Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications

Picciotto, Marina R.; Caldarone, Barbara J.; Brunzell, Darlene H.; Zachariou, Venetia; Stevens, Tanya R.; King, Sarah L.

doi:10.1016/s0163-7258(01)00161-9

Cited by 203 publications

(194 citation statements)

References 157 publications

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“…First, ␣4␤2 nAChRs are not only the most sensitive subtype to DH␤E (Harvey et al, 1996;Khiroug et al, 2004), but they are also among the most prominent neuronal nAChRs, accounting for ϳ90% of nAChRs that bind nicotine with high affinity in the brain (Flores et al, 1992;Picciotto et al, 1995). Consistent with these data, ␣4␤2 nAChRs are densely located in the hippocampus (for review, see Picciotto et al, 2001). Second, data from Wehner et al (2004) and Davis and Gould (2007) indicate that nicotine fails to enhance contextual fear conditioning in ␤2 nAChR subunit KO mice.…”

Section: Discussionmentioning

confidence: 91%

Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning

Davis¹,

Kenney²,

Gould³

2007

J. Neurosci.

101

122

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Nicotine is known to enhance learning and memory in hippocampus-dependent tasks such as contextual fear conditioning. The present study was designed to directly examine whether the hippocampus plays a role in mediating this enhancement and which nicotinic acetylcholine receptor (nAChR) subtypes localized to the hippocampus are critical for enhanced learning. Contextual fear conditioning consisted of two white noise conditioned stimuli presentations, each coterminating with a 2 s, 0.57 mA footshock separated by a 120 s intertrial interval. Nicotine (0.09, 0.18, and 0.35 g per side) was bilaterally infused into the dorsal hippocampus before training and testing. Infusions of nicotine into the dorsal hippocampus produced a dose-dependent enhancement of contextual fear conditioning. To determine which nAChRs are critical to the enhancing effect of nicotine, the preferential ␣4␤2 nAChR antagonist, dihydro-␤-erythroidine (DH␤E) (6.00 and 18.00 g per side), or the preferential ␣7 nAChR antagonist, methyllycaconitine (MLA) (13.50 and 27.00 g per side), was bilaterally infused into the dorsal hippocampus before systemic injections of nicotine (0.09 mg/kg). DH␤E infusions dose-dependently blocked the enhancement of contextual fear conditioning by nicotine, whereas MLA infusions yielded an intermediate effect. In addition, neither DH␤E nor MLA had an effect on contextual fear conditioning in the absence of systemic nicotine. The present results suggest a critical role for ␣4␤2 nAChRs in the dorsal hippocampus for mediating the enhancing effect of nicotine on contextual fear conditioning.

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Section: Discussionmentioning

confidence: 91%

Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning

Davis¹,

Kenney²,

Gould³

2007

J. Neurosci.

101

122

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“…Nicotine is a major component of tobacco smoke whose behavioural effects are due to its interactions with a family of acetylcholine (ACh)-gated channels (nicotinic ACh receptors, nAChRs) present in the central and peripheral nervous systems [1][2][3][4][5]. These share a common basic structure but have specific pharmacological and functional properties that are due to the very different subunit combinations that make distinctive subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…The recent development of genetically engineered mice with the targeted deletion of specific subunits (knockout mice, Ko) or mutations in critical receptor domains (knockin mice, Kin), as well as Ko mice made to re-express nAChR subunits in selected brain regions by means of lentiviral vectors, has led to the in vivo identification of complex subtypes and allowed the study of individual subtypes in specific cells and complex neurobiological systems (reviewed in [1,[9][10][11][12]). …”

Section: Introductionmentioning

confidence: 99%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

414

428

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions.We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the meso-striatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

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“…These submicromolar concentrations of nicotine, which act at heterooligomeric ␣4␤2 high-affinity and homomeric ␣7 lowaffinity nAChR abundantly expressed in GABAergic interneurons of the frontal cortex (FC) and hippocampus (12)(13)(14), may improve cognitive function in laboratory animals and also in normal human subjects (1, 2).…”

mentioning

confidence: 99%

“…Although the effect of submicromolar concentrations of nicotine on cognition and perception is reduced with chronic treatment with nicotine because of nAChR desensitization (1,10,12), repeated exposure to nicotine also results in a long-term homeostatic increases of several synaptic proteins (15) including: (i) ␣4␤2 and ␣7 nAChR (3,4) and (ii) AMPA, NMDA, and GluR1 receptors (15). Chronic nicotine treatment also results in an increase of (i) dendritic length and spine density in the pyramidal neurons of the cingulate cortex (16) and (ii) long-term potentiation of hippocampal neuronal responses (17).…”

mentioning

confidence: 99%

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

Satta

Maloku

Zhubi

et al. 2008

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

178

118

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Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD 67 expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 mol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD 67 expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD67 promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 mol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD67 expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors.antagonists ͉ epigenetic mechanisms ͉ nicotinic acetylcholine receptor agonists ͉ schizophrenia T obacco smoking is frequently abused by schizophrenia patients (SZP) (for reviews see refs. 1 and 2). Because nicotine is a potent cholinergic receptor agonist that is inhaled with tobacco smoking and both the expression and function of nicotinic acetylcholine receptors (nAChRs) are down-regulated in the brain of SZP, one may conclude that the high level of tobacco smoking in these patients represents an attempt to self-medicate; i.e., correction of some disease-associated abnormalities of cholinergic (nicotinic) neurotransmission (3, 4), possibly related to the decrease of GABAergic function occurring in the brain of SZP (5-9).Typically, plasma nicotine levels in heavy smokers (Ϸ20-30 cigarettes a day) oscillate between 0.3 and 0.6 M. Because in humans nicotine half-life is Ϸ2 h, the nicotine plasma levels in heavy smokers progressively increase during the day but fluctuate in a ''peak and trough'' fashion after each cigarette (10, 11). These submicromolar concentrations of nicotine, which act at heteroolig...

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Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications

Cited by 203 publications

References 157 publications

Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning

Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning

Structural and functional diversity of native brain neuronal nicotinic receptors

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

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