Differences in mechanisms underlying reinstatement of cigarette smoke extract- and nicotine-seeking behavior in rats

Cross, Sarah J.; Reynaga, Daisy D.; Cano, Michelle; Belluzzi, James D.; Zaveri, Nurulain T.; Leslie, Frances M.

doi:10.1016/j.neuropharm.2019.107846

Cited by 12 publications

(13 citation statements)

References 46 publications

(93 reference statements)

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“…However, as compared to the addition of CSE into NS, the MAOA inhibition of non-nicotine constituents might be an important factor for the enhancement on nicotine, which would lead to stronger DA release and reinforcement properties. This is consistent with previous studies using the MAOA inhibitor (Guillem et al, 2005;Lotfipour et al, 2011;Smith et al, 2015Smith et al, , 2016 or CSE of normal nicotine content cigarettes (Costello et al, 2014;Hall et al, 2014;Gellner et al, 2016;Cross et al, 2020), but it is worth highlighting that this study complemented the effects of the mixture of non-nicotine constituents.…”

Section: Discussionsupporting

confidence: 92%

Non-nicotine constituents in cigarette smoke extract enhance nicotine addiction through monoamine oxidase A inhibition

et al. 2022

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Tobacco addiction has been largely attributed to nicotine, a component in tobacco leaves and smoke. However, extensive evidence suggests that some non-nicotine components of smoke should not be overlooked when considering tobacco dependence. Yet, their individual effect and synergistic effect on nicotine reinforcement remain poorly understood. The study herein focused on the role of non-nicotine constituents in promoting the effects of nicotine and their independent reinforcing effects. Denicotinized cigarettes were prepared by chemical extracting of cut tobacco, and the cigarette smoke extracts (CSE, used as a proxy for non-nicotine ingredients) were obtained by machine-smoking the cigarettes and DMSO extraction. The compositions of harmful components, nicotine, and other minor alkaloids in both cut tobacco and the CSE of experimental denicotinized cigarettes were examined by GC-MS, and compared with 3R4F reference cigarettes. individually and in synergy with nicotine were determined by conditioned place preference (CPP), dopamine (DA) level detection, the open field test (OFT), and the elevated plus maze (EPM). Finally, the potential enhancement mechanism of non-nicotinic constituents was investigated by nicotine metabolism and monoamine oxidase A (MAOA) activity inhibition in the striatum of mice and human recombinant MAOA. Thenicotine content in smoke from the experimental denicotinized cigarettes (under ISO machine-smoking conditions) was reduced by 95.1% and retained most minor alkaloids, relative to the 3R4F reference cigarettes. It was found that non-nicotine constituents increased acute locomotor activities. This was especially pronounced for DA levels in NAc and CPP scores, decreased the time in center zone. There were no differences in these metrics with DNC group when compared to the NS group. Non-nicotine constituents alone did not show reinforcing effects in CPP or striatum DA levels in mice. However, in the presence of nicotine, non-nicotine constituents further increased the reinforcing effects. Furthermore, non-nicotine constituents may enhance nicotine’s reinforcing effects by inhibiting striatum MAOA activity rather than affecting nicotine metabolism or total striatum DA content in mice. These findings expand our knowledge of the effect on smoking reinforcement of non-nicotine constituents found in tobacco products.

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Section: Discussionsupporting

confidence: 92%

Non-nicotine constituents in cigarette smoke extract enhance nicotine addiction through monoamine oxidase A inhibition

et al. 2022

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“…Responses on the non-reinforced (Non-Reinf) lever were recorded but had no consequences. Procedures modeled previous work ( 54 , 55 ).…”

Section: Methodsmentioning

confidence: 99%

“…Nicotine-prime injections contained 0.15 mg/kg nicotine and was administered intraperitoneally immediately before the reinstatement test. The nicotine-prime dose was chosen based on previous work (26,54). Between reinstatement tests, animals were returned to extinction condition for a minimum of two days, or until extinction criteria were 10.3389/fpsyt.2022.1064211 met.…”

Section: Cue and Nicotine-induced Reinstatementmentioning

confidence: 99%

Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human CHRNA6 3′-UTR polymorphism (rs2304297)

Carreño

Lotfipour

2023

Front. Psychiatry

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RationaleLarge-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the CHRNA6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6GG (risk) vs. α6CC (non-risk) allele carriers, without having baseline effects on natural rewards.MethodsUsing CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the CHRNA6 3′-UTRC123G polymorphism in Sprague-Dawley rats. Genetically modified adolescent male and female rats were food trained under a fixed-ratio (FR)1 schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (15 μg/kg/infusion) at FR5. Upon reaching stable responding, reinforced behavior was extinguished by removal of drug and cues. Reinstatement testing began for cue only, nicotine only, and nicotine + cue in a Latin Square Design. Animals were returned to extinction conditions for 2 days minimum between testing.ResultsFor natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6GG and α6CC) rats exhibited equivalent behaviors. Male α6GG rats show enhanced nicotine + cue-primed reinstatement when compared with male α6CC rats. This genotype effect on reinstatement was not seen in female rats.ConclusionOur findings support the in vivo functional role of the human CHRNA6 3′-UTR SNP genetic variant in sex-dependently enhancing nicotine seeking behavior in adolescent rats. Overall, the findings support clinical and preclinical data highlighting a role of α6 nAChRs mediating sex heterogeneity in substance use and related phenotypes.

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“…Indeed, some studies have shown that CSE produces a greater effect on nicotine self-administration than can be explained based solely on nicotine content, though none of these studies document in vivo MAO inhibition by CSE. Possibly the most compelling differences between self-administration of nicotine and CSE is reported by Costello et al (2014) , though this response was not replicated in subsequent studies ( Gellner et al, 2016a ; Cross et al, 2020 ; possibly because of small methodological details, Gellner et al, 2016a ). Costello et al (2014) reported that an aqueous extract of cigarette smoke increased self-administration of smaller doses of nicotine compared to nicotine alone, a shift of the nicotine dose-response curve consistent with the effects of MAO inhibition noted above; similar results were reported by Marusich et al (2019) .…”

Section: Monoamine Oxidase Inhibition By Cigarette Smoke and Nicotine...mentioning

confidence: 95%

Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation

et al. 2022

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Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation.

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Differences in mechanisms underlying reinstatement of cigarette smoke extract- and nicotine-seeking behavior in rats

Cited by 12 publications

References 46 publications

Non-nicotine constituents in cigarette smoke extract enhance nicotine addiction through monoamine oxidase A inhibition

Non-nicotine constituents in cigarette smoke extract enhance nicotine addiction through monoamine oxidase A inhibition

Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human CHRNA6 3′-UTR polymorphism (rs2304297)

Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation

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