Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine-Seeking Behavior in Rats

Liu, Xiu; Caggiula, Anthony R.; Yee, Susan K.; Nobuta, Hiroko; Sved, Alan F.; Pechnick, Robert N.; Poland, Russell E.

doi:10.1038/sj.npp.1301129

Cited by 64 publications

(53 citation statements)

References 88 publications

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“…It is especially promising that in this study clofibrate had a protective effect against both nicotine-and cue-induced reinstatement. Clofibrate's ability to counteract nicotinerelated cues is consistent with the findings that PPARa agonists downregulate nicotinic receptors and that cue-induced nicotine-seeking depends upon the action of acetylcholine at nicotinic receptors (Liu et al, 2007). If clofibrate can indeed counteract the effects of smoking-related cues, this could make it a valuable adjunct or alternative to bupropion, varenicline, and nicotine patch therapies, which do not appear to protect against cueinduced nicotine craving in humans (Ferguson and Shiffman, 2009) or cue-induced nicotine-seeking in rats (Wouda et al, 2011;Liu et al, 2008).…”

Section: Discussionsupporting

confidence: 73%

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Panlilio

Justinová

Mascia

et al. 2012

Neuropsychopharmacol

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Experimental drugs that activate a-type peroxisome proliferator-activated receptors (PPARa) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARa-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

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Section: Discussionsupporting

confidence: 73%

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Panlilio

Justinová

Mascia

et al. 2012

Neuropsychopharmacol

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“…Smoking denicotinized cigarettes (i.e., cue alone) produces an equal amount of smoke intake and similar or even higher levels of satisfaction compared to nicotine-containing cigarettes (i.e., cue plus nicotine) (Butschky et al 1995;Gross et al 1997;Rose et al 2000). In recent animal studies, we (Liu et al 2006;Liu et al 2007) and others (LeSage et al 2004;Cohen et al 2005;Paterson et al 2005) have found that reintroduction of nicotine-associated cues after extinction resulted in increased responding on the lever previously reinforced by nicotine delivery. Taken together, these data indicate that environmental stimuli repeatedly associated with the administration of nicotine acquire conditioned incentive value, which critically contributes to reinstatement of nicotine-seeking behavior in animals and smoking relapse in humans.…”

Section: Introductionmentioning

confidence: 99%

Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

et al. 2007

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Rationale-The motivational effects of nicotine-associated cues have been demonstrated in animal studies. However, it is unknown whether the effectiveness of nicotine cues in reinstating nicotineseeking varies with the extent of prior nicotine self-administration. In addition, the issue of whether bupropion (an FDA-approved smoking cessation medication) interferes with the conditioned incentive of nicotine cues remains to be addressed.Objective-This study determined the relationship of cue-reinstated nicotine-seeking and the levels of prior self-administration and examined the effect of bupropion on cue-induced reinstatement of nicotine-seeking in comparison with that on self-administration. Materials and methods-MaleSprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine at different doses (0, 0.015, 0.03, 0.06 mg/kg/infusion) and to associate an auditory/visual cue with each nicotine delivery. After extinction, three reinstatement tests at 15 day intervals were conducted with re-presentation of the cue without nicotine delivery. In separate groups of rats trained with 0.03 mg/kg/infusion nicotine, bupropion (0, 10, 20, 40 mg/kg) was intraperitoneally administered to different groups before the reinstatement and in a withinsubject design before the self-administration tests.Results-Cue-induced reinstatement of active lever responses was observed at all nicotine doses in the first reinstatement test, but at only the two highest doses during the second and third tests. The magnitude of reinstatement was positively correlated with level of prior responding for nicotine. Bupropion pretreatment decreased nicotine self-administration but enhanced cue-reinstated nicotineseeking.Conclusions-These results demonstrate the positive correlation of cue-reinstated nicotineseeking with prior responding for nicotine self-administration and the persistence of the cue effect after taking higher doses of nicotine. The results of pharmacological tests suggest that although it is able to help achieve smoking cessation, bupropion may have little clinical benefit for the prevention of relapse associated with exposure to environmental smoking cues.

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“…Moreover, these sensory cues seem to be particularly important in highly addicted smokers (Brauer et al 2001). Additionally, in experimental animals high rates of responding for nicotine are only observed in the drug infusions are paired with a sensory stimulus (Caggiula et al Following extinction of responding for nicotine, the presentation of a cue previously paired with the nicotine infusions elicits reinstatement of responding (LeSage et al 2004;Liu et al 2007). Cueinduced reinstatement of nicotine-seeking behaviour is attenuated by the prior administration of the mGluR5 antagonist MPEP (Bespalov et al 2005).…”

Section: Mglur5 Receptors and Models Of Relapsementioning

confidence: 99%

“…mGluR5 receptors regulate the activation of glutamate NMDA receptors acting as an enhancer of NMDA-activated currents and increased phosphorylation of the receptor through intracellular signalling MAPK/ERK and calcium responsive element binding (O'Brien et al 2004;Liu et al 2007) via a Src-family tyrosine kinase (Kotecha et al 2003).…”

Section: Neurobiology Of Mglur5mentioning

confidence: 99%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

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RationaleMost habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor.Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. ObjectiveThe purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. ResultsImaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. ConclusionsAlthough mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many "off target" effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

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Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine-Seeking Behavior in Rats

Cited by 64 publications

References 88 publications

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

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