David J.K. Balfour

Evidence that Tobacco Smoking Increases the Density of (−)‐[3H]Nicotine Binding Sites in Human Brain

Abstract: In a postmortem study of nicotinic receptors in human brain, cigarette smoking was found to be associated with increased (−)‐[3H]nicotine binding to membranes prepared from gyrus rectus (Brodmann area 11) (p < 0.001), hippocampal neocortex (Brodmann area 27), cerebellar cortex (p < 0.01), hippocampal formation (Ammons horn + subiculum), and the median raphe nuclei of the midbrain (p < 0.05) but not the medulla oblongata. Analysis of the binding data suggested that the increased binding reflected an increase in the density of the receptors rather than a change in their affinity for (−)‐nicotine. The effects of smoking were not influenced significantly by either the sex or age of the subject. It is concluded that smoking evokes an increase in high‐affinity nicotine binding similar to that observed previously in animals treated chronically with nicotine and that the effect of smoking on these sites is probably caused by the nicotine present in the tobacco smoke.

Guidelines on nicotine dose selection for in vivo research

RationaleThis review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.ObjectivesThis review capitalizes on the authors’ collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.ResultsSeven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.ConclusionsThe selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose–response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity

1 The effects of acute and subchronic nicotine and (+)‐amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely‐moving rats by use of in vivo microdialysis. 2 In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg−1) caused a dose‐dependent increase (P < 0.01) in spontaneous activity and evoked significant increases (P < 0.05) in the extracellular levels of DOPAC and HVA. 3 Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg−1) resulted in increased basal levels of dopamine (P < 0.01) and decreased basal levels of DOPAC (P < 0.05) in the NAc dialysates. 4 Pretreatment with nicotine (0.1 or 0.4 mg kg−1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P < 0.05). 5 If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg−1) resulted in significant increases (P < 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P < 0.05) the dopamine response to a challenge dose of nicotine. 6 Subcutaneous injections of (+)‐amphetamine (0.2 or 0.5 mg kg−1) evoked dose‐dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug. 7 The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.

The neurobiology of tobacco dependence: A preclinical perspective on the role of the dopamine projections to the nucleus

It is now widely accepted that nicotine is the primary addictive component of tobacco smoke and that a majority of habitual smokers find it difficult to quit smoking because of their dependence upon this component of the smoke. However, although nicotine replacement therapy elicits a clinically valuable and significant improvement in the number of quit attempts that are ultimately successful, its efficacy remains disappointingly low. This review considers some of the reasons for this problem. It focuses on the hypothesis that stimulation of the dopamine (DA) projections to the medial shell and the core of the nucleus accumbens play complementary roles in the development of nicotine dependence. The hypothesis proposes that increased extra-synaptic DA in the medial shell of the accumbens confers hedonic properties on behaviors, such as smoking, which deliver nicotine, and thereby increase the probability that the response is learned. It also summarizes the evidence that the primary role of the increased DA overflow, observed in the accumbal core of nicotine-pretreated individuals, challenged with nicotine, is the attribution of incentive salience to cues associated with delivery of the drug and the transition to Pavlovian responding to these conditioned stimuli. The review argues that sensitization of the DA projections to the accumbal core, and the behaviors that depend upon this process, play a pivotal role in the maintenance of the tobacco smoking habit and that it is this component of the dependence that is inadequately addressed by nicotine replacement therapy.

The effects of nicotine on brain neurotransmitter systems

In spite of the fact that the effects of nicotine in the central nervous system have been the subject of many experimental studies, the precise mechanisms involved in the behavioral and centrally-mediated physiological responses to the drug are by no means fully understood. Clearly the interaction of nicotine with post-synaptic nicotinic receptors must play an important part in the production of its effects. However, it is increasingly obvious that many of its central effects are mediated through or are dependent upon changes in the secretion of a number of different neurotransmitters. The purpose of the present review is to summarize the available data on the effects of nicotine on brain neurotransmitter release and turnover and to attempt to examine the extent to which the changes observed can be related to the pharmacological properties of the drug. The vast majority of the work on this topic has been concerned with the effects of the drug on acetylcholine, the catecholamines and 5-hydroxytryptamine and this is reflected by the emphasis put on these transmitter systems in this review.

Pharmacology of nicotine and its therapeutic use in smoking cessation and neurodegenerative disorders

During the last decade, nicotine has been used increasingly as an aid to smoking cessation and has been found to be a safe and efficacious treatment for the symptoms of nicotine withdrawal. This period has also seen significant advances in our understanding of the mechanisms underlying the psychopharmacological responses to nicotine, including, particularly, those that have been implicated in nicotine addiction. This paper reviews this decade of progress in the specific context of the therapeutic application of nicotine to the treatment of smoking cessation. Other putative future applications, particularly in the treatment of neurodegenerative disorders, are also reviewed.

The Effects of Nicotine on Neural Pathways Implicated in Depression: A Factor in Nicotine Addiction?

The prevalence of tobacco smoking varies considerably between different groups within the community, tobacco smoking being particularly prevalent in patients with depressive disorder. This review will focus on results, derived from animal studies, which suggest that, in addition to its primary reinforcing properties, nicotine also exerts effects in stressful environments, which may account for its enhanced addictive potential in depressed patients. It focuses on the evidence that depression sensitises patients to the adverse effects of stressful stimuli, and that this can be relieved by drugs that stimulate dopamine release in the forebrain. This mechanism, it is proposed, contributes to the increased craving to smoke in abstinent smokers exposed to such stimuli, because they become conditioned to use this property of nicotine to produce rapid alleviation of the adverse effects of the stress. The review also explores the possibility that chronic exposure to nicotine elicits changes in 5-HT formation and release in the hippocampus which are depressogenic. It is postulated that smokers are protected from the consequences of these changes, while they continue to smoke, by the antidepressant properties of nicotine. However, they contribute to the symptoms of depression experienced by many smokers when they first quit the habit.

Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine

1 The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg−1 day−1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg−1 day−1 for 5 days) of the drug. 2 The extracellular dopamine concentration in the NAc was significantly increased (P<0.05) following a challenge dose of nicotine (0.4 mg kg−1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3 The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P<0.01) by the prior administration of mecamylamine (2.0 mg kg−1, s.c.) but not by hexamethonium (2.0 mg kg−1, s.c). 4 The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg−1 day−1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine‐pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg−1 day−1 was also significantly (P<0.05) higher than that observed in the rats treated acutely with nicotine. 5 Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine (0.4 mg kg−1, s.c), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg−1 day−1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion. 6 The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.

Sensitization of the mesoaccumbens dopamine response to nicotine.

This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.

Estimating the Harms of Nicotine-Containing Products Using the MCDA Approach

Background: An international expert panel convened by the Independent Scientific Committee on Drugs developed a multi-criteria decision analysis model of the relative importance of different types of harm related to the use of nicotine-containing products. Method: The group defined 12 products and 14 harm criteria. Seven criteria represented harms to the user, and the other seven indicated harms to others. The group scored all the products on each criterion for their average harm worldwide using a scale with 100 defined as the most harmful product on a given criterion, and a score of zero defined as no harm. The group also assessed relative weights for all the criteria to indicate their relative importance. Findings: Weighted averages of the scores provided a single, overall score for each product. Cigarettes (overall weighted score of 100) emerged as the most harmful product, with small cigars in second place (overall weighted score of 64). After a substantial gap to the third-place product, pipes (scoring 21), all remaining products scored 15 points or less. Interpretation: Cigarettes are the nicotine product causing by far the most harm to users and others in the world today. Attempts to switch to non-combusted sources of nicotine should be encouraged as the harms from these products are much lower.