article is to explore the contribution of nAChRs to complex cognitive functions referred to as executive processes. The management of these processes provides the maintenance of goal representation, the appropriate adaptation of behavior in a changing environment, the organization of sequences of actions over time, and the inhibition of prepotent or previous responses (20). Former work in humans and animals has shown that these processes require prefrontal and͞or cingulate activation (21-24). Behavioral protocols known to rely on the integrity of these structures were adapted to mice.We developed an automated analytical procedure for locomotor behavior (25) in the mouse. This method makes possible the distinction and quantitative evaluation of high-level executive components from low-level motor behavior. Furthermore, to study an index of adapted responses to a context that potentially leads to conflict resolution, we designed a procedure aimed at the distinction between several types of sequential behaviors in a social context. Interestingly, the ''supervisory planning'' organization of mouse locomotor behavior and conflict resolution were found selectivel...

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The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion

Cited by 108 publications

References 26 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

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Executive and social behaviors under nicotinic receptor regulation

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