Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing ¹¹ C-nicotine

Abstract

Tobacco smoking is a chronic, relapsing disorder that constitutes one of the primary preventable causes of death in developed countries. Two of the popular hypotheses to explain the development and maintenance of strong nicotine dependence in cigarette smokers posit (i) a rapid brain nicotine accumulation during cigarette smoking and/or (ii) puff-associated spikes in brain nicotine concentration. To address these hypotheses, we investigated the dynamics of nicotine accumulation in the smoker's brain during actual cigarette smoking using PET with 3-s temporal resolution and 11 C-nicotine loaded into cigarettes. The results of the study, performed in 13 dependent smokers (DS) and 10 nondependent smokers (NDS), suggest that puff-associated spikes in the brain nicotine concentration do not occur during habitual cigarette smoking. Despite the presence of a puff-associated oscillation in the rate of nicotine accumulation, brain nicotine concentration gradually increases during cigarette smoking. The results further suggest that DS have a slower process of brain nicotine accumulation than NDS because they have slower nicotine washout from the lungs and that DS have a tendency to compensate for their slower rate of brain nicotine accumulation compared with NDS by inhaling a larger volume of smoke. For these reasons, smokers' dependence on cigarette smoking, or the resistance of NDS to becoming dependent, cannot be explained solely by a faster brain nicotine accumulation.cigarette smoking | nicotine dependence | tobacco | addiction | lung T obacco smoking is a chronic, relapsing disorder that constitutes one of the leading preventable causes of death in developed countries. Smoking leads to the development of a strong dependency, and the efficacy of smoking cessation treatments is very low (1, 2). One vital issue in developing improved strategies to assist with smoking cessation is to understand the mechanisms that underlie nicotine dependence in cigarette smokers.Nicotine is the one of the ingredients of cigarette smoke that is most closely linked to tobacco dependence (3). This alkaloid interacts with both central and peripheral neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs belong to the superfamily of ligand-gated ion channels and are composed of five protein subunits. To date, nine α-subunits (α2-α10) and three β-subunits (β2-β4) have been identified in the nervous system (reviewed in ref. 4). Most of these subunits may form a heteromeric complex, but others (α7-α9) appear to function predominantly as a homomeric group. High diversity in neuronal nAChR subunits can potentially lead to an enormous variety of these receptors in the nervous system.After acute administration of nicotinic agonists, the nAChR channel complex is activated and becomes permeable for sodium, potassium, and calcium ions. Nonetheless, prolonged exposure of nAChRs to nicotinic agonists leads to desensitization of the receptors. The desensitization diminishes channel permeability and the capability of the receptors to be activate...

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

“…For patients who smoke, which is often the case in, for example, schizophrenia, the possible interaction between the PAM and systemic nicotine from cigarettes could theoretically cause adverse effects. It has been estimated that nicotine concentrations reach 40 nM upon a single cigarette puff and~360 nM upon smoking one cigarette [103], which are concentrations potentiated by 10 lM NS9283 in vitro [56]. An obvious adverse effect to consider here, in addition to typical cardiovascular and gastrointestinal adverse effects seen with cholinergic agents, is induction of convulsions or seizures [104].…”

Nicotine vaccines to treat tobacco dependence

“…The accumulation of the nicotine in the brain starts approximately 7 sec after inhalation. 22 Nicotine binds to nicotinic acetylcholine receptors in brain that leads to a release of adrenaline and dopamine. This improves mood and reinforces the behavior.…”

Neuroimaging - Clinical Applications

“…The alkaloid is readily absorbed by the lung or intestinal tissue, distributed by the blood and transported across the blood-brain barrier (Allen & Lockman, 2003;Oldendorf et al, 1979). When inhaled it takes about seven seconds for nicotine to reach the brain (Rose et al, 2010), where it binds with high affinity to the heteromeric α4β2 and the homomeric α7 nAChRs, the two most abundant nAChR populations (Changeux, 2010). In the brain, nAChRs are involved in attention and cognition, locomotion, vigilance control, and rewarding mechanisms (Changeux, 2010;Graef et al, 2011), and they are suggested to play a major role in brain development Ross et al, 2010).…”