Nicotine physical dependence and tolerance in the mouse following chronic oral administration

Grabus, Sheri D.; Martin, Billy R.; Batman, Angela M.; Tyndale, Rachel F.; Sellers, Edward M.; Damaj, M. Imad

doi:10.1007/s00213-004-2007-3

Cited by 81 publications

(74 citation statements)

References 26 publications

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“…All nicotine doses are reported as free base. Mice were given nicotine in the drinking water for 28 d, and withdrawal studies were conducted using the spontaneous nicotine withdrawal model as previously described (4,27).…”

Section: Methodsmentioning

confidence: 99%

“…We next sought to determine the functional consequences of chronic nicotine treatment and withdrawal on the spontaneous AP activity in the MHb. To analyze tolerance to chronic nicotine, we used a previously described protocol (4,27). Mice were given nicotine in the drinking water for 28 d and recorded on the last day or withdrawn from nicotine and recorded on the next day (see experimental paradigm in Fig.…”

Section: Block Of Hcn Channel-mediated Pacemaker Activity In Mhb Neuronsmentioning

confidence: 99%

“…In rodents that have been chronically treated with nicotine, withdrawal can be induced either by pharmacological precipitation or by cessation of nicotine administration. Somatic and affective signs of withdrawal differentially manifest in these two cases (3,4). Additionally, studies in knockout mice have revealed a distinct contribution of various nAChR subtypes to somatic and affective withdrawal signs (5,6), illustrating the molecular complexity of nicotine dependence, withdrawal, and relapse.…”

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confidence: 99%

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Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Görlich

Antolin-Fontes

Ables

et al. 2013

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

110

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The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula-interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for α3, β4, and α5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2-10 Hz generated by hyperpolarization-activated cyclic nucleotidegated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, α3β4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse.nAChRs | TRAP profiling T he tobacco epidemic kills nearly six million smokers a year, primarily from lung cancer. The success rate for smoking cessation without pharmacological treatment is only 3-5% and less than 30% with nicotine-replacement therapies (1). Nicotine, the addictive component of tobacco, mediates its action by activating nicotinic acetylcholine receptors (nAChRs), which respond to the endogenous neurotransmitter acetylcholine (ACh). Like other drugs of abuse, chronic nicotine exposure promotes adaptations in neuronal circuits that sustain the use of cigarettes (2, 3). Upon nicotine cessation in humans, a withdrawal syndrome-characterized by negative somatic and affective symptoms such as irritability, anxiety, depressed mood, and loss of concentration-develops (2, 3) and contributes to the high probability of smoking relapse. In rodents that have been chronically treated with nicotine, withdrawal can be induced either by pharmacological precipitation or by cessation of nicotine administration. Somatic and affective signs of withdrawal differentially manifest in these two cases (3, 4). Additionally, studies in knockout mice have revealed a distinct contribution of various nAChR subtypes to somatic and affective withdrawal signs (5, 6), illustrating the molecular complexity of nicotine dependence, withdrawal, and relapse.Converging evidence from genome-wide association studies...

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Section: Methodsmentioning

confidence: 99%

Section: Block Of Hcn Channel-mediated Pacemaker Activity In Mhb Neuronsmentioning

confidence: 99%

mentioning

confidence: 99%

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Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Görlich

Antolin-Fontes

Ables

et al. 2013

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

110

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“…When injected with nicotine, body temperature decreases, due in part to vasoconstriction. Repeated nicotine injection leads to tolerance to the hypothermic effects of nicotine but sensitization to pain induced by footshock or tail pinch [65]. While there are likely to be differences human responses and animal models, partly due to difficulties in assessing this complex phenotype, upregulation of high-affinity nicotinic receptors is observed following chronic nicotine administration or tobacco use across species examined to date (see for instance, [66][67][68][69]).…”

Section: Modeling and Testing Nicotine Addiction In Animalsmentioning

confidence: 99%

Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction

Mineur

Picciotto

2008

Biochemical Pharmacology

122

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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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“…Many factors contribute to the development and maintenance of nicotine addiction, and these processes have been investigated in both human populations and animal models to better understand underlying mechanisms. Cessation of chronic nicotine produces withdrawal symptoms in both animals (Grabus et al 2005;Malin et al 1992) and humans (Hughes 2007;Hendricks et al 2006), and avoidance of withdrawal symptoms is one factor that contributes to the maintenance of smoking and relapse during quit attempts. Conversely, studies have also shown that the severity and duration of nicotine withdrawal symptoms strongly predict relapse (Piasecki et al 1998(Piasecki et al , 2000.…”

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confidence: 99%

Translational Research in Nicotine Dependence

Turner

Gold

Schnoll

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Nicotine addiction accounts for 4.9 million deaths each year. Furthermore, although smoking represents a significant health burden in the United States, at present there are only three FDA-approved pharmacotherapies currently on the market: (1) nicotine replacement therapy, (2) bupropion, and (3) varenicline. Despite this obvious gap in the market, the complexity of nicotine addiction in addition to the increasing cost of drug development makes targeted drug development prohibitive. Furthermore, using combinations of mouse and human studies, additional treatments could be developed from off-the-shelf, currently approved medication lists. This article reviews translational studies targeting manipulations of the cholinergic system as a viable therapeutic target for nicotine addiction.

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Nicotine physical dependence and tolerance in the mouse following chronic oral administration

Abstract: These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.

Cited by 81 publications

References 26 publications

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction

Translational Research in Nicotine Dependence

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