The neurobiological basis for partial agonist treatment of nicotine dependence: Varenicline

Tobacco Dependence Program, UMDNJ School of Public Health, New Brunswick, NJ 08901, USA.
International Journal of Clinical Practice (Impact Factor: 2.57). 06/2006; 60(5):571-6. DOI: 10.1111/j.1368-5031.2006.00955.x
Source: PubMed

ABSTRACT Smoking cessation has major health benefits for men and women of all ages. However, most smokers are addicted to nicotine and fail repeatedly in their attempts to quit. Stimulation of nicotinic receptors in the brain, particularly alpha4beta2 receptors, releases dopamine in the meso-limbic area of the brain and is reinforcing. Nicotine abstinence reduces dopamine release, and this is associated with withdrawal symptoms and craving for nicotine. Eight current pharmacotherapies--bupropion, nortriptyline, clonidine and nicotine patch, gum, inhaler, lozenge and nasal spray--are moderately effective aids to smoking cessation. Each is significantly better than placebo, but approximately 80% of patients using one of these medications return to smoking within the first year. Varenicline, a specific alpha4beta2 nicotinic receptor partial agonist, is a new pharmacotherapy that stimulates dopamine and simultaneously blocks nicotine receptors. Phase II and III trials have yielded promising results suggesting that varenicline could be an important advance in the treatment of nicotine dependence.

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    • "The ability of varenicline to act as an effective smoking cessation aid is often considered to derive from its actions as a partial agonist of α4β2-containing receptors (Brose et al. 2013; Cahill et al. 2012; Gonzales et al. 2006; Jorenby et al. 2006). However, this is far from clear, as varenicline has varying efficacy at different nAChRs and this varies depending upon the specific assay and duration of drug exposure (Coe et al. 2005; Foulds 2006; Mihalak et al. 2006; Rollema et al. 2007). Still, the observation in the present study that varenicline does not appear to act as a primary reinforcer, while being readily self-administered when combined with the mildly reinforcing VS suggests that these two actions of nicotine result from actions on nAChRs of different subunit compositions. "
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    ABSTRACT: Varenicline (VAR), a smoking cessation aid that is a partial agonist at nicotinic receptors, mimics the reinforcement-enhancing effects of nicotine. Varenicline, when accompanied by non-drug cues, is self-administered by rats, though it is unclear whether this results from varenicline acting as a primary reinforcer or a reinforcement enhancer of the cues. This study sought to disentangle these two potential actions. Rats were allowed to self-administer intravenous nicotine, saline, or varenicline during 1-h sessions in operant chambers equipped with two levers. Five groups had concurrent access to drug infusions and a moderately reinforcing visual stimulus (VS) for responding on separate levers. Meeting the reinforcement schedule on one lever was reinforced with VAR (0.01, 0.06, 0.1 mg/kg/infusion), nicotine (0.06 mg/kg/infusion), or saline, while meeting the same schedule on the other lever delivered the VS. Additional groups were reinforced for pressing a single "active" lever and received VAR paired with the VS, the VS with response-independent infusions of VAR, or VAR alone (0.1 mg/kg/infusion). Rats readily responded for VAR paired with VS on a single lever. However, when VAR was the only reinforcer contingent on a response, rats did not respond more than for saline. These findings show that VAR does not serve as a primary reinforcer in rats at doses that increase responding for non-drug reinforcers. These data are consistent with research showing that the primary reinforcing effects of VAR are weak, at best, and that the primary reinforcing and reinforcement-enhancing actions of nicotinic drugs are pharmacologically distinct.
    Psychopharmacology 09/2014; 232(5). DOI:10.1007/s00213-014-3732-x · 3.88 Impact Factor
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    • "Cytisine (CYT)-related VAR tartrate (Chantix or Champix) is a partial agonist of α4β2* and α6β2 * nAChR subtypes and a full agonist of α7 and α3β4 nAChRs. It acts on β2-containing receptors and induces the release of mesolimbic dopamine, which counteracts withdrawal symptoms and reduces smoking satisfaction (Foulds 2006; Mihalak et al. 2006; Rollema et al. 2007). Clinical trials indicate that VAR is effective in decreasing relapse to smoking in humans (Cahill et al. 2011; Gonzales et al. 2006; Jorenby et al. 2006; Tonstad et al. 2006; Zierler-Brown and Kyle 2007), but adverse cardiovascular effects and/or neuropsychiatric events have recently been reported including (but not limited to) depression, suicidal ideation, suicide attempts , and completed suicide (Freedman 2007; Moore et al. 2011; Singh et al. 2011). "
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    ABSTRACT: Rationale Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation. Objectives This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP. Methods CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001–5 mg/kg), CC26 (0.001–1 mg/kg), cytisine (0.1–2.5 mg/kg), and varenicline (1–10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [3H]-Epibatidine (Epi) and [125I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes. Results CC4 and CC26 induced CPP with an inverted U-shaped dose–response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors. Conclusions We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC.
    Psychopharmacology 05/2014; 231(24). DOI:10.1007/s00213-014-3619-x · 3.88 Impact Factor
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    • "However, if he continues to smoke, he would invariably experience what is known as the ''pleasure of tobacco.'' Although research on brain waves (Knott, 1977) and mechanisms of pharmacological treatment (Foulds, 2006) suggest that the ''pleasure of tobacco'' experienced by smokers can be attributed to the resolution of nicotine withdrawal , the most important point is that Boy A will begin to experience the rewarding effects of smoking. After this, Boy A will change his behavior and start to buy cigarettes for himself regularly. "
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    ABSTRACT: The neural reward circuit and cognitive distortion play an important role in addiction; however, the relationship between the two has not yet been addressed. In this article, we review recent findings on nicotine dependence and propose a novel hypothesis. Previous research using functional magnetic resonance imaging (fMRI) has shown that while activation of the reward circuit (ventral striatum) appears in response to tobacco-related rewards in nicotine dependence, responses to rewards other than tobacco (e.g. food and money) are reduced. Moreover, this change is observed at the very early stages of smoking, even when a person has smoked fewer than 10 cigarettes in his/her lifetime. Thus, we propose the following hypothesis, called the Paradise Lost theory: given addicts' lower ventral striatal responses to non-tobacco rewards, nicotine addiction disables smokers from sensing the pleasures of ordinary life (the Paradise Lost state). However, since smokers do not notice this, they produce an overestimation of tobacco (cognitive distortion), such that they do not have many pastimes other than smoking or feel that quitting smoking would reduce the happiness and pleasure and increase the difficulty of life. Cognitive distortion thus makes it difficult for smokers to take the initiative to quit smoking and even causes relapse after smoking cessation. This theory furthers our understanding of addiction and could improve our approach to the prevention and treatment of addiction.
    Addiction Research and Theory 04/2014; 22(2):158-165. DOI:10.3109/16066359.2013.793312 · 1.03 Impact Factor
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