β-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats

Harris, Andrew C.; Muelken, Peter; LeSage, Mark

doi:10.1016/j.pbb.2020.173041

Cited by 6 publications

(8 citation statements)

References 93 publications

(116 reference statements)

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“…In the present study, we further revealed the underlying molecular mechanism that harmine stimulates PDGF‐BB generation by promoting Id2 and AP‐1 expression during the process of osteoclastic differentiation. However, the administration of harmine may cause several adverse effects, such as neurotoxicity 21,22 . The lack of clinical data is also a challenge.…”

Section: Discussionmentioning

confidence: 99%

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Huang

Xia

et al. 2021

J Cellular Molecular Medi

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Osteoporosis is one of the most common metabolic bone diseases affecting millions of people. We previously found that harmine prevents bone loss in ovariectomized mice via increasing preosteoclast platelet‐derived growth factor‐BB (PDGF‐BB) production and type H vessel formation. However, the molecular mechanisms by which harmine promotes preosteoclast PDGF‐BB generation are still unclear. In this study, we revealed that inhibitor of DNA binding‐2 (Id2) and activator protein‐1 (AP‐1) were important factors implicated in harmine‐enhanced preosteoclast PDGF‐BB production. Exposure of RANKL‐induced Primary bone marrow macrophages (BMMs), isolated from tibiae and femora of mice, to harmine increased the protein levels of Id2 and AP‐1. Knockdown of Id2 by Id2‐siRNA reduced the number of preosteoclasts as well as secretion of PDGF‐BB in RANKL‐stimulated BMMs administrated with harmine. Inhibition of c‐Fos or c‐Jun (components of AP‐1) both reversed the stimulatory effect of harmine on preosteoclast PDGF‐BB production. Dual‐luciferase reporter assay analyses determined that PDGF‐BB was the direct target of AP‐1 which was up‐regulated by harmine treatment. In conclusion, our data demonstrated a novel mechanism involving in the production of PDGF‐BB increased by harmine, which may provide potential therapeutic targets for bone loss diseases.

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Section: Discussionmentioning

confidence: 99%

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Huang

Xia

et al. 2021

J Cellular Molecular Medi

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“…A variety of experimental evidence has been produced showing that MAO inhibition enhances behavioural responses to nicotine in rats ( Guillem et al, 2005 ; Villegier et al, 2006 , 2011 ; Smith et al, 2016b ; Harris et al, 2020 ) but the extension to human smoking behaviour is less clear. MAO activity is well known to be reduced in smokers ( Fowler et al, 1996a , b ) with the inhibition being believed to be irreversible ( Yu and Boulton, 1987 ).…”

Section: Monoamine Oxidase Inhibitorsmentioning

confidence: 99%

“…As well as the potential for effects on addiction, MAO enzymes are drug targets for a variety of neurological disorders including depression, mood, anxiety, attention deficit hyperactivity, Tourette’s syndrome, Parkinson’s disease and Alzheimer’s disease ( Sharama, 2016 ; Borroni et al, 2017 ). Of the known MAO inhibitors in tobacco smoke, high concentrations of harman and norharman can affect responses to nicotine ( Harris et al, 2020 ) and may act as antidepressants ( Farzin and Mansouri, 2006 ; Smith et al, 2013 ) in animals. However, when used in amounts relevant to smokers, they were not seen to affect rat self-administration of nicotine ( Smith et al, 2015 ) and no pharmacological effects have been reported from the known tobacco MAO inhibitors at physiologically relevant concentrations.…”

Section: Monoamine Oxidase Inhibitorsmentioning

confidence: 99%

“…A strong theme coming through the literature is that components in tobacco smoke other than nicotine, possibly monoamine oxidase (MAO) inhibitors, may enhance tobacco dependence, or may have positive effects on mood ( Fowler et al, 2003 ; Rose, 2006 ; Hogg, 2016 ; Harris et al, 2020 ). Thus, apart from the effects of nicotine, the observed difficulty that people have in stopping smoking could be influenced by other chemical components of the tobacco smoke.…”

Section: Introductionmentioning

confidence: 99%

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Biologically Active Compounds Present in Tobacco Smoke: Potential Interactions Between Smoking and Mental Health

et al. 2022

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Tobacco dependence remains one of the major preventable causes of premature morbidity and mortality worldwide. There are well over 8,000 compounds present in tobacco and tobacco smoke, but we do not know what effect, if any, many of them have on smokers. Major interest has been on nicotine, as well as on toxic and carcinogenic effects and several major and minor components of tobacco smoke responsible for the negative health effects of smoking have been elucidated. Smokers themselves report a variety of positive effects from smoking, including effects on depression, anxiety and mental acuity. Smoking has also been shown to have protective effects in Parkinson’s Disease. Are the subjective reports of a positive effect of smoking due to nicotine, of some other components of tobacco smoke, or are they a manifestation of the relief from nicotine withdrawal symptoms that smoking provides? This mini-review summarises what is currently known about the components of tobacco smoke with potential to have positive effects on smokers.

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“…self-administration) and in humans ( Wise, 1996 ; Negus and Miller, 2014 ). Supporting the utility and sensitivity of ICSS for tobacco constituent evaluation, we have used this methodology to evaluate the relative abuse liability of smokeless tobacco extracts ( Harris et al, 2012 , 2015b ), EC liquids ( LeSage et al, 2016 ; Harris et al, 2017 , 2018b ), and isolated non-nicotine constituents [i.e., β-carbolines, minor alkaloids, and the EC solvent propylene glycol (PG) ( Harris et al, 2015a , 2018a , 2020 )]. However, effects of CS or EC aerosol extracts on ICSS have not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Cigarette Smoke Extract, but Not Electronic Cigarette Aerosol Extract, Inhibits Monoamine Oxidase in vitro and Produces Greater Acute Aversive/Anhedonic Effects Than Nicotine Alone on Intracranial Self-Stimulation in Rats

et al. 2022

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Conventional tobacco cigarettes appear to have greater abuse liability than non-combusted products such as electronic cigarettes (ECs) and nicotine replacement therapy (NRT). This may be due to the higher levels of behaviorally active non-nicotine constituents [e.g., monoamine oxidase (MAO) inhibitors such as β-carbolines] in cigarette smoke (CS) compared to non-combusted products. To evaluate this hypothesis, the current studies compared the relative abuse liability of CS and EC aerosol extracts containing nicotine and a range of non-nicotine constituents to that of nicotine alone (NRT analog) using intracranial self-stimulation (ICSS) in rats. Effects of formulations on brain MAO activity in vitro and ex vivo were also studied to evaluate the potential role of MAO inhibition in the ICSS study. CS extract contained higher levels of several behaviorally active non-nicotine constituents (e.g., the β-carbolines norharmane and harmane) than EC extract. Nicotine alone reduced ICSS thresholds at a moderate nicotine dose, suggesting a reinforcement-enhancing effect that may promote abuse liability, and elevated ICSS thresholds at a high nicotine dose, suggesting an aversive/anhedonic effect that may limit abuse liability. CS extract elevated ICSS thresholds to a greater degree than nicotine alone at high nicotine doses. Effects of EC extract on ICSS did not differ from those of nicotine alone. Finally, CS extract significantly inhibited MAO-A and MAO-B activity in vitro, whereas EC extract and nicotine alone did not. None of the formulations inhibited MAO measured ex vivo. These findings indicate greater acute aversive/anhedonic effects for CS extract compared to nicotine alone, suggesting lower abuse liability. Although confirmation of our findings using other dosing regimens, preclinical addiction models, and tobacco product extracts is needed, these findings suggest that the centrally-mediated effects of MAO inhibitors and other non-nicotine constituents may not account for the greater abuse liability of cigarettes compared to non-combusted products. Nonetheless, identifying the specific constituent(s) mediating the effects of CS extracts in this study could help clarify mechanisms mediating tobacco addiction and inform FDA product standards.

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β-Carbolines found in cigarette smoke elevate intracranial self-stimulation thresholds in rats

Cited by 6 publications

References 93 publications

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Biologically Active Compounds Present in Tobacco Smoke: Potential Interactions Between Smoking and Mental Health

Cigarette Smoke Extract, but Not Electronic Cigarette Aerosol Extract, Inhibits Monoamine Oxidase in vitro and Produces Greater Acute Aversive/Anhedonic Effects Than Nicotine Alone on Intracranial Self-Stimulation in Rats

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