McKee SA, Weinberger AH, Harrison EL, Coppola S, George TP. Effects of the nicotinic receptor antagonist mecamylamine on ad-lib smoking behavior, topography, and nicotine levels in smokers with and without schizophrenia: a preliminary study. Schizophr Res 115: 317-324

Division of Substance Abuse, Department of Psychiatry, Yale University School of Medicine, 2 Church St South, Suite 109, New Haven, CT 06519, United States.
Schizophrenia Research (Impact Factor: 3.92). 09/2009; 115(2-3):317-24. DOI: 10.1016/j.schres.2009.07.019
Source: PubMed


Individuals with schizophrenia have higher plasma nicotine levels in comparison to non-psychiatric smokers, even when differences in smoking are equated. This difference may be related to how intensely cigarettes are smoked but this has not been well studied. Mecamylamine (MEC), a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist, which has been shown to increase ad-lib smoking and to affect smoking topography, was used in the current study as a pharmacological probe to increase our understanding of smoking behavior, smoking topography, and resulting nicotine levels in smokers with schizophrenia. This preliminary study used a within-subject, placebo-controlled design in smokers with schizophrenia (n=6) and healthy control smokers (n=8) to examine the effects of MEC (10mg/day) on ad-lib smoking behavior, topography, nicotine levels, and tobacco craving across two smoking deprivation conditions (no deprivation and 12-h deprivation). MEC, compared to placebo, increased the number of cigarettes smoked and plasma nicotine levels. MEC increased smoking intensity and resulted in greater plasma nicotine levels in smokers with schizophrenia compared to controls, although these results were not consistent across deprivation conditions. MEC also increased tobacco craving in smokers with schizophrenia but not in control smokers. Our results suggest that antagonism of high-affinity nAChRs in smokers with schizophrenia may prompt compensatory smoking, increasing the intensity of smoking and nicotine exposure without alleviating craving. Further work is needed to assess whether nicotine levels are directly mediated by how intensely the cigarettes are smoked, and to confirm whether this effect is more pronounced in smokers with schizophrenia.

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Available from: Andrea H Weinberger, May 07, 2015
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    • "ct a nicotine - mecamylamine interaction unrelated to withdrawal . Regardless of its interpretation , this effect is of interest because mecamylamine exposure occurs in the presence of acute nicotine exposure in animal models ( Cohen et al . , 2003 ; Liu et al . , 2007 ; Struthers et al . , 2009 ) and in human smokers ( McClernon and Rose , 2005 ; McKee et al . , 2009 ) . It is well established that adolescent and adult rodents can differ in their response to pharmacological manipulation of nAChRs ( e . g . , Shram et al . , 2006 , 2008a ; Torres et al . , 2008 ) . For example , adolescents exhibit attenuated somatic signs compared to adults during mecamylamine - precipitated withdrawal from a chroni"
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    ABSTRACT: High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults.
    Frontiers in Pharmacology 11/2015; 6:239. DOI:10.3389/fphar.2015.00239 · 3.80 Impact Factor
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    • "In that regard, it has been proposed that the high affinity antagonism to nicotine and acetylcholine receptors in schizophrenic smokers could induce a more intense cigarette smoking. Nevertheless, the metabolic deficit in brain neurons associated to schizophrenia (insufficient expression and/ or low transport/receptors efficacy) results in a higher smoking behavior; this suggests that even when the nicotine exposure augments, the need for smoking does not decrease (McKee et al. 2009, Mexal et al. 2010). The number of alpha-7 neuronal nicotine receptor in the brain of schizophrenic smokers (post mortem analysis) is low; nevertheless, when comparing schizophrenic smokers versus schizophrenic non-smokers, an increase of alpha-7 neuronal nicotine receptor is observed among the smokers, suggesting that smoking induces genetic changes (Mexal et al. 2010). "
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    ABSTRACT: Objective: tobacco smoking is the most commonly substance abused in psychiatric patients; among them, patients with schizophrenia are the highest abusers. Smoking is related to a decrease in the quality life and life expectancy, as well as interacting with psychotropic drugs. In Mexico, there is not basic descriptive knowledge about the main variables related to cigarette smoking in psychiatric population. The aim of this study was to know the relation among variables (beginning and course of the disease, use of other drugs and times of hospitalization among others) and cigarette smoking in a Mexican population of hospitalized schizophrenic patients. Method: The relation between the main variables and smoking were evaluated in a Mexican population of schizophrenic patients while hospitalized. A casuistic sampling was performed in 96 patients diagnosed with schizophrenia and they were divided into three groups: 1) non-smokers, 2) ex-smokers and 3) smokers; according to their score on the Fagerström Test for Nicotine Dependence. Results: The results showed that hospitalized schizophrenic patients smoke 2.7 times more than the general population. Most of these patients showed moderate to high dependence of nicotine, as well as a higher risk for other drugs abuse (marihuana mainly). Most patients started smoking before the first positive symptoms of schizophrenia appeared, and their symptoms started at an earlier age than in patients without a smoking background. Conclusions: Similar studies will allow deepening into specific aspects that modify and or improve the prescribed treatments for each psychiatric patient in hospital settings.
    Clinical Neuropsychiatry 01/2015; 12(3):51-56.
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    • "Apart from mecamylamine (Marx et al., 2000; McKee et al., 2009; Rose et al., 2001, 2003), these considered the effects of bupropion, a dopamine re-uptake inhibitor (Cousins et al., 2001; Hatsukami et al., 2004; Hussain et al., 2010) and amphetamine, a dopamine re-uptake inhibitor (Cousins et al., 2001). Acute administration of mecamylamine led to an increase in smoking intensity, both in terms of CPD and puff volume (Marx et al., 2000; McKee et al., 2009; Rose et al., 2001, 2003), whereas chronic mecamylamine administration leads to decreased number of cigarettes smoked daily and expired air carbon monoxide , presumably through an extinction mechanism (Rose et al., 1998). Bupropion, a smoking cessation drug, was administered to smokers not motivated to quit smoking. "
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    ABSTRACT: The extent of compensation when switching to lower yield cigarettes is important for assessing risk of reduced yield products. Both completeness of and reasons for compensation are judged differently in the scientific and health community. We quantified compensation in a meta-analysis of suitable cross-sectional and brand-switching studies. For each dataset, we derived a compensation index (CI), 1 indicating complete and 0 no compensation. Meta-analyses provided overall estimates. We also reviewed evidence on compensation for nicotine and other factors. The unweighted mean CI (95% confidence interval) was 0.628 (0.513-0.742) from 38 estimates from 26 cross-sectional studies, and 0.723 (0.651-0.796) from 23 estimates from 19 brand-switching studies. Inverse-variance weighted estimates were 0.781 (0.720-0.842) and 0.744 (0.682-0.806). Brand-switching data indicate smokers compensate more completely over a narrower yield range. Smokers predominantly compensate by changing puffing volume, and little by changing cigarette consumption. The findings support compensation for nicotine, but other factors may also be relevant. Further investigation is needed using larger studies and different approaches to elucidate their role. We conclude that smokers switching to lower-yield cigarettes only partially compensate. Pharmacological nicotine effects are important, but other factors, including cigarette draw resistance, sensory effects of nicotine and conditioned stimuli may also contribute.
    Regulatory Toxicology and Pharmacology 09/2014; 70(3). DOI:10.1016/j.yrtph.2014.09.008 · 2.03 Impact Factor
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