February 1999 - Volume 5 Number 1
‘Got a Match?’
The Challenge of Pharmacotherapy
By David Kalman, Ph.D.
Brown University
The decade of the 90s, which is rapidly drawing to a close, has witnessed a remarkable growth in the development and availability of medications to treat nicotine dependence.
Two nicotine replacement products are now available as over-the-counter medications, and two others are available by prescription. In addition, the antidepressant bupropion recently received approval from the U.S. Food and Drug Administration as a medication for the treatment of nicotine dependence, and several other pharmacotherapies are being tested aggressively.
By contrast, 10 years ago, nicotine gum was the only available medication for the treatment of nicotine dependence. As testimony to the progress researchers in our field have made, one need only consult the American Psychiatric Association’s Practice Guideline for the Treatment of Patients With Nicotine Dependence, published in 1996, which recommends four pharmacotherapies and describes six others as promising.1 This is truly an impressive achievement.
But, as the saying goes, this is no time to rest on our laurels. While pharmacotherapies have helped many people to become nonsmokers, there is plenty of room for improvement as relapse rates to this pernicious addiction are still unacceptably high. Relatedly, we know that as more and more smokers quit, those who are left behind are not responding to the standard treatments of today. These are the heavy smokers who tend to be the most highly nicotine dependent and who may have other complicating psychiatric disorders. Increasingly, our challenge is to meet the special needs of these smokers. We know that nicotine replacement therapy tends to help heavy smokers as well as light smokers, so, arguably, part of the mission is to get more smokers to use nicotine replacement for quitting.
Perhaps an intuitively appealing way to help these smokers is to develop and recommend treatments that are specifically tailored to their needs, or, in other words, to adopt a treatment matching strategy. As Neil Benowitz points out, "Different smokers smoke for different reasons, consume different amounts of nicotine from tobacco, experience different withdrawal symptoms and are different in other ways...It is likely that different therapies will be more or less effective in different smokers" (p. 166-167).2
The good news is that as our armamentarium of treatments expands (as it already has), we can begin testing such a strategy (as we already have). For example, we have begun investigating whether smokers with a history of depressive disorder will respond differentially to antidepressants; whether anxious smokers will respond differentially to an anxiolytic; and whether highly nicotine dependent smokers will respond differentially to higher doses of nicotine replacement therapy. This approach is a very positive development for our field.
But we also are quickly learning (or, perhaps more accurately, confirming for ourselves) that what may appear to be a reasonably well-marked path takes some interesting twists and turns. Thus, Sharon Hall and colleagues3 found that the antidepressant nortriptyline appears to work equally well for smokers regardless of whether they have a history of depressive disorder. In addition, while there was a significant effect of medication on mood (from Profile of Mood States data but not Beck Depression Inventory data), these investigators found that post-quit increases in poor mood predicted abstinence only for subjects without a history of depressive disorder.
Findings from a placebo-controlled trial by Richard Hurt and colleagues4 add yet another interesting twist to the story: While subjects receiving the antidepressant bupropion had significantly better outcomes (again, regardless of depression history), the medication did not seem to have an effect on mood following cessation (based on BDI data). Thus, these investigators concluded that the "mechanism for bupropion’s efficacy is unlikely to be its antidepressant effects" (p. 1201). Clearly, these studies have produced some very provocative findings. But most would agree that their implications for treatment matching are hardly robust.
Recent findings with the anxiolytic buspirone also raise more questions than they answer. For example, it is difficult to reconcile a key finding in two recent studies.
In one of these studies, Paul Cinciripini and colleagues5 reported a significant treatment effect for "high anxiety" subjects but only during active treatment. By 12 months, the abstinence rate favored (although nonsignificantly, probably due to sample size) "high anxiety" subjects in the placebo vs. medication condition (23% vs. 12%, respectively). On the other hand, in another study of buspirone, Schneider and colleagues6 reported that there was no treatment effect during active treatment. But inspection of Figure 1 (p. 571) shows that the one-year abstinence rates favored subjects in the medication vs. placebo group (21% vs. 11%, respectively; although, again, the difference was nonsignificant, probably due to sample size). This is precisely the reverse of the former study—from which we can only conclude with a familiar refrain: that more research is needed, preferably with larger samples, so that, among other things, the interaction between treatment and anxiety levels pre- and post-quit can be more definitively elucidated.
Another potential matching strategy involves individualizing the dose of nicotine replacement based on pre-quit cotinine levels. This may be particularly useful for highly dependent smokers, because they are frequently underdosed with the 21-mg patch and 4-mg gum. In support of this hypothesis, David Sachs and colleagues7 found that subjects who achieved 100% replacement had the highest end-of-treatment abstinence rates. Dale et al. also found that the percentage of replacement was positively associated with short-term abstinence (odds ratio: 1.7) in their study comparing the 11-mg, 22-mg and 44-mg patches.8 While these findings are encouraging, as John Hughes9 points out, they may reflect the effect of smoking history on outcome7 or a simple dose-response effect8, rather than any genuine advantage of dose tailoring. Again, additional research is needed to clarify this issue.
Smokers might also respond differentially to one or another of the nicotine replacement systems. For example, "peak seekers" might respond best to nicotine nasal spray or the inhaler, and "trough maintainers" might respond best to the patch. This possibility is suggested in a study by West et al.10 in which relief from craving by nicotine gum was correlated with scores on the stimulant (as well as dependent) subscale of the Smoking Motives Questionnaire (SMQ) among recently abstinent smokers. On the other hand, in a study by Parrott and Craig, none of the SMQ subscale scores predicted outcome among smokers using nicotine gum to help them quit.11
In addition, while this hypothesis may merit further investigation, the distinction between these two hypothetical types of smokers itself needs further validation. This is suggested by the finding that smoking motives are often the result of a complex interaction between several variables, including situational cues and needs arising from nicotine deprivation.12 Indeed, it seems that this finding provides one of the rationales for investigating the use of combination treatments (e.g., the inhaler plus patch).
Of course, the mechanisms by which any of the pharmacotherapies exert their ameliorative influence are not clearly understood. For example, does nicotine replacement therapy work by alleviating withdrawal symptoms? Or by its ability to suppress cravings? Or by alleviating negative affect following quitting? Studies have weighed in on both sides of each of these questions.
Why antidepressants work is no more clear. As already noted, Hurt and colleagues were not able to demonstrate an effect of bupropion on mood, and yet they found a significant treatment effect; and while Hall and colleagues did demonstrate a significant medication effect on mood (at least as measured by the POMS), mood was not consistently related to outcome. Perhaps, as Hurt et al. speculate, bupropion (and maybe nortriptyline as well) works through its dopaminergic and noradrenergic activity, with the former mediating an effect on positive reinforcement and the latter on withdrawal effects. However, neither Hurt et al. nor Hall et al. were able to demonstrate an effect of medication on withdrawal; and the neurochemical mechanisms underlying nicotine’s psychological and physiological effects are, themselves, not clearly understood. In any event, these findings underscore the need to investigate not only whether our treatments work, but how they work.
That researchers are making steady progress on many fronts is abundantly clear from a perusal of the abstracts from the 1998 SRNT Annual Meeting. In the neurosciences and in our psychology laboratories, we are continuing to clarify nicotine’s actions on the brain and their relationship to its psychophysiological effects. In clinical trials, researchers are continuing to test new medications and combinations of medications for nicotine dependence. Naturalistic and laboratory studies are helping us to better understand the experience of quitting and the relapse process. These lines of research will lead to stronger pharmacological and psychosocial treatments.
And on a relatively new front, harm reduction strategies are now being tested. The next few years will undoubtedly see many new developments in these and other areas. This is, indeed, an exciting time to be a researcher in our field.
References
1. Work Group on Nicotine Dependence (1996). Practice guideline for the treatment of patients with nicotine dependence. American Journal of Psychiatry, 153 (10), 1-31.
2. Benowitz, N. L. (1993). Nicotine replacement therapy: What has been accomplished—can we do better? Drugs, 45(2), 157-70.
3. Hall, S. M. et al. (1998). Nortriptyline and cognitive-behavioral therapy in the treatment of cigarette smoking. Archives of General Psychiatry, 55, 683-90.
4. Hurt, R.D. et al. (1997). A comparison of sustained-release bupropion and placebo for smoking cessation. The New England Journal of Medicine, 337(17), 1195-202.
5. Cinciripini, P. M. et al. (1995). A placebo-controlled evaluation of the effects of buspirone on smoking cessation: differences between high- and low-anxiety smokers. Journal of Clinical Psychopharmacology, 15, 182-91.
6. Schneider, N. G. et al. (1996). Efficacy of buspirone in smoking cessation: a placebo-controlled trial. Pharmacology and Therapeutics, 60, 568-75.
7. Sachs, D. P. L., Benowitz, N. L., Bostrom, A G., & Hansen, M. D. (1995). Linearity of serum nicotine concentration and success of nicotine patch therapy in tobacco dependency treatment. Paper presented at the College on Problems of Drug Dependence, Scottsdale, AZ.
8. Dale, L. C., Hurt, R. D., Offord, K. P., Lawson, G. M., Croghan, I. T. & Schroeder, D. R. (1995). High-dose nicotine patch therapy. The Journal of the American Medical Association, 274, 1353-1358.
9. Hughes, J. (1995). Treatment of nicotine dependence: Is more better? The Journal of the American Medical Association, 274(17), 1390-91.
10. West, R. J., Hajek, P. & Belcher, M. (1986). Which smokers report most relief from craving when using nicotine chewing gum? Psychopharmacology, 89, 189-91.
11. Parrott, A. C. & Craig, D. (1995). Psychological functions served by nicotine chewing gum. Addictive Behaviors, 20(3), 271-78.
12. Pomerleau, O. F. (1986). Nicotine as a psychoactive drug: anxiety and pain reduction. Psychopharmacology Bulletin, 22(3), 865-69.
David Kalman, Ph.D., is on the faculty at the Center for Alcohol and Addictions Studies, Brown University and conducts research at the Edith Nourse Rogers Memorial VAMC in Bedford MA. He recently received funding from NIDA to conduct a smoking cessation study with heavy smokers with a past history of alcohol dependence.
Telephone: 781-687-3019.
Email: davidwk@bedford.va.gov.
The Future of SRNT
By Jack E. Henningfield, Ph.D.
SRNT President, 1998-1999
Serving as the president of SRNT for the past year has given
me a renewed appreciation for the scientific and public health value of the Society.
We have been called upon to provide expertise to a variety of organizations. The U.S. Food and Drug Administration requested guidance regarding the criteria for evaluating treatment effectiveness and appropriate treatment endpoints, and this should lead to an SRNT special conference in the coming year. We have been asked to brief various governmental staff and agencies on five continents on the underpinnings of tobacco use and treatment.
We have been invited to co-sponsor major meetings, including the very successful Addicted to Nicotine meeting, convened last July by the National Institute on Drug Abuse (NIDA). In turn, NIDA will hold a special session on research training opportunities at our forthcoming meeting in San Diego (March 6).
Perhaps most exciting was the result of our first non-U.S.-based major scientific meeting, held in Copenhagen last August. From 32 countries, it drew approximately 400 participants, including representatives of the World Health Organization and other major health, science, and policy organizations from around the world.
There is clearly an interest and a need in what our Society can offer. But what is it that we offer that is so valuable? We need to understand this if we are to successfully guide the course and growth of the Society—especially as we are now being issued more challenges and opportunities than we can, or probably should, take on.
I believe that the primary value that the Society for Research on Nicotine and Tobacco provides is a scientific basis for health-related decision making. My belief is that the Society provides a forum for disseminating the most definitive scientific guidance on the nature of tobacco dependence that is possible, as well as the implications of the understanding of dependence for treatment and prevention.
The Society has other offerings as well: We are, for example, vociferous advocates for building a stronger commitment to scientific exploration and training. But I believe that our core purpose is to provide a scientific basis for improvement of health. There is probably varied opinion on our purpose, and I hope that we all continuously appraise our mission, as well as our strengths and our weaknesses, as we head into the next millennium. Only then can we make rational decisions about the course that we should take.
How do we then accomplish our goals? Here, too, I think it is worth thinking about our past and our future. Most importantly, we provide a forum for public scientific exchange: through our annual meeting, this newsletter, the Internet, and now, through our own journal.
These activities alone are quite an undertaking, but there is more that we do and much more that we could do. Should we do more? Should our primary activities change? Here, too, we should continually self-appraise, collect data where possible, and self-correct. We are an experiment in progress, and an exciting one at that.
What does the Society provide to us as individuals? It gives us an opportunity to contribute to an area of science that is relevant to one of the most important health problems of our day. We can share our discoveries, challenge doctrine, and advance our knowledge base—it helps us make a difference.
To the extent that the Society serves in these ways, it can be valuable to each of us. And the opportunities for us to contribute are many and diverse. Such an undertaking requires scientists from the molecular to the macro-economic, it requires skilled health communicators, it requires product developers, and it requires public policy professionals.
I am personally enormously appreciative of the opportunity to have served the Society as its president over this past year. I look forward to continuing to contribute in any way that I can to advance the scientific understanding of tobacco use, and to the prevention and treatment of dependence. Thank you for your commitment to the Society.
The SRNT policy committee is generating a list of gaps in tobacco and nicotine research.
Building on the U.S. National Cancer Institute’s recent Tobacco Research Implementation Plan (www.dccps.nci.nih.gov/tcrb/trip/html) and the U.S. National Institute on Drug Abuse’s highlighting of nicotine addiction, the committee hopes to generate a list of up to ten areas needing research.
They also hope to obtain input from other tobacco-related agencies and organizations, as well as from scientists, to cover research areas not related to cancer or addiction.
The committee members have indicated that having a list of pressing needs will be useful in informing the U.S. Congress of the need for more research money. Additionally, they prefer that working scientists help set research agendas. This will also provide the scientific community with a way to help granting agencies maintain accountability on research areas where progress might be slow.
The committee points to several indications of growth in awareness of the need for nicotine and tobacco research. For example, they note that that a significant proportion of the NIDA medication development center grants are focused on nicotine, and that the U.S. Veterans Administration has recently issued a call for tobacco research centers. SRNT has engaged in advocacy work at both organizations.
SRNT members with ideas or comments on these or other policy issues are encouraged to contact John Hughes (information, page 16).
The Role of Biobehavioral Animal Models:
A Mainstay in Nicotine, Tobacco Research
By Martha M. Faraday, M.S., and Neil E. Grunberg, Ph.D.
Department of Medical & Clinical Psychology,
Uniformed Services University of the Health
Sciences, Bethesda, Maryland
The tremendous progress over the last 50 years in understanding
why people smoke cigarettes and how best to help them quit has been built on many different methods of scientific
investigation.
These approaches have included epidemiological studies, human clinical investigations, human laboratory experiments, animal biobehavioral experiments, neuroscience studies, and most recently, molecular biology. Each approach has made unique and critical contributions to our understanding of tobacco use and the actions of nicotine. The strength of nicotine and tobacco research has been the integration and synthesis that have occurred among the many subdisciplines of our field.
Over the last 10 years, active research using most of these approaches has accelerated. We are concerned, however, that one important approach—biobehavioral animal models—is not expanding to its full potential. Historically, animal models have been essential to the nicotine and tobacco research effort and continue to provide a valuable complement to other methods. Currently, animals are widely used in nicotine research to examine biological variables (e.g., biochemical, neurochemical, neuroanatomic, electrophysiologic).
It is the biobehavioral use of animal models— in which biologic and behavioral variables are evaluated—that could be expanded. Perhaps a consideration of the ways in which animal models can be conceptualized and interpreted will encourage their increased use. Biobehavioral animal models can be used in three ways: (1) as face valid models; (2) as mechanistic models; and (3) as models in which responses are free-standing indices.
Face Valid Models
One type of face valid models involves animals’ self-administering tobacco smoke or nicotine to parallel the human condition. These models are analogous to the intermittent self-administration that characterizes human smoking patterns. As a group, these models have provided compelling evidence about the addictive properties of nicotine and tobacco.
For example, reports that monkeys smoke cigarettes and that preference for cigarette smoke declined when mecamylamine, a central and peripheral nicotinic cholinergic blocking agent, was introduced were critical studies to pinpoint nicotine as the agent in tobacco that produced addiction and reward (e.g., Glick, Canfield, & Jarvik, 1970; Glick, Jarvik, & Nakamura, 1970). Nicotine self-administration models indicate that rats self-administer nicotine (e.g., Hanson, Ivester, & Morton, 1979; Goldberg, Spealman, & Goldberg, 1981; Cox, Goldstein, & Nelson, 1984; Corrigall & Coen, 1989; Donny, Caggiula, Knopf, & Brown, 1995) and that, with unlimited access, self-administration occurs throughout much of the animal’s active cycle (e.g., Valentine, Hokanson, Matta, & Sharp, 1997), indicating that rats, like humans, find nicotine reinforcing.
Another type of face valid model involves administering nicotine and then examining self-administration of opiates in order to evaluate pharmacologic aspects of the Gateway Hypothesis (Klein, 1997).
Mechanistic Models
In mechanistic models, the variables measured are indices of an outcome that may reveal underlying behavioral, psychological, or biological mechanisms. Early mechanistic models revealed that in animals with low or high activity levels at baseline, individual differences in nicotine’s locomotion effects (i.e., whether nicotine increased or decreased activity) were, in part, the result of differential inhibition of forebrain serotonergic systems (Rosecrans, 1971).
More recently, mechanistic models have helped to establish that nicotine’s reinforcing properties are associated with activation of the mesolimbic dopamine system through the ventral tegmental area (Corrigall, Coen, & Adamson, 1994) and that nicotine reinforcement differs from cocaine reinforcement in that opiate antagonists reduce cocaine self-administration, but not nicotine self-administration (Corrigall & Coen, 1991).
In addition, recent work indicates that brain reward function decreases markedly during nicotine withdrawal, a consequence that may serve as the neurobiological underpinnings of human craving (Epping-Jordan, Watkins, Koob, & Markou, 1998).
These models also have established that nicotine’s body weight- and appetite-reducing effects are related to changes in peripheral and central hormone levels that regulate feeding and body weight (i.e., glucose, insulin) as well as to nicotine’s effects on energy expenditure (e.g., Grunberg, 1988; Grunberg et al., 1988; Grunberg & Bowen, 1985). Another use of mechanistic models is to experimentally examine potential pathophysiologic (e.g., hyperactivity), psychopathologic (e.g., attentional deficit disorder), or therapeutic (e.g., to treat cognitive or motor deficits) effects of nicotine (e.g., Slotkin, 1992; Levin, Christopher, Briggs, & Rose, 1993; Tizabi, Popke, Rahman, Nespor, & Grunberg, 1997; Popke, Tizabi, Rahman, Nespor, & Grunberg, 1997). Genetically manipulated animals (e.g., nicotinic 2 knockout mice) allow examination of biological mechanisms underlying specific actions of nicotine (e.g., Picciotto et al., 1995).
Models with Free-Standing Indices Responses
These models use behavioral or biological responses as indices of changes that may be used to infer processes that relate to humans. For example, changes in simple behaviors (e.g., feeding, body weight, locomotion, acoustic startle reflex) have been used as evidence for the development of nicotine tolerance and withdrawal and used to test drugs for withdrawal alleviation potential (e.g., Clarke & Kumar, 1983; Cohen, Welzl, & Bättig, K., 1991; Collins, Romm, & Wehner, 1988; Helton, Modlin, Tizzano, & Rasmussen, 1993; Malin et al., 1992). In addition, the effects of varying nicotine dosages on locomotion, startle, and other behaviors have been used to examine underlying behavioral dose response curves in different strains of mice and rats that may be relevant to differential nicotine addiction liability in humans (e.g., Collins, Miner, & Marks, 1988; Faraday, Rahman, Scheufele, & Grunberg, 1998; Faraday, O’Donoghue, & Grunberg, in press).
Expanding Biobehavioral Animal Models
Biobehavioral animal models examining effects of nicotine and tobacco should be used more extensively to complement human studies. The face valid, mechanistic, and free-standing models all are relevant to effects of tobacco and nicotine. In particular, biobehavioral animal models could be used to study the following: behavioral and biologic variables relevant to youth tobacco prevention, use, and cessation; the relationship between the use of tobacco and other drugs, including alcohol and illicit substances; the interaction between nicotine and stress; individual differences, including genotypic differences, in responses to nicotine and tobacco; and innovative therapeutic uses of nicotine and nicotine analogs.
References
Clarke, P.B.S., & Kumar, R. (1983). The effects of nicotine on locomotor activity in non-tolerant and tolerant rats. British Journal of Pharmacology 80(3):587-594.
Cohen, C., Welzl, H., & Bättig, K. (1991). Effects of nicotine, caffeine, and their combination on locomotor activity in rats. Pharmacology Biochemistry & Behavior 40:121-123.
Collins, A.C., Miner, L.L., & Marks, M.J. (1988). Genetic influences on acute responses to nicotine and nicotine tolerance in the mouse. Pharmacology Biochemistry & Behavior 30:269-278; 1988.
Collins, A.C., Romm, E., & Wehner, J.M. (1988). Nicotine tolerance: An analysis of the time course of its development and loss in the rat. Psychopharmacology 96(1):7-14.
Corrigall, W.A., & Coen, K.M. (1989). Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 99(4), 473-478.
Corrigall, W.A., & Coen, K.M. (1991). Opiate antagonists reduce cocaine but not nicotine self-administration. Psychopharmacology, 104(2), 167-170.
Corrigall, W.A., Coen, K.M., & Adamson, K.L. (1994). Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Research, 653(1-2), 278-284.
Cox, B.M., Goldstein, A., & Nelson, W.T. (1984). Nicotine self-administration in rats. British Journal of Pharmacology, 83(1), 49-55.
Donny, E.C., Caggiula, A.R., Knopf, S., & Brown, C. (1995). Nicotine self-administration in rats. Psychopharmacology, 122, 390-394.
Epping-Jordan, M.P., Watkins, S.S., Koob, G.F., & Markou, A. (1998). Dramatic decreases in brain reward function during nicotine withdrawal. Nature, 393(6680), 76-79.
Faraday, M.M., O’Donoghue, V.A., & Grunberg, N.E. (In press). Effects of nicotine and of stress on startle and sensory-gating depend on rat strain and sex. Pharmacology Biochemistry & Behavior.
Faraday, M.M., Rahman, M.A., Scheufele, P.M., & Grunberg, N.E. (1998). Nicotine impairs sensory-gating in Long-Evans rats. Pharmacology Biochemistry & Behavior 61(3), 281-289.
Glick, S.D., Canfield, J.L., & Jarvik, M.E. (1970). A technique for assessing strength of a smoking preference in monkeys. Psychological Reports, 26, 707-710.
Glick, S.D., Jarvik, M.E., & Nakamura, R.K. (1970). Inhibition by drugs of smoking behavior in monkeys. Nature, 227, 969-971.
Goldberg, S.R., Spealman, R.D., & Goldberg, D.M. (1981). Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science, 214(4520), 573-575.
Grunberg, N.E. (1988). Nicotine and body weight: Behavioral and biological mechanisms. In M.J. Rand & K. Thurau (Eds.), The Pharmacology of Nicotine: ISCU Symposium Series (pp. 97-110). Washington, DC: IRC Press.
Grunberg, N.E., & Bowen, D.J. (1985). The role of physical activity in nicotine's effects on body weight. Pharmacology Biochemistry and Behavior, 23, 851-854.
Grunberg, N.E., Popp, K.A., Bowen, D.J., Nespor, S.M., Winders, S.E., & Eury, S.E. (1988). Effects of chronic nicotine administration on insulin, glucose, epinephrine, and norepinephrine. Life Sciences, 42, 161-170.
Hanson, H.M., Ivester, C.A., & Morton, B.R. (1979). Nicotine self-administration in rats. NIDA Research Monograph, 23, 70-90.
Helton, D.R., Modlin, D.L., Tizzano, J.P., & Rasmussen, K. (1993). Nicotine withdrawal: A behavioral assessment using schedule controlled responding, locomotor activity, and sensorimotor reactivity. Psychopharmacology 113(2), 205-210.
Klein, L.C. (1997). Sex differences and the effects of stress on subsequent opioid consumption in adult rats following adolescent nicotine exposure: A psychopharmacologic examination of the Gateway Hypothesis. Unpublished doctoral dissertation, Uniformed Services University of the Health Sciences, Bethesda, MD.
Levin, E.D., Christopher, N.D., Briggs, S.J., & Rose, J.E. (1993). Chronic nicotine reverses working memory deficits caused by lesions of the fimbria or medial basalocortical projection. Cognitive Brain Research, 1, 137-143.
Malin, D.H., Lake, J.R., Newlin-Maultsby, P., Roberts, L.K., Lanier, J.G., Carter, V.A., Cunningham, J.S., & Wilson, O.B. (1992). Rodent model of nicotine abstinence syndrome. Pharmacology Biochemistry & Behavior, 43(3), 779-784.
Picciotto, M., Zoli, M., Léna, C., Bessis, A., Lallemand, Y., LeNovère, N., Vincent, P., Pich, E.M., Brûlet, P., & Changeux, J.P. (1995). Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature, 374, 65-67.
Popke, E.J., Tizabi, Y., Rahman, M.A., Nespor, S.M., & Grunberg, N.E. (1997). Prenatal exposure to nicotine: Effects on prepulse inhibition and central nicotinic receptors. Pharmacology Biochemistry & Behavior, 58(4), 8443-849.
Rosecrans, J.A. (1971). Effects of nicotine on behavioral arousal and brain 5-hydroxytryptamine function in female rats selected for differences in activity. European Journal of Pharmacology 14, 29-37.
Slotkin, T.A. (1992). Prenatal exposure to nicotine: What can we learn from animal models? In I.S. Zagon & T.A. Slotkin (Eds.), Maternal Substance Abuse and the Developing Nervous System, New York: Academic Press, pp. 97-124.
Tizabi, Y., Popke, E.J., Rahman, M.A., Nespor, S.M., & Grunberg, N.E. (1997). Hyperreactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors. Pharmacology Biochemistry & Behavior, 58, 1-6.
Valentine, J.D., Hokanson, J.S., Matta, S.G., & Sharp, B.M. (1997). Self-administration in rats allowed unlimited access to nicotine. Psychopharmacology 133(3), 300-304.
The opinions or assertions contained herein are the private ones of the authors and are not to be construed
as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health
Sciences.
Adapted from Grunberg, N.E., & Faraday, M.M. (In press). The value of animal models to examine the Gateway
Hypothesis. In Kandel, D., et al. (Eds.), Stages and Pathways of Involvement in Drug Use: Examining the Gateway
Hypothesis. New York: Cambridge University Press.
Researchers Don’t Get No Respect
A Call for Civil Actions
By John R. Hughes
University of Vermont
I have noticed two etiquette slips that many of us make repeatedly, and I would like to bring them to people's attention.
The first slip is when someone asks me if I reviewed his or her paper or grant, or, more aggravatingly, says, "I know you reviewed my paper," or, "You probably reviewed this grant." Confidentiality of reviews is still the norm for grant reviews and for most article reviews
I have often been very sure that so-and-so wrote a review, only later to find out that this person could not have reviewed it. Sometimes when the number of reviewers is small and only a few have smoking expertise, I think I can tell who reviewed my grant application. But let me warn you, I have been on many review committees in which I was one of only two people who knew anything much about smoking, but I was not the primary reviewer of the smoking studies. This occurred because, being the only psychiatrist on the committee, I was assigned to review comorbidity studies, etc.
Some people think they can tell who the reviewer is by citations in the review. If so, I have gotten a lot of people in trouble by citing mostly their work and none of my own.
When asked these embarrassing questions, I would like to take credit for grants that were funded (sometimes we fight hard to get a grant funded) and avoid credit for those that failed, but if I do either I get myself in trouble. Or if the pool of reviewers is limited, I get someone else in trouble. The only way to respond is to demur.
The second etiquette slip is in critiquing others’ work. Peer review is an essential function, and, in fact, I think we do not do enough of it in our group. However, this should be done diplomatically, not by hedging our criticism but by using several rules:
So now that I have said this, I expect everyone will be criticizing me when I do not follow the above. That's okay—just follow the above when criticizing me for criticizing.
Publications, Communications Responsibilities Realigned
The SRNT Publications and Communications Committee has been
divided, allowing the two new committees the resources to devote greater attention to setting policy appropriate
to their specific functions.
The SRNT Council has now grown to the point where reporting lines and activities can no longer be subsumed under one general committee. Starting in March, the activities of the former Publications and Communications Committee will come under two separate committees—Publications, chaired by Ovide Pomerleau, and Communications, chaired by Ted Klein. The Publications Committee will now focus exclusively on issues having to do with SRNT’s new scientific journal, Nicotine & Tobacco Research. The Communications Committee will now include Public Information.
Al Collins
Treasuring New Ideas, New Knowledge
By Raine Riggs
SRNT Newsletter Assistant Editor
When Al Collins—now a professor of pharmacology and psychology and author of more than 200 publications—was
twelve years old, he wanted to be a professional basketball player. When he realized that he wasn’t going to be
tall enough, he decided to get a bachelor’s degree in pharmacy.
"For a few weeks in my life, I wanted to be a pharmacist," he says.
As a graduate student at the University of Wisconsin, Madison, where he earned a Ph.D. in pharmacology, Collins studied reproductive biochemistry. As he was becoming frustrated with his attempts to design a male anti-fertility pill, he was recruited by the University of Colorado for a postdoctoral position.
He went to work in Colorado for Richard Deitrich, or "god," as Collins likes to refer to him. Collins reflects that working for Deitrich was like "turning on a light bulb." He was quickly seduced by the potential of developing drugs that might help cure human illnesses, particularly alcoholism.
He accepted a faculty position at the University of Colorado in 1972. A few months later, he inherited a laboratory and graduate students from a colleague who had died. One of those graduate students happened to be interested in nicotine research. Specifically, the student was conducting research on the genetic regulation of nicotine and behavioral responses. That is when Collins first began his productive career in nicotine research.
"I always like to tell people that I’ve had a lot of fun studying the three major human vices: sex, booze, and butts," he jokes. "Ask any of my graduate students about the ‘boogedy boogedy dance’ that I do in the lab. This is a really fun job."
The highlights of Collins’ fun-filled career include the discovery of the paradoxical up-regulation of nicotinic receptors, which he refers to as "a kick," the discovery that chronic nicotine treatment results in desensitization, and a recent discovery that has him "giggling like mad." Collins is a bit less forthcoming on this finding, but does say that "we have data that argue that many of the behavioral effects of nicotine are due not to receptor activation but to receptor desensitization." He hopes to publish these data in the next few months.
"What’s most fun about nicotinic systems is that virtually every prejudice we have is wrong. This field is just full of surprises," he says. "I’ve had a lot of fun ruffling people’s feathers. Convincing the doubters is the fun of science. It’s an amazing thing to think thoughts that people haven’t thought before."
For example, Collins’ lab was the first to observe that chronic nicotine treatment increases the number of nicotinic receptors in the brain. "Knowing what no one in the whole history of humankind has known is a major reward for me. The thrill of being the first person in the lab to know something, no matter how small, is indescribable," he reports.
When Collins began his career as a researcher, he hoped to help develop cures for alcoholism and nicotine dependence. Now, he says, he is less optimistic about that happening during his career. He says that genetics research enables scientists to predict susceptibility and then to prevent people from developing diseases. He believes that even if only one person is helped, the research is still important.
Collins credits his postdoctoral mentor, Deitrich, as being one of the most important people in his development as a scientist. Deitrich taught by example and encouraged independence in his students. "He taught me to think for myself. He never once said, ‘This is what you will do,’ and I have tried to emulate that philosophy with my own students."
Collins considers his wife, Dr. Jeanne Wehner, an expert on the genetics of learning and memory, to be the "most solid scientist I’ve ever known." Collins says that she gives him excellent advice on every scientific question he has.
Finally, Collins explains that many of the discoveries people attribute to him should actually be credited to Mike Marks, a colleague with whom he has worked for more than twenty years. He says that he and Marks are "symbiotic organisms with complementary skills."
"Instead of saying Al Collins, people should say Al Collins and Mike Marks. Maybe even Al Marks and Mike Collins, or Collin Marks and Mike Allan. That’s how closely we’ve worked over the years," he says. "He has been a tremendous influence on me professionally and personally."
While Collins reports that he has enjoyed his career in basic science, he has also been frustrated by aspects of it. For example, he laments the instability of funding. He says that he has spent too much time trying to get grants in a review system that is flawed.
"Science has become very faddy. If you’re not using the most up-to-date techniques, you’ll find yourself on the outside looking in," he says. "The problem is that new techniques aren’t always the answer. It would be better to focus on what the important questions are, rather than what the latest fad is."
Novel ideas often are met with resistance and disdain in all fields of science, he notes, including nicotine research. This makes it more difficult for researchers to get funding for new and interesting ideas. Furthermore, since resources are limited, researchers become more conservative in their grant proposals, believing, rightly so, that well-established ideas will more likely receive funding.
He advises young investigators to read the literature, know what’s been done, and do something different, despite the risk that the research might not be funded.
"You do run a risk by not doing the same stuff everyone else is doing, but life should be a gamble," he adds. "It’s like a horse race. Let’s say that you could bet on a sure-win horse, with 2:1 odds, versus a long-shot horse, with 20:1 odds. Which one would you want to see win? Which one would give you the biggest pay-off? Science is like that. You have to be willing to take a risk to win big and make an important contribution."
Also, Collins sees a shortage of talented, skilled personnel in basic science research of nicotine. "At the Neuroscience conference, you’ll see 60 to 70 posters on nicotine, but ten times that many for glutamate. Now, I think the nicotinic receptor system is much more important than all of the glutamate stuff. But basic research in nicotine has just never really taken off." He sees this as an opportunity for young investigators to become involved in an area where they can make important contributions relatively quickly.
Despite these problems, Collins envisions a bright future for nicotine research, believing that the field is on the threshold of major discoveries and important progress. He says that significant progress will be made in the areas of addiction, Tourette’s Syndrome, learning and memory, Alzheimer’s Disease, and schizophrenia.
"Neuroscience developed the techniques and approaches to study these diseases. Now we have a big stick to whack at awful problems," he says.
"When I started my career, we knew of one brain nicotinic receptor, and we said it didn’t do anything. We know of multiple receptors now, but we still don’t know what all of them do. That’s where the tools of neuroscience come in to play."
Collins predicts that the next five to seven years will be a "hell of a lot of fun," with even more surprise discoveries. He cautions that the business of science can be extremely competitive. "We’re like hungry pigs at the trough biting each other," he says, but that competition also fosters progress.
"This research is extraordinarily worthwhile. Plus, it’s lots of fun. What more could you ask for in life than to do something important and fun? Well, maybe you could ask for a million dollars, but who cares about that anyway?"
By Ursula Kunze, Anita Schmeiser-Rieder,
and Rudolf Schoberberger
In Austria, 30% of the population smoke, 42% of men and 27% of women1. There is some evidence that the number of smoking women has been increasing, while the number of smoking men is remaining stable. Regarding treatments for smokers, nicotine replacement therapy is widely available. The 2mg and 4mg nicotine chewing gum, nicotine skin patches, and nicotine inhaler are all available over the counter, while the nicotine nasal spray is a prescription-only medication.
Regarding anti-smoking legislation, smoking in public places such as cinemas is forbidden, but the law is not being enforced. Tobacco advertising is not allowed on TV and radio. In most hospitals, smoking is prohibited outside special smoking areas.
Research on smoking is concentrated primarily at the Institute of Social Medicine in Vienna directed by Professor Michael Kunze. Other members of the team include Professor Rudolf Schoberberger, Professor Anita Schmeiser-Rieder, Dr. Ernest Groman, and Dr. Ursula Kunze.
A Nicotine Institute has been set up recently focusing on diagnosis and treatment of tobacco dependence. Recent research projects include a study of the level of tobacco dependence in smokers1. In a representative sample of 6000 Austrian smokers, 30% had very low dependence (FTND=0-2), 34% showed low dependence (FTND=3-4), and the remaining 36% were divided between the medium, high and very high dependence groups. We have also shown that smokers with lung cancer have a higher level of nicotine dependence than the general smoking population average2. Finally, we measured CO concentration in 173 medical students and found 9% being current smokers.3 An on-going project involves a development of a questionnaire to diagnose nicotine dependence.
References and Further Reading
1. Kunze, M., Schoberberger, R., Fagerström, K.O.. (1994). Epidemiology of nicotine dependence. In: Future directions in nicotine replacement therapy. Chester: Adis International , pp. 58-62.
2. Kunze, U., Schoberberger, R., Schmeiser-Rieder, A., Fagerström, K.O. (1996). Preventive oncology and nicotine addiction: first results of a field study. 2nd International Congress on Lung Cancer. In International Proceedings Division, G. Antypas (Eds.), Monduzzi Editore , 551-554.
3. Groman, E., Kunze, U., Schmeiser-Rieder, A., Schoberberger, R. (1998) Measurement of expired carbon monoxide among medical students to assess smoking behaviour. Sozial und Praventivmedizin, 43, 322-324.
Future Events
SRNT Fifth Annual Meeting, 5-7 March 1999, at the Sheraton
Hotel, San Diego, California, USA. Held in conjunction with the 20th Annual Meeting of the Society of Behavioral
Medicine. See www.srnt.org, or telephone (608) 836-3787.
Workshop on State-of-the-Art Smoking Cessation Interventions, 11-12 March 1999, University Place Conference Center, Indianapolis, Indiana, USA. Sponsored by the Indiana University schools of Medicine and Dentistry and the Indiana University Nicotine Dependence Program. For more information, telephone (317) 274-8353 or (800) 622-4989.
American Society of Preventive Oncology 23rd Annual Meeting, 14-16 March 1999, Houston, Texas, USA. Telephone (608) 263-6809.
90th Annual Scientific Meeting of the American Association for Cancer Research, 10-14 April 1999, Philadelphia, Pennsylvania, USA. Topics include cancer prevention. Contact AACR, fax (215) 440-9313, email aacr@aacr.org.
11th World Conference on Tobacco or Health, 6-10 August 2000, Chicago, Illinois, USA. Theme "Tobacco: the growing epidemic." Fax (404) 325-2217.
News and Other Offerings
Newly Minted. The new SRNT journal, Nicotine &
Tobacco Research, is being printed and mailed to subscribers early in March. All SRNT members receive the journal
as part of their membership benefits. Other subscriptions are also available, and members are encouraged to notify
institutional libraries and other organizations of the publication of this journal. Four quarterly issues will
be published in 1999, as well as two special issues featuring presentations at two outstanding conferences—the
1997 Sundance meeting on Tobacco Prevention: Strategies, Overcoming Challenges, and Building Bridges; and the 1998
Addicted to Nicotine meeting.
This first issue of the journal includes abstracts from 50 of the best presentations at the 1998 SRNT Annual Meeting, and features peer-reviewed original research and review articles on an array of topics. A sampling of the articles reflects the diversity of topics covered in the first issue: nicotine self-administration, oral spit tobacco, schizophrenia, psychometrics, tailored interventions, cessation in women, and reactions to a radio-type message about cigarettes. High-quality manuscripts are welcome; see author guidelines at www.carfax.co.uk/ntr-ad.htm .
Update Yourself. Members whose contact information has changed during the last two years should fill out and return the yellow postcard enclosed with this newsletter. Please use the card to notify SRNT of any change in name, address, work location, telephone number, fax number, or email address. Note that postage is required for mailing. Any member who is not certain that SRNT has the most current information should fill out and mail the card.
Find-a-Member. If you have access to the Web, you now have access to SRNT’s latest membership information. A recent addition to the ever-growing SRNT Web site is a searchable directory of SRNT members. The directory is searchable by name (first, last, or both), state, and country. This feature allows users to locate other SRNT members in their locality. Eventually, the listings will also be searchable by interest area, once interest-area designations have been revised and members’ interest areas have been categorized. Those not wanting their contact information (name, affiliation, telephone, address) listed on the Web site should contact Rick Brown at telephone (401) 455-6254, or by email at Richard_Brown@brown.edu.