Translational research in medication development for nicotine dependence

Lerman, Caryn; LeSage, Mark; Perkins, Kenneth A.; O’Malley, Stephanie S.; Siegel, Steven J.; Benowitz, Neal L.; Corrigall, William A.

doi:10.1038/nrd2361

Cited by 152 publications

(157 citation statements)

References 249 publications

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“…11B). The observed decrease (ϳ50%) in nicotine self-administration induced by intra-VTA perfusion of CntxMII is comparable with that observed in the same paradigm after the administration of other nicotinic antagonists, such as mecamylamine and dihydro-␤-erythroidine (for review, see Lerman et al, 2007).…”

Section: Effects Of Intra-vta Perfusion Of Cntxmii On Intravenous Nicsupporting

confidence: 50%

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

Gotti¹,

Guiducci²,

Tedesco³

et al. 2010

J. Neurosci.

209

236

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␣6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of ␣6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of ␣6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of ␣6* nAChR in the mesostriatal system is heterogeneous, with (non-␣4)␣6␤2* being predominant in the mesolimbic pathway and ␣4␣6␤2* in the nigrostriatal pathway. We verified whether ␣6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists ␣-conotoxin MII (CntxMII) (␣3/␣6␤2* selective) or ␣-conotoxin PIA (CntxPIA) (␣6␤2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the ␣6␤2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that ␣6␤2*-selective compounds capable of crossing the blood-brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.

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Section: Effects Of Intra-vta Perfusion Of Cntxmii On Intravenous Nicsupporting

confidence: 50%

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

Gotti¹,

Guiducci²,

Tedesco³

et al. 2010

J. Neurosci.

209

236

View full text Add to dashboard Cite

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“…A key problem for the development of medications to treat nicotine addiction is the lack of animal models with sufficient predictive validity to support translation of pre-clinical findings to clinical research (Lerman et al, 2007). The promotion of therapies that target treatment among relapsed smokers interested in quitting is critical; however, to date few animal models have used paradigms that mimic the repeated cycle of nicotine exposure and withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

Hilário

Turner

Blendy

2012

Neuropsychopharmacol

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Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.

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“…One obstacle in the discovery of more effective compounds for smoking cessation is the absence of preclinical animal model bioassays that have convincing predictive validity for human nicotine addiction (55). In this context, it is important to note that rsFC can be measured in anesthetized animals and revealed circuits similar to awake human subjects (23).…”

Section: Discussionmentioning

confidence: 99%

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

Hong

Hodgkinson

Yang

et al. 2010

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

153

131

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Whole-genome searches have identified nicotinic acetylcholine receptor α5-α3-β4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key α5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.genetics | imaging | smoking | functional connectivity | nAChR S moking is influenced by both genetic and environmental factors, although the major factors associated with persistent smoking are genetics [heritability at 75% with minimal shared environmental contribution (1, 2)] and mental illnesses [smoking rate at 50-80% in many mental illnesses (3, 4)]. The brain mechanisms linking these factors to smoking behavior are not clear. In this context, the recent discovery of several polymorphisms at the 15q nicotinic acetylcholine receptor (nAChR) α5-α3-β4 gene cluster is important because they were found based on genomewide searches (5-7), have been replicated a considerable number of times (SI Methods), and provide a starting point to dissect the neurobiological pathways leading to persistent smoking. The most replicated functional marker associated with smoking, and secondarily to lung cancer, is the α5 subunit gene (CHRNA5) rs16969968 or Asp398Asn polymorphism that changes aspartic acid (Asp) to asparagine (Asn) (5-7), with the Asn risk allele reducing α4β2α5 receptor function (6). The α4β2 nAChR is a key regulator of nicotine addiction (8-10), and the participation of the α5 subunit substantially impacts α4β2 function (11).Identifying relevant genes is only the first step in finding more effective therapeutic agents. Identifying the brain circuit(s) linking the "risk alleles" to smoking is an important next step. Brain regions consistently associated with smoking-related behaviors and nicotine actions are the cingulate, striatum, orbitofrontal and prefrontal cortex, insula, and thalamus (12-16). The extant literature suggests that the α5 subunit is expressed cortically mainly in the cingulate; its mRNA expression is found in layer VIb in rats, with the highest concentration in the cingulate (17) and the cortical expression pattern of α5 seen in the cingulate and retrosplenial cortex (18). Subcortically, the α5 subunit is expressed in striatum, thalamus, hippocampus, and amygdala (SI Methods) (17,...

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Translational research in medication development for nicotine dependence

Cited by 152 publications

References 249 publications

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

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