Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation

Broide, Ron S.; Salas, Ramiro; Ji, Daoyun; Paylor, Richard; Patrick, James W.; Dani, John A.; Biasi, Mariella De

doi:10.1124/mol.61.3.695

Cited by 64 publications

(61 citation statements)

References 46 publications

(52 reference statements)

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“…The three nAChR subunits that have an effect on nicotine withdrawal in mice (␣2, ␣5, and ␤4) have in common an overlapping expression pattern: the ␤4 subunit is highly expressed in the MHb and is present in the IPN (Salas et al, 2004), the ␣5 subunit is present in the MHb (Broide et al, 2002) and is highly expressed in the IPN , and the ␣2 subunit is highly expressed in the IPN (Ishii et al, 2005). Although these subunits are also expressed in other areas, no other brain system contains an expression pattern consistent with shared functions.…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Salas

Sturm²,

Boulter³

et al. 2009

J. Neurosci.

283

303

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In humans, tobacco withdrawal produces symptoms that contribute to the difficulty associated with smoking cessation. Nicotine withdrawal symptoms can also be observed in rodents. A major standing question is which nicotinic receptor subtypes and which areas of the brain are necessary for nicotine withdrawal to occur. Using knock-out mice, we previously showed that the ␤4, but not the ␤2 subunit of nicotinic acetylcholine receptors, is necessary for the somatic manifestations of nicotine withdrawal. Since the ␤4 subunit is highly expressed in the medial habenula, we focused our studies on the medial habenula and its primary target, the interpeduncular nucleus. In particular, we studied nicotine withdrawal in mice lacking the ␣2 or the ␣5 nicotinic receptor subunits, which are highly expressed in the interpeduncular nucleus. We precipitated withdrawal by systemically injecting the nicotinic antagonist mecamylamine in mice chronically treated with nicotine. Both the ␣2 and the ␣5 null mutations abolished the somatic manifestations of nicotine withdrawal. In addition, in wild-type mice chronically treated with nicotine, mecamylamine precipitated withdrawal when microinjected into the habenula or the interpeduncular nucleus, but not into the cortex, ventral tegmental area or hippocampus. Our results demonstrate a major role for the habenulo-interpeduncular system and the nicotinic receptor subunits expressed therein, in nicotine withdrawal symptoms. Our data suggest that the efforts to develop new smoking cessation therapies should concentrate on these areas and receptor types.

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Section: Discussionmentioning

confidence: 99%

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Salas

Sturm²,

Boulter³

et al. 2009

J. Neurosci.

283

303

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show abstract

“…Specifically, homozygous α7 KI mice that have a leucine to threonine (L250T) point mutation in the pore-forming domain of the α7 subunit will die after birth, but heterozygotes remain viable and exhibit increased sensitivity to nicotine induced seizures [11,51,124]. These studies reveal that a gain of function in the α7 nAChR can produce substantial alterations of nicotine-related phenotypes; thus, a more complete evaluation of the effects of nicotine in α7 KI mice is necessary.…”

Section: The α7 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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“…Hypersensitive α7 knockin mice are barely viable since homozygotes die almost immediately after birth. Breeding of heterozygous animals showed that mice with hypersensitive α7 nAChR function showed nicotine-induced seizures at low doses (inversely correlated with oral nicotine intake in inbred strains of mice), whereas α7 null-mutants showed normal nicotine-induced seizure thresholds [128,129].…”

Section: The α7 Subunit [89]mentioning

confidence: 99%

Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction

Mineur

Picciotto

2008

Biochemical Pharmacology

119

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Human twin studies have suggested that there is a substantial genetic component underlying nicotine dependence, ongoing smoking and ability to quit. Similarly, animal studies have identified a number of genes and gene products that are critical for behaviors related to nicotine addiction. Classical genetic approaches, gene association studies and genetic engineering techniques have been used to identify the gene products involved in nicotine dependence. One class of genes involved in nicotinerelated behavior is the family of nicotinic acetylcholine receptors (nAChRs). These receptors are the primary targets for nicotine in the brain. Genetic engineering studies in mice have identified a number of subunits that are critical for the ability of nicotine to activate the reward system in the brain, consisting of the dopaminergic cell bodies in the ventral tegmental area and their terminals in the nucleus accumbens and other portions of the mesolimbic system. In this review we will discuss the various lines of evidence suggesting that nAChRs may be involved in smoking behavior, and will review the human and animal studies that have been performed to date examining the genetic basis for nicotine dependence and smoking.

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Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation

Cited by 64 publications

References 46 publications

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

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

Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction

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