President, SRNT

The Board of Directors of SRNT met in November 1996 and discussed a wide range of issues of interest to Society members. I would like to bring the members up-to-date about the state of the and the Society's plans for the future.

Unidad de Tabaquismo, Hospital Princesa

Georgetown University

If you're reading this you probably have at least a passing interest in nicotinic receptors (and if you don't, you probably won't want to read much farther). Actually, apparent interest in these receptors has grown remarkably in the last 10 years, at least judging from the number of papers presented at the Society for Neuroscience Meetings. In 1986, the key word index of the Meeting's abstracts listed approximately 60 entries for nicotinic receptors or closely related topics; in 1996, that number had grown to more than 180. In fact, no less than eight sessions at the latest Meeting were devoted to studies of these receptors. This analysis, although simplistic, is consistent with the results of Ian Stolerman's MEDLINE search, which, as he reported in this column last year,1 traced the sharp rise in publications on nicotinic receptors to about 1983. Most of this attention during the last decade has been directed at the neuronal nicotinic receptors.

Why this surge of interest in neuronal nicotinic receptors, beginning in the early 1980's? A better question might be: Why the delay in interest in these receptors? The nicotinic receptor certainly didn't represent a new topic—just the opposite, in fact. It was J.N. Langley's studies of the actions of nicotine and curare, along with Paul Ehrlich's studies of antibodies, that formed the basis for the receptor concept in the early years of this century.2,3 Moreover, the muscle-type nicotinic receptor has been one of the most thoroughly studied proteins in biology for more than 40 years.4,5 Furthermore, if you buy into the receptor concept, it would be difficult to deny the essential involvement of brain nicotinic receptors in the effects of nicotine, including its addictive properties; and from there it is just a short step to the broader question of the normal physiological role of these receptors in the brain. In fact, it would not be unreasonable to assume that these receptors play an important role in the CNS. After all, the entire autonomic nervous system (both branches) depends on neuronal nicotinic receptors in ganglia for the transmission of signals to nearly all organs.

So, why the delay? And what happened in the 1980's that sparked wider interest in neuronal nicotinic receptors? Possibly, the answers to both of these questions are linked to the introduction in the early 1980's of relatively simple methods to measure brain nicotinic receptor binding sites that have high affinity for nicotinic cholinergic agonists. (Methods for studying brain nicotinic binding sites with high affinity for the snake toxin a-bungarotoxin but relatively low affinity for nicotinic agonists had been introduced about 5 years earlier.6,7) Thus, by the mid-1980's, the brain binding site with high affinity for nicotinic agonists had been well characterized pharmacologically 8-10 and its brain region distribution mapped by receptor autoradiography.11,12 Moreover, lesion studies indicated that this receptor was located on dopamine neurons and axon terminals,13,14 which fits well with previous studies showing that nicotine could release dopamine from brain tissues.15-17 This, in turn, was consistent with the idea that several drugs of abuse have in common the ability to augment dopamine-stimulated reward mechanisms in brain.18-20 In addition, during this time two different laboratories reported that chronic administration of nicotine to rats or mice increased the density of brain nicotinic receptor binding sites labeled by agonists.21-24 This quirky property of neuronal nicotinic receptors stimulated a lot of interest, since it suggested a concrete biological change that could conceivably be related to nicotine addiction.

During the last 10 years, molecular cloning studies25-29 and studies with antibodies30-32 have demonstrated that neuronal nicotinic receptors are comprised of a and b subunits, and that these neuronal subunits are related to but different from the subunits in muscle receptors. Most important, these studies have established the existence of multiple a and b neuronal nicotinic receptor subunits. Furthermore, different combinations of these a and b subunits can be expressed in frog oocytes to form defined receptor subtypes with distinct functional and pharmacological properties.33-35 As of the end of 1996, eight different a and three different b subunits have been cloned from vertebrate neuronal tissues. And this brings me to the purpose of this article, which the Editor said should be about "what's new."

By the early 1990's, the field of neuronal nicotinic receptors had a growing problem. Based on functional combinations of a and b subunits expressed in oocytes, there are a lot of potential nicotinic receptor subtypes; moreover, most tissues that have been examined express mRNA for two or more different a and b subunits. Consequently, there are few if any mammalian tissues in which to study a single receptor subtype in isolation. Receptors expressed in frog oocytes are excellent model systems for many kinds of studies, but the oocyte model has certain limitations. (For example, cellular and biochemical studies and binding site measurements in oocytes are usually difficult to carry out on a routine basis.) Tumor-derived clonal cell lines, such as PC12 and IMR32 cells, that express neuronal nicotinic receptors are also very useful;36 but it's not entirely clear which subtype(s) of receptor these cell lines express, except that they probably don't express the a4/b2 subtype, which is one of the main subtypes found in the mammalian brain. Thus, it is apparent that the development of genetically engineered mammalian cell lines that stably express one or another of these receptor subtypes, as defined by their subunit combination, would complement the other model systems and offer a renewable and consistent model for cellular, pharmacological, and genetic studies of neuronal nicotinic receptor subtypes.

The first of these stable cell lines, produced by Lindstrom and colleagues in 1991,37 provided a model system in which to study the a4/b2 receptor subtype, and within a few years studies with this cell line provided important insights into how nicotine can affect the metabolism of these receptors.38 In the last two years, two different cell lines engineered to stably express nicotinic receptors comprised of a7 subunits (without any b subunit partners) have provided new information about the properties of this receptor subtype, which has high affinity for a-bungarotoxin.39,40 And at the last meeting of the Society for Neuroscience, stable cell lines expressing no fewer than five different neuronal nicotinic receptor subunit combinations were presented by four different laboratories.41-44 These cell lines should become important resources for delineating and understanding the similarities and differences among this diverse family of ligand gated channels.

How useful these cell lines will be depends to some extent on what other tools can be applied to them. For example, measurements of a receptor's binding site can often rapidly provide important information about the pharmacology and regulation of that receptor. But until recently, only the a4/b2 and the a7 receptor subtypes could be measured by radioactive ligands. That is because the available radiolabeled nicotinic agonist ligands such as [3H]nicotinic and [3H]cytisine appear to have sufficiently high affinity to measure only the a4/b2 subtype reliably, while [3H]- or [125I]-labeled a-bungarotoxin labels only the a7 subtype. That changed with the introduction of [3H]epibatidine, an agonist with very high affinity for a4/b2 nicotinic receptors in brain,45 as well as for non-a4/b2 neuronal nicotinic receptors, such as those found in the adrenal gland45 and retina.46 [3H]epibatidine has already proven useful for measuring and characterizing several of the receptor subtypes expressed in stably transfected cell lines,41,42 most of which could not have been labeled by other agonist radioligands. Very recently, an [125I]iodinated analog of epibatidine, [125I]IPH, has been synthesized with specific radioactivities greater than 1500 Ci/mmol (compared to » 50 Ci/mmol for [3H]epibatidine).47 This new ligand has virtually all of the binding characteristics that make epibatidine so useful,48 and because of its high specific radioactivity, it is particularly useful for measuring nicotinic receptors in very small tissues (e.g. autonomic ganglia) and for receptor autoradiography, where the exposure times are one or two days rather than two to six months.

Brown University

Cue reactivity has gained increasing attention in smoking research.1,2 Cue reactivity is a global term used to describe the various cognitive, affective, and physiological reactions that smokers, as well as persons with other addictive disorders, exhibit in response to environmental and interoceptive substance use cues.2 Although the precise mechanism through which cue reactivity is conditional is unclear (e.g., conditioned withdrawal, motivational-appetitive systems; see Niaura et al.2), a number of recent findings suggests that cue reactivity is nonetheless important for furthering our understanding and treatment of addictive behaviors. First, the cue reactivity paradigm itself is useful for demarcating the cognitive, physiological, and affective mechanisms which regulate addictive behaviors. Second, reactivity to smoking cues may be an important marker for risk of treatment failure and relapse. Third and relatedly, cue reactivity has implications for the assessment and treatment of addictive behaviors. Our goal in this essay is to review and summarize current thinking on cue reactivity within each of these domains.

Manipulation effects. Smokers show heart rate and blood pressure reactivity, report greater urges to smoke, and report lower self efficacy in avoiding smoking in response to a wide variety of cues. These cues have included in vivo interpersonal interaction cues,3,4 standardized positive and negative affect scripts,5-8 cognitive stressors,9 in vivo visual and olfactory cues,4,10-12 and high risk for relapse settings.13

It is unclear which cue manipulation method most reliably produces reactivity, or whether certain cues are more likely to produce increased reactivity than others. Some studies suggest that both in vivo and standardized scripts produce relatively equivalent levels of reactivity14 and that scripted cues produce equivalent levels of reactivity despite variations in script content.15 We recently completed a study that compared four distinct classes of cue manipulation (e.g., in vivo, affectively-valenced scripts, idiographically or personally relevant cues, standard stressors) across a number of physiological and cognitive responses.16 We found that each these different exposure classes produced divergent levels of reactivity and furthermore, different standardized scripts, produced different levels or reactivity. Clearly, then, there may be wide variation in responses across different cue manipulations. Thus, at this point, different manipulations should not be treated as though they produce equivalent levels of reactivity.

Correspondence of indices. Generally speaking, associations between different physiological responses and cognitive variables are not common.15 Furthermore, at best, the same response variables are often only modestly correlated with one another across manipulations. These findings suggest that different individuals respond with greater reactivity to some manipulations compared to other manipulations. Thus, investigators of cue reactivity should not expect that increases in heart rate will necessarily correspond to increases in smoking urges, for example. A divergence across response variables poses some definitional and theoretical problems for understanding the underlying mechanisms that drive reactivity, although we have argued elsewhere that this divergence is more consistent with motivational-appetitive theories than other conditioning theories (see Niaura et al.,2 ); or as others have suggested, it may be that these divergent responses reflect unique cognitive processing of the cue information17 rather than a unitized motivational drive per se.

Moderators of reactivity. A number of individual difference variables have been studied as potential moderators of cue reactivity. First, even though gender differences are becoming increasingly important to study among smokers,18 information about gender differences in cue reactivity is lacking for smokers. We recently compared the cue reactivity of men and women smokers across a number of cue manipulations and found that in general, women showed greater reactivity to negatively valanced cues,3,16 which clearly underscores the importance of examining gender as a moderator of reactivity. Second, recent evidence has suggested that nicotine dependence and its interaction with levels of nicotine deprivation may be important moderators of cue reactivity as well.19 Third, the personal relevance of the cue manipulation my be an important moderator of cue reactivity. That is, personally relevant or idiographically designed manipulations should elicit greater reactivity compared to standardized manipulations due to the fact that the idiographic manipulations take into account individual differences in cue content which may be important for eliciting reactive.2 In a recent study, however, we failed to find superiority of idiographically designed cues over standard cues for eliciting reactivity.16

Summary of findings. There is evidence that increased cue reactivity predicts a decreased likelihood of successful cessation.3,10,12,13 We have found that relapsers react with higher heart rates in response to interpersonal interaction cues when a confederate smoked a cigarette, compared to long term abstainers and nonsmokers10—and more specifically, that at the moment a cigarette is lit by a confederate, relapsers evidence a steady deceleration in heart rate over time compared to abstainers.12 In accordance with Baker and colleagues’ suggestions, this difference may reflect differences in cognitive processing of cue stimuli.20 By extension, then, ex-smokers who eventually relapse may actively process cues, whereas successful abstainers may divert attention away from cues and focus on executing strategies to cope with the consequences of the cue.17

Summary of findings. Exposure-based treatments have shown promise in treating some addictive disorders.1 To date, no randomized controlled trials that test the efficacy of cue exposure treatment for smoking relapse prevention have been published which demonstrates the superiority of cue exposure treatment for smoking over current "gold standard" treatments.21-25 Although some of these studies were randomized trials, each of them suffered from limitations (e.g., lack of appropriate control groups, lack of internal validity checks). We recently completed a controlled, randomized trial that addressed each of these limitations, testing the effectiveness of cue exposure treatment as an adjunct relapse prevention strategy for cognitive-behavioral skills training in combination with use of Nicorette gum.26 Despite the relative rigor of this trial, however, we found no incremental effect of adding cue exposure treatment to an established cognitive behavioral treatment protocol that incorporated nicotine gum treatment. This treatment outcome study suggest that cue-exposure-based treatment may not be a useful or cost-effective addition to the best currently available cognitive behavioral plus nicotine gum treatments.

Clearly, cue reactivity among smokers is a valid and reliable phenomenon that has provided insight into possible mechanisms of action involved in regulating addictive behaviors, and may be an important marker for failure to quit. At present, the use of exposure-based treatments for nicotine dependence do not appear warranted. We recommend that future research address the following concerns: 1) Clarify the theoretical mechanisms driving cue reactivity. Impressive progress has been made in documenting the phenomenon of cue reactivity and demonstrating its importance to treatment outcome. It would now seem prudent to begin work to disentangle the mechanisms responsible for these effects. 2) Address the seeming differences in response parameters brought about by different manipulation types as well as further exploring this role of important individual difference moderators on reactivity. Other manipulation types, such as videotaped cues or pictorial stimuli, are relatively unexplored in the smoking cue reactivity literature, even though they have gained use in studies of reactivity in other addictive behaviors.27 3) Despite the disappointing treatment outcome results with exposure-based treatments for nicotine dependence, it still may be too early to dismiss it as a non-viable treatment option. For example, it may be that important individual difference variables (e.g., level of reactivity, personal relevance of cues) moderate the effect of cue exposure treatment on outcome; or that once the mechanisms which regulate reactivity are better understood, more effective treatments can be developed.

Oregon Research Institute

It is important to emphasize that there are interesting and important research questions associated with all policy approaches. Broad questions of interest include the consequences of particular policies on smoking behavior (policy as the independent variable), and analysis of factors or processes that contribute to or impede effective policy development (policy as the dependent measure). Federal (e.g., the National Cancer Institute), State (e.g., California with Proposition 99 funds), and foundation (e.g., Robert Wood Johnson) research sponsors are devoting increasing resources to policy research. Interested readers should consult papers by Ron Davis1 and a supplemental issue of Tobacco Control2 for detailed discussions of various policy intervention issues and strategies.

It is also possible to conduct experimental evaluations of ways of developing or strengthening policies. In collaboration with a Portland based Indian organization (the Northwest Portland Area Indian Health Board), we developed and evaluated a consultation intervention to enhance the tobacco use policies of the 39 recognized tribes in the Pacific Northwest. In a trial with tribes randomized to receive immediate or delayed consultation, we demonstrated the effectiveness of the intervention using standardized telephone interview to assess stringency of policies.3 We later delivered the intervention to the wait-list tribes and replicated the intervention effect.4

The second category of public health intervention research takes strategies that have been shown to be efficacious in clinical or field trials with self-selected, convenience samples and applies them to populations such that they attain greater penetration or impact.5,6 An essay by David Abrams in this column (SRNT Newsletter, Spring 1996) discussed the rationale for this approach. Communities, work-sites, and health care settings have been the major venues for this work. The common strand in these population-based studies is that all smokers in the particular setting are considered to be the targets of the intervention program although a representative cohort may be identified and measured for purposes of experimental evaluation. Quit rates in such studies are expected to be much lower than those attained in more intensive clinical interventions but the overall population impact on quitting is likely to be much higher.5,6

My colleagues at the Center for Health Research in Portland and at ORI have been engaged in this task for more than 10 years and have conducted both efficacy and effectiveness trials in managed care, fee-for-service, inpatient, outpatient, and dental settings. This work which has several unifying features has been summarized in a couple of recent publications.7,8 We strongly believe that for an intervention to be sustainable, it must be accepted and endorsed by the entire system, and that intervention tasks must be distributed in a way that minimizes the burden on the key clinician, usually the physician or dentist. A tracking system that provides feedback on the consistency with which smokers are identified and assisted is also seen to be critical for maintenance for any intervention program.

The basic procedural features of this approach are, first, to identify all smokers visiting the health care system though a program may choose to deliver counseling only to those displaying some degree of readiness to quit. Second, the lead clinician gives direct advice to smokers that quitting is the best thing they could do for their health. A 30-second message, couched to respect patients' right to make health decisions for themselves, is all that is asked of the lead clinician. Third, we make use of short videos developed for the particular patient population of interest.9 The videos help to gain patients' attention, standardize the motivational and skill building messages, and also lighten clinician burdens, since providers can be engaged in other activities while the patients watch the video. Fourth, a nurse (or similar allied health professional such as a dental hygienist or respiratory therapist) debriefs the video and provides brief counseling attempting to get patients who are considering quitting to set a quit date. Fifth, patients are given short written materials, sometimes tailored for the program and sometimes borrowed from materials provided by Federal or voluntary agencies. Finally, there are one or perhaps two follow-up telephone calls to provide additional support, accountability, and some problem-solving for smokers, especially those who have indicated they would set a quit date. We believe telephone counseling is an effective and feasible way to augment brief, office-based interventions.10

The program described here has been shown to be effective in outpatient, inpatient, and dental settings, the latter focusing on smokeless tobacco users. The approach is also entirely consistent with the recently published Agency for Health Care Policy and Research (AHCPR) guidelines for health care settings.11 We expect that these guidelines will be an important stimulus for the development and implementation of programs in health care settings such as the one described here. The model described here can also be seen as a first step in a stepped care approach.6 The approach could be augmented by nicotine replacement strategies or by emerging technologies such as computer-driven expert systems or touch screen interactive videos. Such additions would probably produce a more effective program, but there is always a tradeoff; additional complexity may detract from the consistency and feasibility of implementation.

Lynn Kozlowski, who has served ably as Chair of the Publications and Communications Council since 1995, asked to be relieved from his duties in November. At the semi-annual meeting of the SRNT Board on November 16, I was asked to replace him as Council Chair. The following is an update on progress and prospects:

The current literature on smoking is characterized by two rather different and somewhat noncommunicating schemes for assessing nicotine dependence, emerging from two historical traditions and differing along two major dimensions. Though not every study adheres slavishly to one school or the other, the two can be generally described as follows:

1. With the introduction of nicotine replacement and need to identify those who would profit from its use, it became clearer than ever before that some people found it much more difficult to quit than others. In 1978, Karl-Olov Fagerstrom published his somewhat misnamed Tolerance Questionnaire, perhaps (along with its offspring, the Fagerstrom Test for Nicotine Dependence) the most widely-used such scale for evaluating nicotine dependence.1,2 A feature of the scale is that degree of dependence is measured as a continuous variable, although a cutoff of 6 or 7 (on a scale of 0 to 11) is often used to differentiate highly dependent smokers from their less dependent counterparts. Another feature is that dependence is implicitly defined in reference to current smoking status. More precision can be achieved (e.g., as does the Center for Disease Control) by defining an eversmoker as someone who had smoked at least 100 cigarettes in his/her lifetime. An exsmoker is an eversmoker who was currently abstinent from smoking; for research purposes, an abstinence period of at least a year is sometimes specified.

2. The inclusion of Nicotine Dependence in the DSM-III-R,3 which promoted the "psychiatrization" of smoking, led to the adoption of a nosological or criterion-based approach that uses the concept of "lifetime" smoking (blurring the distinction between current and exsmoker) and number and/or severity of symptoms to categorize smokers as nondependent, mildly dependent, highly dependent, and so forth. Perhaps the most extreme application of these criteria occur in a paper by Breslau et al.,4 in which exsmokers are lumped with smokers and nondependent smokers are lumped with neversmokers¾a system of categorization that may make many smoking researchers somewhat uncomfortable. Yet a parallel distinction is common in the alcohol field.

My point is not to argue in favor of one model or the other, but to emphasize that both models rest on assumptions that require further testing. A few efforts have been made to reconcile or at least compare the two schemes¾for example, by Covey5¾but we still lack a fully-developed rationale for choosing one over the other. A happy byproduct of our attempts to clarify these issues will undoubtedly be a better understanding of smoking in particular and substance use in general.

1. Fagerstrom KO. (1978). Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav, 3:235-241.