The consistency of acute responses to nicotine in humans

Transcription

1 Nicotine & Tobacco Research Volume 5, Number 6 (December 2003) The consistency of acute responses to nicotine in humans Kenneth A. Perkins, Chris Jetton, Amy Stolinski, Carolyn Fonte, Cynthia A. Conklin [Received 8 August 2002; accepted 12 February 2003] Nicotine has many acute subjective, physiological, and behavioral effects in humans, some of which may explain why nicotine produces dependence. Individual differences in the magnitude of these effects (i.e., nicotine sensitivity) are of interest to many researchers, such as those examining vulnerability to dependence and processes related to chronic tolerance. However, such characterization of individual differences depends on the consistency of the observed responses, and the consistency of acute effects of nicotine in humans has not been studied systematically. We examined the consistency of the acute effects of the same dose of nicotine administered by nasal spray across multiple drug administration trials, within as well as between sessions. Subjective (i.e., self-reported effects), cardiovascular, and performance measures were assessed following each of four dosing trials of nicotine (20 mg/kg) on three sessions and of placebo on one session. For those measures in which the main effect of nicotine vs. placebo was significant, intraclass correlations were calculated for different sets of trials across different numbers of sessions. Our objective was to determine whether the consistency of responses declined when those responses were based on smaller numbers of trials or sessions, in an effort to guide future research in this area. Results indicated that the consistency of nicotine effects is generally high, even across trials within just one session. Additional research is needed to determine the generalizability of these findings to other methods of nicotine administration, including smoking, and to clarify the extent to which this consistency reflects characteristic consistency of the pharmacological actions of nicotine per se vs. consistency of nonspecific responses to the drug administration procedure. Introduction Laboratory studies show that nicotine, whether administered by tobacco smoking or novel means (such as via nicotine replacement therapy), induces a variety of acute subjective, physiological, and behavioral effects in humans (Benowitz & Gourlay, 1997; Heishman, Taylor, & Henningfield, 1994; Kalman, 2002). The number of such studies has increased sharply since the early 1990s, greatly adding to our knowledge of the acute actions of nicotine. For example, one review that focused solely on nicotine s acute subjective mood effects identified 72 relevant studies (Kalman, 2002). Nicotine s ability to produce Kenneth A. Perkins, Ph.D., Chris Jetton, B.A., Amy Stolinski, B.S., Carolyn Fonte, R.N., and Cynthia A. Conklin, Ph.D., Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Correspondence: Kenneth A. Perkins, Western Psychiatric Institute & Clinic, University of Pittsburgh School of Medicine, 3811 O Hara Street, Pittsburgh, PA 15213, USA. Tel: z1 (412) ; Fax: z1 (412) ; perkinska@msx.upmc.edu dependence is likely due to some of these effects (Perkins, 1999; Perkins & Stitzer, 1998), although which effects are responsible for dependence is not known. A topic of growing interest in the nicotine field, as well as in other areas of substance abuse, is individual differences in the magnitude of the acute effects of the drug (e.g., Perkins, Gerlach, Broge, Grobe & Wilson, 2000; Radel & Goldman, 2001). For example, some theories of vulnerability to drug abuse, including nicotine dependence, propose that individuals at greater future risk for dependence have greater initial sensitivity to the drug s acute effects, perhaps due to genetic or other constitutional factors (e.g., Marks, Stitzel, & Collins, 1989; Pomerleau, 1995). Yet other research, notably with alcohol (Schuckit, 1984), suggests that blunted initial sensitivity, or smaller response, to a drug s acute effects is associated with greater risk of dependence. Aside from possibly indexing future risk of vulnerability to dependence, stable individual differences in sensitivity to a drug ISSN print/issn X online # 2003 Society for Research on Nicotine and Tobacco DOI: /

2 878 ACUTE RESPONSES TO NICOTINE IN HUMANS also can be a consequence of differential chronic exposure to the drug. Differences in acquired sensitivity may indicate the onset of drug tolerance (attenuated responding) or sensitization (enhanced responding), either of which may reflect processes involved in the onset of drug (and nicotine) dependence (see Hasin, Paykin, Meydan, & Grant, 2000; Heishman & Henningfield, 2000; Perkins, 2002). An overlooked practical issue in efforts to relate nicotine sensitivity to dependence vulnerability or processes involved in dependence onset is the need for careful assessment of individual differences in the magnitude of nicotine s acute effects in humans. Accurately determining the magnitude of the acute effects of nicotine and other drugs can be challenging (Foltin & Evans, 1993; Perkins & Stitzer, 1998). One key methodological concern is the uncertain consistency of nicotine s acute effects. If the observed effects of nicotine were inconsistent across time, variability in these effects between subjects assessed on only one occasion would be difficult to attribute to stable individual differences in drug sensitivity but instead may be due to mere random error. To illustrate the importance of consistent responses in assessing individual differences, a study of mice compared responses of different strains (i.e., genetic variants) on standard behavioral tests across several different laboratories (Crabbe, Wahlsten, & Dudek, 1999). Despite great efforts to standardize all procedures, including starting the study on the same date with mice of the exact same age, differences in responding among strains varied across laboratories. Such variability, the authors concluded soberly, indicated that studies aiming to characterize genetic influences on these responses may produce results that do not generalize beyond the particular laboratory conducting the research. A similar variability in nicotine effects in humans across time would suggest that studies attempting to identify individual differences in these effects may produce results that do not generalize beyond the moment of testing. The first step toward ensuring consistency of observed drug responses is to administer drug doses in a controlled fashion across individuals and test trials. Nicotine intake via smoking can be quite variable, owing to the ease with which smokers can alter their puff topography to increase or decrease smoke (and nicotine) consumption. Methods to standardize nicotine exposure, by controlling puff number and duration or by administering nicotine via novel methods (such as transdermal or nasal spray nicotine), have received some attention from researchers interested in studying acute nicotine responses in humans (Pomerleau, Pomerleau, & Rose, 1989; see also Perkins, 2002). Seldom addressed, however, is the consistency of the acute responses to nicotine (or any other psychoactive drug) even when a method of controlled drug exposure is used. For practical reasons, acute effects of a dose of nicotine typically are obtained in only one session and often following only a single administration of drug (see, for example, Kalman, 2002). One recent exception was a study by Heishman and Henningfield (2000), in which escalating doses of nicotine gum (0, 2, 4, 8 mg) were administered over time to nonsmokers in each of eight sessions. The onset of chronic tolerance to nicotine across sessions was the primary interest of that study, however, and consistency of responses across sessions was not examined. Thus, to our knowledge, no research has systematically examined the consistency of acute responses to nicotine administered by any means (including tobacco smoking) in humans across multiple assessments under the same conditions. The present study addressed the consistency of subjective, cardiovascular, and performance responses to nicotine spray in humans across drug administrations, both across trials within one session and between sessions. Our key interest was in determining whether the relative magnitude of response for a given individual is consistent across assessments, such that those with greater responding at time 1 also show greater responding at time 2. Repeated drug administration trials within each session were conducted to determine whether such a procedure, which is more practical than use of multiple sessions involving only one trial per session, would improve consistency of responses despite the likely onset of acute tolerance (see Heishman & Henningfield, 2000; Perkins, Grobe, et al., 1994). Multiple sessions involving multiple trials of administration of the same dose of nicotine were included to determine if these extra sessions were needed to obtain consistent measures of sensitivity to nicotine and, thus, might be warranted in research on individual differences in nicotine sensitivity. Consistency was determined by intraclass correlations of responses across various sets of trials or sessions. The goal was to address the practical question of, What are the fewest numbers of trials or sessions a study similar to this one could have and still provide a consistent measure of sensitivity to nicotine s acute effects? Method Subjects Subjects were 16 smokers (eight male, eight female) meeting Diagnostic and statistical manual of mental disorders, 4th edition, criteria for tobacco dependence (American Psychiatric Association, 1994). Participants were recruited from flyers and ads placed in the surrounding university community and were paid for their participation. Sample characteristics were as follows: age (mean SE~ years), daily smoking rate ( cigarettes per day), number

3 NICOTINE & TOBACCO RESEARCH 879 of years smoking ( years), and Fagerström Tolerance Questionnaire score ( ; Fagerström, 1978). All subjects were examined by a physician to rule out current or recent medical or psychiatric problems. Subjects were excluded for excessive alcohol use (w20 drinks per week), as determined by interview. No subjects reported prior experience with nicotine nasal spray. Subjective, cardiovascular, and performance measures Subjective measures included the Profile of Mood States (POMS; McNair, Loor, & Droppelman, 1971) and visual analog scale (VAS) items of specific effects. The VAS items were rated on scales of 0 (not at all) to 100 (extremely) and included head rush, relaxed, dizzy, and jittery. The POMS scales included tension, confusion, fatigue, and vigor, and the composite scale of arousal (determined by adding scores for tension and vigor and then subtracting scores for confusion and fatigue ). POMS scale scores were divided by the maximum possible score for each scale and multiplied by 100 to equate those scores with the VAS scores (i.e., each on scales). These measures were selected because they are used widely in research on nicotine and other drugs (e.g., Fischman, & Foltin, 1991; Kalman, 2002), including studies of the individual differences in nicotine effects (e.g., Perkins et al., 2001; Perkins, Grobe, et al., 1994). Heart rate and blood pressure were assessed with a Dinamap blood pressure recorder (Critikon; Tampa, FL). Performance tasks were finger-tapping speed and handsteadiness, included to determine the generalizability of the consistency of nicotine s acute effects across a response domain other than subjective or physiological responses. Previous research indicates that these tasks are sensitive to nicotine effects and show little influence due to practice (e.g., Perkins, Gerlach, et al., 2001; Perkins, Grobe, et al., 1994). Each task is presented and scored by computer and is described in detail elsewhere (Perkins, Gerlach, et al., 2001; Perkins, Grobe, et al., 1994). Briefly, fingertapping speed was assessed by instructing subjects to tap on one key of a keypad as quickly as possible for 30 s. For handsteadiness, subjects held a metal stylus (2 mm in diameter) within a 3-mm hole without contact against the sides of the hole for two 20-s periods. Duration of contact was measured to the nearest.01 second, and the time was averaged between the two trials. Nicotine or placebo spray Nicotine (20 mg/kg) or placebo was delivered via a rapid, controlled-dose nasal spray delivery procedure developed in our laboratory (see Perkins, Grobe, et al., 1994). Bioavailability of the 20 mg/kg nicotine dose is comparable to about one-half of one typical cigarette (Perkins, Grobe, et al., 1994). This moderate dose was selected in the hope that a substantial amount of nicotine could be administered without extensive residual effects during subsequent trials. Doses were corrected for body weight in order to minimize variability in responses between subjects varying widely in body weight. Spray bottles delivered the designated amount of nicotine in saline, along with peppermint flavoring oil, which was used to mask the taste and smell of nicotine. Nicotine via spray was used because nicotine dosing by tobacco smoking is hard to control (Pomerleau et al., 1989) and complicates the determination of the cause of a response (i.e., due to nicotine vs. the thousands of other smoke constituents). In addition, use of cigarettes would introduce other effects on responding due to the familiarity of the method of administration, including subject s expectancies of smoking effects (Brandon, Juliano, & Copeland, 1999). By contrast, the nasal spray was equally novel across subjects and allowed for the isolation of nicotine per se. Procedures Subjects participated in one introductory session to learn the tasks and procedures, as recommended for maximizing the consistency of performance responding to drug administration (e.g., Foltin, & Evans, 1993). They then participated in four experimental sessions, each following overnight smoking abstinence, determined by expired-air carbon monoxide (CO) reading of 13 ppm or less (BreathCO monitor; Lenexa, KS). The placebo session occurred randomly within the sequence of the three nicotine sessions and was included to identify responses showing a significant effect of nicotine (i.e., difference between nicotine and placebo sessions). On each day, subjects engaged in three practice trials with the performance tasks (data not analyzed), followed by a baseline assessment of measures. Subjects then were administered 20 mg/kg nicotine (three sessions) or placebo (one session) every 30 min for 2 hr (trials 1 4). Each dosing was followed by subjective and cardiovascular measures over the first 5 min and performance tasks during the subsequent 5 min. Subjects remained at quiet rest for the remainder of each trial until the next dosing. This study was approved by the University of Pittsburgh Institutional Review Board.

4 880 ACUTE RESPONSES TO NICOTINE IN HUMANS Data analysis Analyses of variance (ANOVAs) were first conducted to compare effects of nicotine vs. placebo on each measure, combining responses for the three nicotine sessions. Response was defined as change from baseline. Significant effects of nicotine are requisite here because consistency in the absence of a drug effect is of questionable relevance. These ANOVAs also examined the main effect of nicotine sessions (three) and the interaction of nicotine or placebo 6 trials (four) to determine the significance of any systematic changes in responding to nicotine across sessions or trials. Because several measures likely were correlated with each other, sphericity was not assumed, and Huynh-Feldt corrected p values were used. Because of the number of tests, we used a modified Bonferroni procedure for multiple comparisons, based on the ordered p values of the individual tests as described by Simes (1986). For the main analyses of consistency, intraclass correlations (ICCs) were calculated for responses to nicotine (change from baseline). Only the measures for which a significant effect of nicotine was found in the ANOVAs were included in the consistency analyses. To identify the fewest number of trials or sessions necessary to allow for a consistent assessment of nicotine responding, we used these analyses to determine whether consistency of nicotine responses was maintained when measures were obtained in fewer than three sessions or when using fewer than four trials per session. Therefore, consistency of the three nicotine session mean responses was determined using session means based on the average of all four trials, the first three trials only, the first two trials only, and the first trial only of each nicotine session. Consistency of responses only to trial 1 across sessions allowed for an examination of consistency in the absence of any possible influence of acute tolerance, because trial 1 responses were not preceded by any other recent nicotine intake. A similar approach was used to determine the consistency of the first two nicotine session means. Finally, the consistency of responses across the separate trials within each nicotine session was determined, comparing all four trials, trials 1 3 only, and trials 1 2 only. Because the results of this last analysis were similar for each of the three individual nicotine sessions, only the results for session 1 are presented (because most studies are likely to include only one session per drug condition). Results Mean responses on each of the four trials of the three nicotine sessions and one placebo session are presented in Figure 1. Significant main effects of nicotine were observed for nine of the 14 dependent measures: POMS scales of arousal, vigor, and fatigue (decrease), the VAS items of head rush and dizzy, all three cardiovascular measures, and handsteadiness. Interactions of dose by trial, indicating differential change in responses to nicotine across dose administrations relative to placebo responses, were observed for POMS scales of confusion and fatigue, VAS items of head rush and dizzy, heart rate, and handsteadiness. These interactions reflected increased nicotine effects across trials for POMS fatigue and for handsteadiness but decreased effects across trials, suggesting acute tolerance, for POMS confusion, VAS head rush and dizzy, and heart rate. However, only POMS fatigue showed a significant effect of nicotine sessions, indicating a significantly smaller response to nicotine on that measure across the three sessions involving nicotine administration. Thus, most of the measures demonstrated significant effects of nicotine, some of these effects varied across trials, but almost none varied systematically across days. Table 1 presents the intraclass correlations for nicotine session means when those means were based on all four trials of each session, the first three trials only, the first two trials only, and the first trial only. ICCs are shown for consistency across all three nicotine sessions (top) and across the first two nicotine sessions only (bottom). These results allow for an examination of any loss of consistency for session means when they were determined by fewer and fewer assessment trials per session, as well as by fewer sessions. For consistency across all three nicotine sessions, all ICCs were significant, even when session means were based on only the first trial. However, ICCs were more modest for systolic blood pressure response regardless of the number of trials examined and for diastolic blood pressure response when only trial 1 was examined. For consistency across only the first two nicotine sessions, ICCs tended to be much lower for all measures except heart rate and handsteadiness. ICCs were not even significant for several measures, especially systolic and diastolic blood pressure, depending on the combination of trials used to determine session means. Thus, consistency was substantially poorer when means across only two sessions were examined, compared with means across three sessions. Shown in Table 2 are the ICCs for consistency across the separate trials of nicotine administration during nicotine session 1, when examining all four trials, the first three trials only, and the first two trials only. The goal was to gauge the loss of consistency with the reduction in number of trials during a single assessment session, by far the most common procedure used in laboratory studies of acute nicotine effects (e.g., Kalman, 2002). ICCs for all measures were highly significant, even when responses were limited to only the first two trials of session 1. Similar ICC values were observed when this same analysis

5 NICOTINE & TOBACCO RESEARCH 881 Figure 1. Mean responses (change from baseline) to administration of nicotine spray (20 mg/kg) on each of 3 days or placebo spray on 1 day. Nicotine or placebo spray was administered every 30 min across four trials on each day. Asterisks indicate a significant main effect of nicotine vs. placebo (***pv.001, **pv.01, *pv.05). The superscript a indicates a significant effect of nicotine days; the dagger indicates a significant interaction of nicotine 6 trials. examined the consistency across trials for session 2 alone or for session 3 alone (neither shown), indicating that the consistency across trials within a session was not unique to the first session of nicotine exposure. Discussion There was little loss of consistency in acute subjective, cardiovascular, and performance effects of nicotine spray across all three nicotine sessions when the means for those sessions were based on four, three, two, or

6 882 ACUTE RESPONSES TO NICOTINE IN HUMANS Table 1. Intraclass correlation coefficients for consistency across the three nicotine session means (top) and across the first two nicotine sessions means (bottom) when those means were based on all four trials, the first three trials only, the first two trials only, and trial 1 only Consistency of session means across sessions 1 3 Measures Trials 1 4 Trials 1 3 Trials 1 2 Trial 1 VAS Head rush.86 (.68.95)***.86 (.68.95)***.87 (.70.95)***.83 (.62.94)*** Dizzy.76 (.45.91)***.80 (.55.92)***.81 (.57.93)***.85 (.65.94)*** POMS Vigor.88 (.72.95)***.85 (.65.94)***.83 (.60.93)***.83 (.62.94)*** Fatigue.70 (.32.89)**.73 (.39 90)***.78 (.49.92)***.86 (.67.95)*** Arousal.86 (.68.95)***.83 (.62.94)***.83 (.62.94)***.83 (.62.94)*** Cardiovascular Systolic blood pressure.62 (.13.85)*.64 (.18.86)**.50 ( )*.63 (.17.86)** Diastolic blood pressure.73 (.38.90)***.78 (.49.91)***.70 (.33.89)**.60 (.09.85)* Heart rate.89 (.76.96)***.90 (.74.96)***.88 (.73.96)***.89 (.74.96)*** Performance Handsteadiness.90 (.78 96)***.89 (.76.96)***.86 (.68.95)***.73 (.40.90)*** even one trial of drug administration. However, consistency was much poorer, and even occasionally nonsignificant, when consistency was examined across only two nicotine sessions. Yet good consistency across trials was observed when multiple trials from Consistency of session means across sessions 1 2 Measures Trials 1 4 Trials 1 3 Trials 1 2 Trial 1 VAS Head rush.73 (.25.91)**.70 (.17.90)*.72 (.23.90)**.71 (.20.90)** Dizzy.62 ( )*.64 (.00.87)*.64 ( )*.79 (.43.93)** POMS Vigor.71 (.20.90)**.57 ( ).50 ( ).59 ( )* Fatigue.65 (.03.88)*.70 (.17.90)*.73 (.25.91)**.79 (.42.93)** Arousal.78 (.37.92)**.72 (.21.90)**.69 (.14.89)*.70 (.17.89)* Cardiovascular Systolic blood pressure.06 ( ).23 ( ).13 ( ).17 ( ) Diastolic blood pressure.60 ( )*.64 ( )*.51 ( ).43 ( ) Heart rate.94 (.82.98)***.93 (.82.98)***.93 (.80.98)***.91 (.75.97)*** Performance Handsteadiness.85 (.60.95)***.87 (.64.95)***.85 (.57.95)***.78 (.38.92)** Note. 95% confidence intervals are provided in parentheses. Only measures showing a significant main effect of nicotine are shown. ***pv.001, **pv.01, *pv.05. only one session were examined, suggesting that only a few trials from a single assessment session may be sufficient to provide consistent measures of acute nicotine effects. However, multiple sessions with the same dose do not improve consistency, especially if Table 2. Intraclass correlation coefficients for consistency across individual trials within nicotine session 1, for all four trials, the first three trials only, and the first two trials only Consistency across trials within nicotine session 1 Measures Trials 1 4 Trials 1 3 Trials 1 2 VAS Head rush.93 (.85.97)***.90 (.77.96)***.83 (.54.94)*** Dizzy.94 (.87.97)***.93 (.84.97)***.83 (.53.94)*** POMS Vigor.84 (.66.94)***.79 (.51.92)***.79 (.41.93)** Fatigue.97 (.94.99)***.96 (.90.98)***.91 (.76.97)*** Arousal.91 (.80.96)***.89 (.74.96)***.81 (.48.93)*** Cardiovascular Systolic blood pressure.89 (.76.96)***.86 (.67.95)***.81 (.46.93)** Diastolic blood pressure.90 (.80.96)***.85 (.65.94)***.84 (.55.94)*** Heart rate.94 (.87.98)***.92 (.82.97)***.84 (.54.94)*** Performance Handsteadiness.93 (.86.97)***.90 (.77.96)***.83 (.52.94)*** Note. 95% confidence intervals are provided in parentheses. As in Table 1, only measures showing a significant main effect of nicotine are shown. ***pv.001, **pv.01, *pv.05.

7 NICOTINE & TOBACCO RESEARCH 883 only two such sessions are used. Therefore, multiple sessions do not appear necessary to obtain a consistent assessment of nicotine sensitivity to most measures. Several responses showed significant interactions of dose by trials suggestive of the onset of acute tolerance, or smaller responding, across repeated nicotine administrations, as demonstrated in previous research (e.g., Perkins, Grobe, et al., 1994). Acute tolerance, by definition, will reduce the magnitude of drug effects across trials within a session, perhaps complicating the effort to reliably determine the size of an individual s characteristic sensitivity to nicotine. However, as noted previously, our key interest here was in determining whether the relative magnitude of response for a given individual is consistent across assessments, and not necessarily whether the absolute response is consistent. Thus, acute tolerance should not affect consistency if the onset of acute tolerance does not differ substantially across individuals. The fact that consistency across sessions was similar whether based on only one or more than one trial per session (see Table 1) suggests that acute tolerance did not influence our findings on consistency. Moreover, if acute tolerance did vary across individuals, such variability would add error to the assessment of responses across later trials, which should decrease the observed consistency. If so, our results involving responses to multiple trials per session may underestimate the consistency of nicotine effects across repeated administrations. Nevertheless, one implication of finding that responding is consistent when examining only one session involving two dosing trials (see Table 2) or three sessions involving only one dosing trial (see Table 1) is that researchers interested in characterizing responses to nicotine may be able to lessen the influence of acute tolerance by including fewer drug administrations during each session without sacrificing consistency. However, our results for the consistency of responses to only the first one or two trials per session may not be fully valid. In each session, subjects always experienced additional trials of nicotine exposure beyond these one or two trials, even though responses to the additional trials were excluded from some of the analyses. That additional exposure may have influenced responses on the first one or two trials of subsequent sessions, the only trials included in those analyses. Studies involving nicotine exposure during only a single trial or two per session are needed to confirm that responding is consistent across so few drug administrations. The generally high consistency of responses to nicotine observed here suggests that individual differences in these responses also are consistent. Therefore, it may be possible to associate these individual differences in drug responding with certain characteristics of those individuals (e.g., trait factors such as personality or genetics). Better understanding of these associations could improve our knowledge of the mechanisms responsible for sensitivity to nicotine (Perkins et al., 2000). Such differences also may be associated with smoking history in a manner that helps explain the onset of chronic tolerance to nicotine (e.g., Perkins, Gerlach, et al., 2001). However, a limitation of the present study is the absence of plasma nicotine data, to verify equal dosing between subjects as well as across administrations within subjects. For example, certain subjects could exhibit consistently greater responses because they experienced consistently greater increases in plasma nicotine following each nasal spray administration, not because they are more sensitive to the pharmacological effects of a given dose of nicotine. This alternative explanation seems unlikely because previous research has shown that the nasal spray procedure used, which corrects nicotine dosing for body weight, provides reliable, dose-dependent increases in plasma nicotine (e.g., Perkins, Gerlach, et al., 2001; Perkins, Grobe, et al., 1994; see also Pomerleau et al., 1989). The conclusions of this study are relevant for responses to nicotine as defined by change from predrug baseline to each drug administration, a common procedure. Consistency of responses to the specific pharmacological actions of nicotine per se, excluding nonspecific effects due to the drug administration procedure (i.e., reactions to any nasal spray), is not as clear from this study and warrants research attention. However, as emphasized, the main objective of this study was practical to determine the fewest numbers of trials or sessions a study could have and still provide a consistent measure of sensitivity to nicotine s acute effects. Therefore, it may be safe to conclude that responses to nicotine administration as a whole (i.e., specific and nonspecific effects of spray) are consistent, although the consistency of responses to nicotine per se remains to be determined. Similarly, these findings may be limited to the specific procedures of this study, which examined only the consistency of certain responses to one moderate dose of nicotine via nasal spray in smokers under resting conditions. These results do not necessarily address the consistency of responses to other doses of nicotine or of responses to nicotine via smoking or other methods of administration, although some research suggests that responses to nicotine are similar whether administered by spray or smoking (Perkins, Sexton, et al., 1994). Also not clear is whether subjects naïve to nicotine (i.e., never-smokers) would exhibit the same consistency, because only dependent smokers were examined. Nor do these results indicate whether other effects of nicotine, such as cognitive performance (Heishman et al., 1994), would be consistent, or whether nicotine responses would be consistent when administered under other environmental conditions (Perkins, 1999; Perkins, & Stitzer, 1998).

8 884 ACUTE RESPONSES TO NICOTINE IN HUMANS Future research should examine the consistency of acute responses to other psychoactive drugs. As in the nicotine literature, few studies have examined the consistency of acute responses to other psychoactive drugs in humans, although repeating session conditions, including the drug dose administered, on separate days is not unusual in some research areas, such as behavioral economics (e.g., Ward, Comer, Haney, Foltin, & Fischman, 1997). Such information on consistency is especially important for efforts to compare individual differences in sensitivity between different drugs (e.g., examining whether individuals who are more sensitive to nicotine are also more sensitive to caffeine, as in Perkins, Fonte, Ashcom, Broge, & Wilson, 2001). These comparisons may be problematic in the absence of information about the consistency of responses to one or both drugs. To conclude, acute responses to nicotine are generally consistent, even across as few as two trials of drug administration in one session. Multiple sessions involving the same drug condition do not appear to improve consistency, and use of only two sessions may impair consistency results. However, these findings may be relevant only to nasal spray administration under the conditions of this study, and they may partly reflect characteristic responding to the drug administration procedure (i.e., specific and nonspecific effects of nicotine nasal spray) and not just to nicotine. Further demonstration that acute effects of nicotine are consistent should aid research aimed at understanding individual differences in nicotine sensitivity. Acknowledgments This research was supported by National Institute on Drug Abuse grants DA05807 and DA The authors thank James Grobe and Rick Blakesley for their assistance. References American Psychiatric Association. (1994). 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