Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography

Hirvonen, Jussi; Zanotti‐Fregonara, Paolo; Gorelick, David A.; Lyoo, Chul Hyoung; Rallis-Frutos, Denise; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Volkow, Nora D.; Huestis, Marilyn A.; Innis, Robert B.

doi:10.1016/j.biopsych.2018.07.009

Cited by 27 publications

(22 citation statements)

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“…The current study did not find any sex‐related effects in either forced choice or the cue‐reactivity procedure. While previous research has shown a decrease in CB1R expression in male smokers that study did not compare males to female smokers (Hirvonen et al., 2018). At this point, there are limited studies investigating sex differences in the context of the CB1 system and nicotine dependence.…”

Section: Discussionmentioning

confidence: 86%

The CB1R rs2023239 receptor gene variant significantly affects the reinforcing effects of nicotine, but not cue reactivity, in human smokers

et al. 2020

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Introduction The cannabinoid CB1 receptor (CB1R) has been shown in preclinical studies to be involved in nicotine reinforcement and relapse‐like behavior. The common single nucleotide polymorphism (SNP) rs2023239 may code for an alternative CB1R protein, alter CB1R expression, and be involved in nicotine dependence. To date, no study has explored the relationship between this SNP in CB1R and specific phenotypes of nicotine dependence. Methods The current study investigated the influence of CB1R rs2023239 in nicotine reinforcement and craving in regular cigarette smokers. Current smokers (n = 104, cigarettes per day ≥ 10) were genetically grouped (C allele group vs. No C allele group) and underwent laboratory measures of nicotine reinforcement and smoking cue‐elicited craving. Nicotine reinforcement was assessed using a forced choice paradigm, while a cue‐reactivity procedure measured cue‐elicited craving. Results These results show that smokers with the C allele variant (CC + CT genotypes) experienced a lower nicotine reinforcement effect compared to those without the C allele (TT genotype). These results were similar in both our subjective and behavioral reinforcement measures, though the subjective effects did not withstand controlling for race. There was no difference between genotype groups with respect to cue‐elicited craving, suggesting a lack of influence in cue reactivity. Conclusion Taken together, these results suggest that the variation in the CB1R (i.e., rs2023239 SNP) may play a larger role in nicotine reinforcement compared to cue reactivity. This work provides impetus to further understand the physiological mechanisms that explain how CB1Rs influence nicotine dependence phenotypes.

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Section: Discussionmentioning

confidence: 86%

The CB1R rs2023239 receptor gene variant significantly affects the reinforcing effects of nicotine, but not cue reactivity, in human smokers

et al. 2020

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“…Tobacco use represents another potential confound, as subjects with psychiatric disorders tended to smoke at much higher rates than controls across studies (Supplemental Tables 1 and 2). A published abstract directly comparing CB 1 availability in smokers and non-smokers using [ 18 F]FMPEP-d 2 found that smokers had significantly lower CB 1 availability throughout the brain [107]. However, this contrasts with supplementary analyses performed in several published studies, which found that smoking status was not associated with CB 1 availability in individuals with comorbid psychopathology [39,41,52,53,64,74].…”

Section: Discussionmentioning

confidence: 96%

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

et al. 2018

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Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB). Cannabis users consistently demonstrated decreased CB binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB binding and others demonstrating decreased CB binding. Evidence of aberrant CB binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.

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“…A sparse to a very low density of receptors was observed in regions such as the hypothalamus, basal amygdala, central gray, thalamus, and brainstem (Herkenham et al, 1990). In a wide range of preclinical and clinical positron emission tomography (PET) studies, altered availability of CB1 receptor has been shown in the context of psychiatric diseases, such as addictive disorders (Gérard et al, 2010;Hirvonen et al, 2012Hirvonen et al, , 2013Hirvonen et al, , 2018Neumeister et al, 2012;Ceccarini et al, 2013bCeccarini et al, , 2014Ceccarini et al, , 2015D'Souza et al, 2016), schizophrenia (Wong et al, 2010;Ceccarini et al, 2013a;Verdurand et al, 2014;Ranganathan et al, 2016), post-traumatic stress disorder (Neumeister et al, 2013;Pietrzak et al, 2014) and eating disorders (Addy et al, 2008;Gérard et al, 2011;Casteels et al, 2014;Ly et al, 2015;Ceccarini et al, 2016;Lahesmaa et al, 2018), furthermore in neurological diseases, such as Parkinson's disease (Casteels et al, 2010b,d;Van Laere et al, 2012;Ceccarini et al, 2019b), Huntington's disease (Casteels et al, 2010c(Casteels et al, , 2011Ooms et al, 2014;Ceccarini et al, 2019a) and epilepsy (Goffin et al, 2008(Goffin et al, , 2011Cleeren et al, 2018). A better understanding of the endocannabinoid system with its receptors will help to refine diagnostic and evidence-based therapeutic strategies for the treatment of associated disorders.…”

Section: Introductionmentioning

confidence: 99%

Quantification of the Cannabinoid Type 1 Receptor Availability in the Mouse Brain

et al. 2020

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Introduction: The endocannabinoid system is involved in several diseases such as addictive disorders, schizophrenia, post-traumatic stress disorder, and eating disorders. As often mice are used as the preferred animal model in translational research, in particular when using genetically modified mice, this study aimed to provide a systematic analysis of in vivo cannabinoid type 1 (CB1) receptor ligand-binding capacity using positron emission tomography (PET) using the ligand [18F]MK-9470. We then compared the PET results with literature data from immunohistochemistry (IHC) to review the consistency between ex vivo protein expression and in vivo ligand binding.Methods: Six male C57BL/6J (6–9 weeks) mice were examined with the CB1 receptor ligand [18F]MK-9470 and small animal PET. Different brain regions were evaluated using the parameter %ID/ml. The PET results of the [18F]MK-9470 accumulation in the mouse brain were compared with immunohistochemical literature data.Results: The ligand [18F]MK-9470 was taken up into the mouse brain within 5 min after injection and exhibited slow kinetics. It accumulated highly in most parts of the brain. PET and IHC classifications were consistent for most parts of the telencephalon, while brain regions of the diencephalon, mesencephalon, and rhombencephalon were rated higher with PET than IHC.Conclusions: This preclinical [18F]MK-9470 study demonstrated the radioligand’s applicability for imaging the region-specific CB1 receptor availability in the healthy adult mouse brain and thus offers the potential to study CB1 receptor availability in pathological conditions.

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Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography

Abstract: Tobacco-smoking healthy men have a widespread reduction of CB receptor density in brain. Reduction of CB receptors appears to be a common feature of substance use disorders. Future clinical studies on the CB receptor should control for tobacco smoking.

Cited by 27 publications

References 30 publications

The CB1R rs2023239 receptor gene variant significantly affects the reinforcing effects of nicotine, but not cue reactivity, in human smokers

The CB1R rs2023239 receptor gene variant significantly affects the reinforcing effects of nicotine, but not cue reactivity, in human smokers

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

Quantification of the Cannabinoid Type 1 Receptor Availability in the Mouse Brain

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