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Impulsive Choice and Impulsive Action Predict Vulnerability to Distinct Stages of Nicotine Seeking in Rats
Impulsive Choice and Impulsive Action Predict Vulnerability to Distinct Stages of Nicotine Seeking in Rats Leontien Diergaarde, Tommy Pattij, Ingmar Poortvliet, François Hogenboom, Wendy de Vries, Anton N.M. Schoffelmeer, and Taco J. De Vries Background: Although heavy smoking has been associated with impulsivity in humans, it is not clear whether poor impulse control represents a risk factor in the etiology of nicotine dependence. Methods: To address this issue, rats were selected on the basis of individual differences in impulsivity in the delayed reward task (impulsive choice) and the 5-choice serial reaction time task (impulsive action). Subsequently, rats were subjected to a nicotine self-administration (SA) paradigm tailored to measure the motivational properties of nicotine and nicotine-associated stimuli. In separate groups, differences in electrically evoked dopamine release in slice preparations obtained from several mesolimbic brain regions were determined. Results: Impulsive action was associated with an enhanced motivation to initiate and maintain nicotine SA. In contrast, impulsive choice predicted a diminished ability to inhibit nicotine seeking during abstinence and an enhanced vulnerability to relapse upon re-exposure to nicotine cues. Impulsive action was associated with reduced dopamine release in the accumbens core and impulsive choice with reduced dopamine release in accumbens core, shell, and medial prefrontal cortex. Conclusions: The strong association between sub-dimensions of impulsivity and nicotine SA implies that interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and/or lead to successful smoking cessation. Key Words: Addiction, dopamine, impulsivity, individual differences, nucleus accumbens, prefrontal cortex, rats
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ecause human studies have suggested a strong association between cigarette smoking and impulsive behavior, elevated impulsivity might form a risk factor for the initiation and maintenance of nicotine dependence. It is not clear, however, whether poor impulse control is a pre-existing vulnerability trait or a consequence of nicotine exposure. To explore a possible role of impulsivity in the susceptibility to nicotine dependence and relapse, animal studies using drugnaïve individuals are required. Impulsivity has a multi-faceted nature (1), and the various behavioral expressions of impulsivity can broadly be divided into two categories (2), namely behaviors resulting from deficits in the ability to withhold responding and thereby reflecting poor inhibitory control (impulsive action), and behaviors that do not result from inhibitory control deficits but result from insensitivity to delay of gratification or delay aversion and consequently lead to impulsive decision-making exemplified by increased preference for immediate reward over more beneficial but delayed reward (impulsive choice). Both dimensions of impulsivity are associated with smoking. Thus, smokers prefer small immediately available reward (e.g., bouts of nicotine) over a variety of larger but delayed rewards, including a healthier future life. Accordingly, impulsive choice is increased in smokers as compared with nonsmoking individuals (3,4). In addition, smoking is
From the Center for Neurogenomics and Cognitive Research, Department of Anatomy and Neurosciences, VU Medical Center, Amsterdam, The Netherlands. Address reprint requests to Leontien Diergaarde, Ph.D., Center for Neurogenomics and Cognitive Research, Department of Anatomy and Neurosciences, VU Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands; E-mail: [email protected]. Received February 15, 2007; revised July 13, 2007; accepted July 13, 2007.
0006-3223/08/$34.00 doi:10.1016/j.biopsych.2007.07.011
associated with impaired inhibitory control (5) and elevated motor impulsivity (4,6). Recent clinical findings suggest that poor decision-making (impulsive choice) might be a reliable predictor of relapse behavior, whereas elevated motor impulsivity (4,6) has been hypothesized as a risk factor in the initiation of smoking behavior. Accordingly, we hypothesize that sub-dimensions of impulsivity might be differentially involved in the various stages of nicotine self-administration (SA) and relapse. To analyze these sub-dimensions of impulsivity in rats, various animal models are available. In the present study we used the 5-choice serial reaction time task (5CSRTT) to tax sustained attention and impulsive action (7), while impulsive choice was determined with the delayed reward task (DRT) (8). Recently, an association between elevated impulsivity and increased SA behavior has been reported for cocaine (9,10). These studies focused on the initiation of drug SA behavior and on a single dimension of impulsivity. In the present study we employed a nicotine SA paradigm tailored to analyze (1) the initiation of nicotine SA, (2) the motivational strength of nicotine (3), the persistence of nicotine seeking after abstinence, and (4) the vulnerability to relapse to nicotine seeking upon re-exposure to nicotine-associated environmental stimuli. Such nicotine-associated cues are of critical importance in maintaining nicotine SA and are potent relapse triggers (11–13). Impaired impulse control has been shown to relate to prefrontal cortical (PFC) dysfunction (14). Accordingly, increased impulsivity has been reported in rats with lesions of the PFC and nucleus accumbens (Acb) or upon manipulation of accumbal dopamine function (15–18). Interestingly, these same brain regions are implicated in the acute rewarding effects of nicotine (19) and play a crucial role in relapse behavior as measured in animal models (20 –23) as well as in human smokers (24). Collectively, these studies suggest that impulsive behavior and nicotine dependence or addictive behavior in general share common neural substrates and therefore are closely interrelated BIOL PSYCHIATRY 2008;63:301–308 © 2008 Society of Biological Psychiatry
302 BIOL PSYCHIATRY 2008;63:301–308 (25). In addition, there is the assumption that impulsive choice and impulsive action are different identities and have distinct neural substrates. Therefore, another aim of the present study was to evaluate the trait characteristics of both sub-dimensions of impulsivity and to explore their underlying neurobiological substrates. As a first step, we focused on differences in dopamine function and determined depolarization-induced dopamine release in slices of the Acb core and shell, dorsal striatum, and medial PFC of rats with high and low levels of either impulsive choice or impulsive action.
Methods and Materials Animals Subjects were male Wistar rats (Harlan CPB, Horst, Netherlands), initially weighing 225–250 g, and housed in pairs in enriched macrolon cages. After 2 weeks habituation, rats were food deprived and maintained at 85%–90% of their free feeding weight until the end of either the 5CSRTT or the delayed reward task (DRT) procedures. Experiments were conducted during the dark phase of a reversed 12-h light-dark cycle (lights on at 7:00 PM). All experiments were approved by the Animal Care committee of the Free University of Amsterdam. Experimental Design Thirty-two rats were screened in the 5CSRTT, and an additional group of rats (n ⫽ 32) were screened in the DRT before being subjected to the nicotine SA procedure. Differences in in vitro neurotransmitter release were determined in separate groups of rats displaying either high (n ⫽ 8) or low (n ⫽ 8) levels of impulsive choice selected from a cohort of 32 rats and in rats displaying high (n ⫽ 10) or low (n ⫽ 10) levels of impulsive action selected from a cohort of 40 rats. 5CSRTT Rats were trained in 12 identical operant chambers (Med Associates, St. Albans, Vermont) to detect a brief (1 s) visual stimulus presented randomly in one of the five nose poke holes as described in more detail previously (26) and in (Supplement 1). Delayed Reward Task The delayed reward paradigm as employed in our laboratory has been described in more detail previously (27) and in Supplement 1. Training was conducted in the same operant chambers as described in the preceding text. Selection of High- and Low-Impulsive Rats Rats screened on the 5CSRTT were labeled as either lowimpulsive (lower quartile) or high-impulsive (upper quartile) on the basis of the mean percentage of premature responses (i.e., number of premature responses / (correct ⫹ incorrect ⫹ perseverative ⫹ premature responses) ⫻ 100%) during the last five stable 5CSRTT sessions. Labeling of rats screened by means of the DRT was based on the delay for which they switched their preference over to the immediate, small reward (i.e., preference for large reward ⬍ 50% [means of last five sessions]). All high-impulsive rats switched their preference at a delay of ⱕ 10 s, whereas all low-impulsive rats switched at a delay of ⱖ 20 s. To determine whether these selection criteria were stable and “trait-like” over time, performance of high- and low-impulsive individuals from previous studies in both paradigms was averaged over five consecutive stable baseline sessions and compared with a baseline session that was performed 4 weeks later. www.sobp.org/journal
L. Diergaarde et al. Nicotine SA Rats were trained to self-administer nicotine as described previously (28) and in Supplement 1. Subsequently, rats were subjected to a between-session progressive ratio schedule, followed by an extinction phase and a relapse test. Neurotransmitter Release Additional groups were trained on either the 5CSRTT or the DRT task to determine differences in dopamine release between high- and low-impulsive rats. Selection criteria were the same as for the rats that underwent nicotine SA experiments. Food was present ad libitum during the 2 weeks after the end of 5CSRTT or DRT; rats were decapitated at the end of this period. The Acb shell and core, dorsal striatum (DS), and medial prefrontal cortex (mPFC; anterior cingulate, infralimbic, and prelimbic cortex) were rapidly dissected from the brain. In replicate experiments, brain tissue of 2 animals was pooled, and slices (.3 ⫻ .3 ⫻ 2 mm) were prepared with a McIlwain tissue chopper and incubated and superfused as described before (29) and in Supplement 1. Statistical Analyses Behavioral data from the 5CSRTT, DRT, and different stages of nicotine SA were subjected to repeated measures analysis of variance (ANOVA) with impulsivity level as between subjects variable (all experiments). Neurotransmitter release in pooled brain structures from high-impulsive rats was calculated as percentage change in neurotransmitter release from low-impulsive rats and analyzed with a one-way ANOVA with the level of impulsivity as between subjects variable. Homogeneity of variance across groups was assessed by the circularity test and, in case of violation of homogeneity, corrected, and more conservative Huynh-Feldt p values were used for subsequent analyses. Statistically significant main effects obtained in the behavioral experiments were followed by further one-way ANOVAs. In addition, to determine the test-retest reliability of trait-like impulsivity in both the 5CSRTT and DRT, a reliability analysis was performed to calculate Cronbach’s ␣. Data were analyzed with NCSS 2004 (Kaysville, Utah), and the criterion for statistically significant effects was set at p ⬍ .05.
Results Selection Criteria for Impulsive Action and Impulsive Choice Are Stable over Time Reliability analyses revealed that levels of impulsive action (5CSRTT) and impulsive choice (DRT) were stable over time (5CSRTT: Cronbach’s ␣ ⫽ .92, and DRT: Cronbach’s ␣ ⫽ .89). A further within-subjects repeated measures ANOVA revealed that baseline performance did not significantly differ from the re-test performance 4 weeks later [5CSRTT: F (1,12) ⫽ 2.70, p ⫽ NS; DRT: F (1,16) ⫽ .17, p ⫽ NS].The individual test-retest data are depicted in Figures 1A [5CSRTT] and 1B [DRT]. Impulsive Action and Nicotine SA 5CSRTT. Under stable baseline performance, the proportion of premature responses amounted to 23 ⫾ 2% in the upper quartile and to 13 ⫾ 1% in the lower quartile of the population of rats [F (1,14) ⫽ 19.24, p ⬍ .001; Figure 2]. Likewise, highimpulsive rats made more perseverative responses [high: 22 ⫾ 3 and low: 10 ⫾ 2 responses; F (1,14) ⫽ 13.27, p ⬍ .005]. Accurate choice was lower in high-impulsive rats [F (1,14) ⫽ 14.25, p ⬍ .005]; however, in-depth analyses indicated that this did not result from reduced attentional capacities, because the total number of correct stimulus detections was comparable across
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Figure 1. Trait impulsivity. (A) Premature responding (%) in low- and highimpulsive rats during baseline testing (means of five consecutive 5-choice serial reaction time task [5CSRTT] sessions) and re-test performance 4 weeks later. (B) Impulsive choice (mean % large reward for 10- and 20-s delays) in low- and high-impulsive rats during baseline testing (five consecutive delayed reward task [DRT] sessions) and re-test performance 4 weeks later. Depicted are individual values (lower quartile: Œ, upper quartile: ) and group means (⫺), ␣ ⬎ .75.
groups [F (1,14) ⫽ .008, p ⫽ NS] and high-impulsive rats only made more incorrect responses [F (1,14) ⫽ 48.9, p ⬍ .001]. No group differences were detected for omissions, correct response latencies, or magazine latencies (data not shown), indicating that there were neither large differences in motivation nor motor activity between high- and low-impulsive rats. Nicotine SA. Rats readily acquired nicotine SA behavior (Figure 3A), and the number of active responses was relatively high during session 1 and did not increase further over sessions, presumably resulting from a long history of instrumental conditioning. Nonetheless, high-impulsive rats made significantly more active responses during acquisition [impulsivity: F (1,14) ⫽ 6.26, p ⬍ .05]. In contrast, responding on the inactive hole tended to decrease over sessions in both groups similarly [session: F (9,123) ⫽ 1.90, p ⫽ .06]. Upon stable nicotine intake after 10 FR1 sessions, response requirements were progressively increased over sessions to FR25 (between-sessions progressive ratio, PR). As a result in both
Figure 2. Stable baseline responding for 5 days in the 5-choice serial reaction time task (5CSRTT) in the lower and upper quartile of rats on the basis of their impulsive action in this paradigm. Depicted is the percentage ⫾ SEM of premature responses in the lower quartile □ and the upper quartile of the population. *p ⬍ .001.
Figure 3. Nicotine self-administration (SA) in the lower and upper quartile of rats screened on impulsive action in the 5-choice serial reaction time task (5CSRTT). Continuous lines symbolize active responses, whereas dashed lines represent inactive responses; lower quartile (Œ) and upper quartile (). (A) Active and inactive responses during acquisition of nicotine SA. (B) Number of active responses (lines) and infusions (histograms) during between-sessions progressive ratio responding for nicotine. (C) Extinction of nicotine SA behavior. (D) Conditioned-cued reinstatement of nicotine seeking behavior compared with nose poking behavior during the last extinction session, active responses () and inactive responses (□). Data represent means ⫾ SEM. *p ⬍ .05.
groups active responses increased over ratios; however, the number of active responses was higher in high-impulsive rats for all response requirements [Figure 3B; ratio: F (7,90) ⫽ 7.32, p ⬍ .001; impulsivity: F (1,14) ⫽ 5.39, p ⬍ .05]. With increasing response requirements, the number of nicotine infusions decreased with high-impulsive rats earning more nicotine rewards [ratio: F (7,90) ⫽ 23.74, p ⬍ .001; F (1,14) ⫽ 4.42, p ⬍ .05]. Likewise, inactive responding decreased over ratios with no differences between groups [ratio: F (7,90) ⫽ 4.18, p ⬍ .001]. After PR responding, rats were subjected to four additional FR3 sessions. During the last FR3 session, high- and low-impulsive individuals displayed equal numbers of active responding (low: 41 ⫾ 6 and high: 32 ⫾ 5). Then, extinction training commenced for 14 subsequent sessions (Figure 3C). In the absence of nicotine and nicotine-associated stimuli, responding in the active hole significantly decreased [session effect: F (13,158) ⫽ 14.30, p ⬍ .001]. High-impulsive rats showed stronger resistance to extinction of nicotine seeking [session ⫻ impulsivity: F (13,158) ⫽ 1.79, p ⬍ .05], but further ANOVAs revealed no significant group differences in individual extinction sessions. Presentation of nicotine-associated cues robustly reinstated responses into the active hole [cue: F (1,14) ⫽ 17.95, p ⬍ .001]. Nonetheless, both high- and low-impulsive rats made comparable numbers of active responses during the conditionedcued reinstatement test (Figure 3D). Finally, low-impulsive indiwww.sobp.org/journal
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viduals displayed a small increase in inactive responses during reinstatement testing [cue ⫻ impulsivity: F (1,14) ⫽ 5.00, p ⬍ .05]. Impulsive Choice and Nicotine SA DRT. As shown in Figure 4, both low- and high-impulsive rats delay-dependently decreased their preference for a delayed, large reward [delay: F (4,52) ⫽ 61.81, p ⬍ .001]. Impulsive choice differed between groups in a delay-dependent manner [delay ⫻ impulsivity: F (4,52) ⫽ 5.28, p ⬍ .01]. Further ANOVAs indicated that for the no-delay condition there was no group difference in the preference for the large reward; however, starting from the 5-s delay high-impulsive rats discounted the large reward more. Furthermore, the total numbers of omissions to start a trial did not differ between high- and low-impulsive individuals (high: 9.7 ⫾ 1.4 and low: 9.5 ⫾ .7). Nicotine SA. Nicotine SA was readily acquired (Figure 5A), and the number of active responses was already high for the first session and did not further increase with repeated training. Highand low-impulsive rats self-administered equal amounts of nicotine during the acquisition phase. Inactive responding was stable during acquisition and was not different between both groups. After 10 FR1 sessions, rats were subjected to a betweensessions PR experiment (Figure 5B), and this resulted in increments in active responses [ratio: F (7,91) ⫽ 9.41, p ⬍ .001], and moreover, high-impulsive rats made more active responses on FR20 and FR25 [ratio ⫻ impulsivity: F (7,91) ⫽ 5.53, p ⬍ .001]. The number of nicotine infusions decreased significantly when response requirement increased, and these decrements were more pronounced in low-impulsive individuals for FR20 and FR25 [ratio: F (7,91) ⫽ 51.72, p ⬍ .001; ratio ⫻ impulsivity: F (7,91) ⫽ 4.62, p ⬍ .001]. In addition, inactive responses decreased with increasing ratios [ratio: F (7,91) ⫽ 4.17, p ⬍ .01] and were not affected by the level of impulsivity. After PR testing rats received three additional FR3 sessions. By the last FR3 session, both groups displayed equal numbers of
Figure 5. Nicotine self-administration (SA) in the lower and upper quartile of rats screened on impulsive choice in the delayed reward task (DRT). Continuous lines symbolize active responses, whereas dashed lines represent inactive responses; lower quartile (Œ) and upper quartile (). (A) Active and inactive responses during acquisition of nicotine SA. (B) Number of active responses (lines) and infusions (histograms) during between-sessions progressive ratio responding for nicotine. (C) Extinction of nicotine SA behavior. (D) Conditioned-cued reinstatement of nicotine seeking behavior compared with nose poking behavior during the last extinction session, active responses () inactive responses (□). Data represent means ⫾ SEM. *p ⬍ .05; **p ⬍ .01.
active (low: 30 ⫾ 5, and high: 33 ⫾ 5) and inactive (low: 5 ⫾ 2, and high: 4 ⫾ 1) responses. Hereafter, nicotine SA was extinguished during 12 subsequent sessions (Figure 5C). Active responses rapidly declined in the absence of nicotine and nicotine-associated stimuli [session: F (11,142) ⫽ 21.40, p ⬍ .001], whereas high-impulsive rats were more resistant to extinction [session ⫻ impulsivity: F (11,142) ⫽ 4.18, p ⬍ .02]. The number of inactive responses decreased similarly across both groups [session: F (11,142) ⫽ 3.38, p ⬍ .02]. Presentation of nicotineassociated cues robustly reinstated responding into the active hole [cue: F (1,11) ⫽ 28.61, p ⬍ .001], and high-impulsive rats made considerably more active responses [Figure 5D; cue ⫻ impulsivity: F (1,11) ⫽ 7.17, p ⬍ .05]. No significant group differences were observed for the number of responses into the inactive hole.
Figure 4. Stable baseline responding for 5 days in the delayed reward task (DRT) in the lower quartile (Œ) and upper quartile () of rats on the basis of their impulsive choice in this paradigm. Plotted is the percentage choice for the delayed, large reward as a function of the delay between choice and delivery of the large reward. Data are expressed as means ⫾ SEM. *p ⬍ .05; **p ⬍ .01; ***p ⬍ .001.
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In Vitro Dopamine Release 5CSRTT. An upper and lower quartile was selected as described before [premature responses low-impulsive rats: 7 ⫾ 1% and high-impulsive rats: 19 ⫾ 1%; F (1,18) ⫽ 243.33, p ⬍ .001]. Control [3H] dopamine release (in low-impulsive rats) amounted to 6.9 ⫾ .3 (mPFC), 2.6 ⫾ .1 (DS), 1.9 ⫾ .1 (Acb shell), and 3.3 ⫾ .2 (Acb core) of total tissue tritium, respectively. As shown in Figure 6A, dopamine release in the Acb shell was
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mine reactivity in the DS was not affected by impulsivity level [F (1,30) ⫽ .26, p ⫽ NS].
Discussion Our study, by combining advanced animal models of impulsivity and nicotine addiction, is the first to demonstrate that poor impulse control might enhance the vulnerability to nicotine SA and that sub-dimensions of impulsivity predict vulnerability to distinct stages of nicotine seeking behavior. Thus, impulsive action mainly reflects a pre-existing vulnerability to initiation and maintenance of nicotine taking, whereas impulsive choice seems primarily related to an inability to inhibit nicotine seeking during abstinence together with an enhanced sensitivity to nicotineassociated cues that precipitate relapse. The different dimensions of impulsivity have a trait-like nature and might originate from differences in reactivity of accumbens and prefrontal dopaminergic nerve terminals.
Figure 6. Electrically evoked release of [3H] dopamine in the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens shell (Acb shell), and core (Acb core) of the lower and upper quartile of rats on the basis of their impulsive action in the 5-choice serial reaction time task (5CSRTT) (A) or impulsive choice in the delayed reward task (DRT) (B). Data of the upper quartile of rats () are expressed as percentage of the release measured in the lower quartile (□). Values represent means ⫾ SEM of four to five experiments. In each brain region evoked [3H] dopamine release was confined to the stimulation period and the next 10-min fraction collected. *p ⬍ .05; **p ⬍ .01; ***p ⬍ .001.
significantly increased in high- compared with low-impulsive rats [F (1,38) ⫽ 4.56, p ⬍ .05]. In contrast, a reduction in dopamine release was found in the Acb core for high- compared with low-impulsive rats [F (1,38) ⫽ 58.06, p ⬍ .001]. No differences in dopamine reactivity were detected in the mPFC or DS [F (1,38) ⫽ .85, p ⬍ .05 and F (1,38) ⫽ .74, p ⫽ NS; respectively]. DRT. An upper and lower quartile was selected as described before, and impulsive choice was again significantly different between groups in a delay-dependent manner [delay ⫻ impulsivity: F (4,90) ⫽ 19.02, p ⬍ .001]. Control [3H] dopamine release (in low-impulsive rats) amounted to 5.0 ⫾ .3 (mPFC), 2.0 ⫾ .1 (DS), 2.2 ⫾ .1 (Acb shell), and 2.8 ⫾ .3 (Acb core) of total tissue tritium, respectively. As shown in Figure 6B, dopamine release in the mPFC [F (1,30) ⫽ 6.05, p ⬍ .02], Acb shell [F (1,30) ⫽ 25.70, p ⬍ .001], and Acb core [F (1,30) ⫽ 6.58, p ⬍ .02] was significantly reduced in high- as compared with low-impulsive rats. Dopa-
Impulsivity and Nicotine SA Impulsive action was associated with higher levels of nicotine SA during the entire acquisition phase. When response requirements were gradually increased, impulsive rats consistently reached higher nicotine intake levels throughout all tested ratio requirements compared with their more self-controlled counterparts, which is generally interpreted as an increased motivation to obtain a particular reinforcer (30,31). Importantly, in the absence of differences on measures reflecting motivation and motor activity in the 5CSRTT, such as omissions and response latencies, the differences in nicotine SA are likely to be caused by disturbances in inhibitory control. This notion is further substantiated by the fact that the number of inactive responses in the nicotine SA paradigm did not differ between individuals selected on the basis of impulsive action and that the observed differences were limited to specific stages of nicotine taking and seeking. Finally, trait impulsivity on the 5CSRTT has been shown to be inversely related to the level of spontaneous locomotor activity (10), indicating that impulsivity rather than hyperactivity underlies the higher rates of nicotine SA. Collectively, high-impulsive rats responded differently as compared with their low-impulsive counterparts in stages where nicotine was available (i.e., when responding was reinforced by nicotine). In the absence of nicotine, extinction responding was only slightly elevated in high-impulsive rats, a short-lived effect, because responding returned to comparable levels within two sessions. One might have predicted that extinction behavior would have been more affected by impulsive action as high motor impulsive rats have difficulties in inhibiting their response. It should be kept in mind, however, that animals were not confronted with the nicotine-associated cues during extinction and therefore were not challenged to respond prematurely. Also, no differences were found between high- and low-impulsive rats when nicotine-associated cues were presented again and nicotine seeking behavior was successfully reinstated. These findings indicate that pre-existing differences in impulsive action predicts sensitivity in particular to the primary reinforcing effects of nicotine but not the secondary reinforcing properties of nicotineassociated cues, the latter being powerful stimuli for relapse to nicotine seeking after abstinence. Impulsive choice predicted vulnerability to other stages of nicotine taking and seeking behavior in our model compared with impulsive action. Similar to impulsive action, there were no large differences in overall levels of activity that might have contributed to these findings. During acquisition of nicotine SA, www.sobp.org/journal
306 BIOL PSYCHIATRY 2008;63:301–308 the number of nicotine infusions was similar in high- and low-impulsive rats. Likewise, during the between-sessions PR experiment, both groups earned similar amounts of nicotine infusions when response ratios were increased up to FR15, possibly indicating that, in contrast to impulsive action, impulsive choice did not affect the reinforcing strength of nicotine. Nonetheless, high-impulsive rats maintained higher levels of responding when response requirements were further increased (FR20 and FR25). This might suggest that rats more prone to impulsive choice are more motivated to self-administer nicotine when response rates are high. Conversely, these higher response rates under increased task demands might also relate to the observed much stronger resistance to extinction when nicotine was no longer available and suggests that impulsive choice is associated with enhanced nicotine seeking behavior after abstinence. In agreement with this view is the finding that, upon re-exposure to nicotine-associated cues, high-impulsive rats showed a more robust reinstatement of nicotine seeking. Collectively, these results suggest that impulsive decision making might increase the risk to relapse after smoking cessation. In addition to the current findings, previous preclinical studies have shown a similar relationship between poor impulse control and increased vulnerability to self-administer other substances of abuse, such as cocaine (9,10) as well as alcohol (32). Together, these findings imply that disturbances in impulse control might be considered as general risk factors for the initiation of addictive behavior. Importantly, although evidence is still limited, clinical studies have indeed confirmed the existence of a relationship between poor impulse control and subsequent drug use. For instance, elevated trait impulsivity has been shown to correlate with a higher probability of experimenting with cigarettes and its progression to regular tobacco use as well as the failure to quit smoking (33). In addition, it has been demonstrated recently that impulsive choice as measured on a neuropsychological test of decision making predicts early relapse in drinking behavior in alcohol-dependent subjects (34). Interestingly, in line with these latter findings, decreased activation of, for example, the dorsolateral prefrontal cortex during performance in a decision-making task has been shown to reliably predict the propensity to relapse in previous methamphetamine users (35). The fact that these relationships can now be studied in animal models (present study) paves the way for the development of novel therapeutic strategies. Further insight in the neurobiological substrates of the multiple forms of impulsivity might lead to new pharmaceutical targets for the improvement of impulse control. Impulsivity and Dopamine Function The two sub-dimensions of impulsivity were associated with distinct differences in depolarization-induced dopamine release in terminal areas of the mesocorticolimbic dopamine system. Because the neurochemical analyses were performed 1 week after the animals were last tested in the impulsivity paradigms and brains were collected from animals in resting conditions, the differences in reactivity of the dopamine nerve terminals can be considered as a trait characteristic. In this respect, it is important to note that we (present study) and others have shown that trait impulsivity in 5CSRTT represents a stable subtype that can be dissociated behaviorally and pharmacologically from other subtypes such as attentive and inattentive subtypes (36). Collectively, these and our data support the idea that impulsivity is not a unitary concept and that various dimensions of impulsivity might have a different neural basis. Although firm conclusions on www.sobp.org/journal
L. Diergaarde et al. a causal relationship of such in vitro findings with the observed behavioral characteristics should be drawn with care, our findings seem in line with recent observations on the role of dopamine function in the Acb and mPFC in measures of impulsivity. A role of dopamine in impulsive action as measured in the 5CSRTT has been clearly demonstrated (17,26) with a particular role of Acb dopamine release (18,37). In this respect, we demonstrated that amphetamine-induced increments in premature responding were particularly sensitive to dopamine D2 receptor blockade in the core but not shell of the Acb. A role of mPFC dopamine in premature responding is less clear cut, and in fact, dopamine efflux in the mPFC seemed not to be related to premature responding in the 5CSRTT (38). Interestingly, our neurochemical analyses revealed that impulsive action was associated with a reduction in electrically evoked release of dopamine from Acb core slices, whereas no differences were observed in the mPFC and the dorsal striatum. In line with the idea that in particular a dys- or hypofunctional dopamine system in Acb might represent a vulnerability factor for both impulse action and addictive behavior are the recent observations by Dalley et al. (10) showing that reduced dopamine D2 receptor function was related to increased cocaine SA in rats displaying high rates of impulsive action. A role of dopamine in impulsive choice has been demonstrated in both animal (2,27) as well as in human (39) versions of delay discounting procedures. With respect to the neuroanatomical substrates involved, Acb core (15) lesions increased impulsive choice in rats, whereas lesioning the mPFC was without effect. Human studies, however, highlight a role of the mPFC, because several studies have demonstrated that patients with PFC damage showed increased impulsive choice on several decision-making tasks (14,40). Our neurochemical data revealed that impulsive choice was associated with reduced dopamine reactivity in both Acb shell and core regions and an attenuated responsiveness of mPFC dopamine terminals. As mentioned earlier, activation patterns within the prefrontal area during performance in a decision-making task has been shown to reliably predict the propensity to relapse in previous methamphetamine users (35). Such relationships are supported by the fact that there is a considerable overlap in the brain regions regulating impulse control and those mediating the reinforcing properties of drugs and drug-associated stimuli, including those of nicotine. Similar to other drugs of abuse, accumbal dopamine plays an important role in the reinforcing properties of nicotine (41,42), and smoking-induced dopamine release in the ventral striatum has recently been demonstrated in humans (43). In particular, selective increases in Acb shell dopamine transmission have been demonstrated upon intravenous nicotine (self-)administration in rats (44,45). In addition, besides its postulated role in impulsivity, the mPFC seems a critical relay station within the neural circuitry mediating conditioned-cued relapse to drug seeking in rats (46). Similarly, human brain imaging studies have demonstrated the involvement of the PFC in cue reactivity in nicotine-deprived smokers and detoxified cocaine users (13,47,48). In conclusion, the strong interrelationship between impulsivity and motivational processes as presented in this study might have its origin in mesocorticolimbic dopamine systems known to play crucial roles in Pavlovian conditioning, relapse to drug seeking, and impulse control (25). In this respect, our neurochemical data are only a first step in unraveling the neurobiological origins of individual differences in distinct measures of impulsivity. Another neurotransmitter system of interest in this
L. Diergaarde et al. respect is the serotonergic system and in particular its interaction with the dopamine system (49). Other candidate brain regions that warrant further analysis, because they have been strongly implicated in impulse control, include the basolateral amygdala, orbitofrontal cortex (50), and subthalamic nucleus (51,52). Our experimental design did not permit the determination of the extent to which impulsive choice and impulsive action would correlate. On the basis of the fact that both the behavioral (i.e., nicotine SA data) and neurochemical profiles of impulsive rats screened on the 5CSRTT and rats screened by means of the DRT differ to a large degree, we speculate that this correlation would be rather low. Also, Winstanley et al. (53), with central serotonin depletion in non-selected rats reported little inter-relationship between action and choice impulsivity. Whether this also holds true for innate impulsivity remains to be established. Concluding Remarks Our data, translated to the human situation, would imply that impulsive action heightens the risk of smoking initiation and promotes continued smoking, whereas impaired decision making (impulsive choice) seems primarily related to failure to quit smoking and enhanced sensitivity to smoking-relating cues that precipitate relapse. These distinct measures of impulsive behavior were associated with specific dopamine imbalances in (fronto)striatal circuitry that might well be responsible for the observed differences in vulnerability to nicotine SA and relapse. Therefore, pharmacological and behavioral interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and continued tobacco abuse or, alternatively, lead to successful smoking cessation. Drs. Diergaarde and Pattij contributed equally to this study. We thank Dr. J.W. Dalley for helpful comments on our manuscript; G. Wardeh, R. Binnekade, H. Raasø, J. de Kieviet, and A. Sah for excellent technical support; and Dr. M.M. van Gaalen for MED programming. The authors do not have any conflicts to disclose. Supplementary materials cited in this article are available online. 1. Evenden JL (1999): Varieties of impulsivity. Psychopharmacology 146: 348 –361. 2. Winstanley CA, Eagle DM, Robbins TW (2006): Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies. Clin Psychol Rev 26:379 –395. 3. Bickel WK, Odum AL, Madden GJ (1999): Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology (Berl) 146:447– 454. 4. Mitchell SH (1999): Measures of impulsivity in cigarette smokers and non-smokers. Psychopharmacology (Berl) 146:455– 464. 5. Spinella M (2002): Correlations between orbitofrontal dysfunction and tobacco smoking. Addict Biol 7:381–384. 6. Skinner MD, Aubin HJ, Berlin I (2004): Impulsivity in smoking, nonsmoking, and ex-smoking alcoholics. Addict Behav 29:973–978. 7. Robbins TW (2002): The 5-choice serial reaction time task: Behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380. 8. Evenden JL, Ryan CN (1996): The pharmacology of impulsive behaviour in rats: The effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 128:161–170. 9. Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005): Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine selfadministration in female rats. Psychopharmacology 178:193–201. 10. Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DE, Laane K, et al. (2007): Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270.
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308 BIOL PSYCHIATRY 2008;63:301–308 35. Paulus MP, Tapert SF, Schuckit MA (2005): Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse. Arch Gen Psych 62:761–768. 36. Blondeau C, Dellu-Hagedorn F (2007): Dimensional analysis of ADHD subtypes in rats. Biol Psychiatry 61:1340 –1350. 37. Cole BJ, Robbins TW (1989): Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: Implications for theories of selective attention and arousal. Behav Brain Res 33:165–179. 38. Dalley JW, Theobald DE, Pereira EA, Li PM, Robbins TW (2002): Specific abnormalities in serotonin release in the prefrontal cortex of isolation-reared rats measured during behavioural performance of a task assessing visuospatial attention and impulsivity. Psychopharmacology (Berl) 164:329–340. 39. de Wit H, Enggasser JL, Richards JB (2002): Acute administration of d-amphetamine decreases impulsivity in healthy volunteers. Neuropsychopharmacol 27:813– 825. 40. Manes F, Sahakian B, Clark L, Rogers R, Antoun N, Aitken M, et al. (2002): Decision-making processes following damage to the prefrontal cortex. Brain 125:624 – 639. 41. Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992): The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107:285–289. 42. Corrigall WA, Coen KM, Adamson KL (1994): Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278 –284. 43. Brody AL (2005): Functional brain imaging of tobacco use and dependence. J Psychiatr Res 40:404 – 418. 44. Lecca D, Cacciapaglia F, Valentini V, Gronli J, Spiga S, Di Chiara G (2006): Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration. Psychopharmacology 184:435– 446.
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B
ecause human studies have suggested a strong association between cigarette smoking and impulsive behavior, elevated impulsivity might form a risk factor for the initiation and maintenance of nicotine dependence. It is not clear, however, whether poor impulse control is a pre-existing vulnerability trait or a consequence of nicotine exposure. To explore a possible role of impulsivity in the susceptibility to nicotine dependence and relapse, animal studies using drugnaïve individuals are required. Impulsivity has a multi-faceted nature (1), and the various behavioral expressions of impulsivity can broadly be divided into two categories (2), namely behaviors resulting from deficits in the ability to withhold responding and thereby reflecting poor inhibitory control (impulsive action), and behaviors that do not result from inhibitory control deficits but result from insensitivity to delay of gratification or delay aversion and consequently lead to impulsive decision-making exemplified by increased preference for immediate reward over more beneficial but delayed reward (impulsive choice). Both dimensions of impulsivity are associated with smoking. Thus, smokers prefer small immediately available reward (e.g., bouts of nicotine) over a variety of larger but delayed rewards, including a healthier future life. Accordingly, impulsive choice is increased in smokers as compared with nonsmoking individuals (3,4). In addition, smoking is
From the Center for Neurogenomics and Cognitive Research, Department of Anatomy and Neurosciences, VU Medical Center, Amsterdam, The Netherlands. Address reprint requests to Leontien Diergaarde, Ph.D., Center for Neurogenomics and Cognitive Research, Department of Anatomy and Neurosciences, VU Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands; E-mail: [email protected]. Received February 15, 2007; revised July 13, 2007; accepted July 13, 2007.
0006-3223/08/$34.00 doi:10.1016/j.biopsych.2007.07.011
associated with impaired inhibitory control (5) and elevated motor impulsivity (4,6). Recent clinical findings suggest that poor decision-making (impulsive choice) might be a reliable predictor of relapse behavior, whereas elevated motor impulsivity (4,6) has been hypothesized as a risk factor in the initiation of smoking behavior. Accordingly, we hypothesize that sub-dimensions of impulsivity might be differentially involved in the various stages of nicotine self-administration (SA) and relapse. To analyze these sub-dimensions of impulsivity in rats, various animal models are available. In the present study we used the 5-choice serial reaction time task (5CSRTT) to tax sustained attention and impulsive action (7), while impulsive choice was determined with the delayed reward task (DRT) (8). Recently, an association between elevated impulsivity and increased SA behavior has been reported for cocaine (9,10). These studies focused on the initiation of drug SA behavior and on a single dimension of impulsivity. In the present study we employed a nicotine SA paradigm tailored to analyze (1) the initiation of nicotine SA, (2) the motivational strength of nicotine (3), the persistence of nicotine seeking after abstinence, and (4) the vulnerability to relapse to nicotine seeking upon re-exposure to nicotine-associated environmental stimuli. Such nicotine-associated cues are of critical importance in maintaining nicotine SA and are potent relapse triggers (11–13). Impaired impulse control has been shown to relate to prefrontal cortical (PFC) dysfunction (14). Accordingly, increased impulsivity has been reported in rats with lesions of the PFC and nucleus accumbens (Acb) or upon manipulation of accumbal dopamine function (15–18). Interestingly, these same brain regions are implicated in the acute rewarding effects of nicotine (19) and play a crucial role in relapse behavior as measured in animal models (20 –23) as well as in human smokers (24). Collectively, these studies suggest that impulsive behavior and nicotine dependence or addictive behavior in general share common neural substrates and therefore are closely interrelated BIOL PSYCHIATRY 2008;63:301–308 © 2008 Society of Biological Psychiatry
302 BIOL PSYCHIATRY 2008;63:301–308 (25). In addition, there is the assumption that impulsive choice and impulsive action are different identities and have distinct neural substrates. Therefore, another aim of the present study was to evaluate the trait characteristics of both sub-dimensions of impulsivity and to explore their underlying neurobiological substrates. As a first step, we focused on differences in dopamine function and determined depolarization-induced dopamine release in slices of the Acb core and shell, dorsal striatum, and medial PFC of rats with high and low levels of either impulsive choice or impulsive action.
Methods and Materials Animals Subjects were male Wistar rats (Harlan CPB, Horst, Netherlands), initially weighing 225–250 g, and housed in pairs in enriched macrolon cages. After 2 weeks habituation, rats were food deprived and maintained at 85%–90% of their free feeding weight until the end of either the 5CSRTT or the delayed reward task (DRT) procedures. Experiments were conducted during the dark phase of a reversed 12-h light-dark cycle (lights on at 7:00 PM). All experiments were approved by the Animal Care committee of the Free University of Amsterdam. Experimental Design Thirty-two rats were screened in the 5CSRTT, and an additional group of rats (n ⫽ 32) were screened in the DRT before being subjected to the nicotine SA procedure. Differences in in vitro neurotransmitter release were determined in separate groups of rats displaying either high (n ⫽ 8) or low (n ⫽ 8) levels of impulsive choice selected from a cohort of 32 rats and in rats displaying high (n ⫽ 10) or low (n ⫽ 10) levels of impulsive action selected from a cohort of 40 rats. 5CSRTT Rats were trained in 12 identical operant chambers (Med Associates, St. Albans, Vermont) to detect a brief (1 s) visual stimulus presented randomly in one of the five nose poke holes as described in more detail previously (26) and in (Supplement 1). Delayed Reward Task The delayed reward paradigm as employed in our laboratory has been described in more detail previously (27) and in Supplement 1. Training was conducted in the same operant chambers as described in the preceding text. Selection of High- and Low-Impulsive Rats Rats screened on the 5CSRTT were labeled as either lowimpulsive (lower quartile) or high-impulsive (upper quartile) on the basis of the mean percentage of premature responses (i.e., number of premature responses / (correct ⫹ incorrect ⫹ perseverative ⫹ premature responses) ⫻ 100%) during the last five stable 5CSRTT sessions. Labeling of rats screened by means of the DRT was based on the delay for which they switched their preference over to the immediate, small reward (i.e., preference for large reward ⬍ 50% [means of last five sessions]). All high-impulsive rats switched their preference at a delay of ⱕ 10 s, whereas all low-impulsive rats switched at a delay of ⱖ 20 s. To determine whether these selection criteria were stable and “trait-like” over time, performance of high- and low-impulsive individuals from previous studies in both paradigms was averaged over five consecutive stable baseline sessions and compared with a baseline session that was performed 4 weeks later. www.sobp.org/journal
L. Diergaarde et al. Nicotine SA Rats were trained to self-administer nicotine as described previously (28) and in Supplement 1. Subsequently, rats were subjected to a between-session progressive ratio schedule, followed by an extinction phase and a relapse test. Neurotransmitter Release Additional groups were trained on either the 5CSRTT or the DRT task to determine differences in dopamine release between high- and low-impulsive rats. Selection criteria were the same as for the rats that underwent nicotine SA experiments. Food was present ad libitum during the 2 weeks after the end of 5CSRTT or DRT; rats were decapitated at the end of this period. The Acb shell and core, dorsal striatum (DS), and medial prefrontal cortex (mPFC; anterior cingulate, infralimbic, and prelimbic cortex) were rapidly dissected from the brain. In replicate experiments, brain tissue of 2 animals was pooled, and slices (.3 ⫻ .3 ⫻ 2 mm) were prepared with a McIlwain tissue chopper and incubated and superfused as described before (29) and in Supplement 1. Statistical Analyses Behavioral data from the 5CSRTT, DRT, and different stages of nicotine SA were subjected to repeated measures analysis of variance (ANOVA) with impulsivity level as between subjects variable (all experiments). Neurotransmitter release in pooled brain structures from high-impulsive rats was calculated as percentage change in neurotransmitter release from low-impulsive rats and analyzed with a one-way ANOVA with the level of impulsivity as between subjects variable. Homogeneity of variance across groups was assessed by the circularity test and, in case of violation of homogeneity, corrected, and more conservative Huynh-Feldt p values were used for subsequent analyses. Statistically significant main effects obtained in the behavioral experiments were followed by further one-way ANOVAs. In addition, to determine the test-retest reliability of trait-like impulsivity in both the 5CSRTT and DRT, a reliability analysis was performed to calculate Cronbach’s ␣. Data were analyzed with NCSS 2004 (Kaysville, Utah), and the criterion for statistically significant effects was set at p ⬍ .05.
Results Selection Criteria for Impulsive Action and Impulsive Choice Are Stable over Time Reliability analyses revealed that levels of impulsive action (5CSRTT) and impulsive choice (DRT) were stable over time (5CSRTT: Cronbach’s ␣ ⫽ .92, and DRT: Cronbach’s ␣ ⫽ .89). A further within-subjects repeated measures ANOVA revealed that baseline performance did not significantly differ from the re-test performance 4 weeks later [5CSRTT: F (1,12) ⫽ 2.70, p ⫽ NS; DRT: F (1,16) ⫽ .17, p ⫽ NS].The individual test-retest data are depicted in Figures 1A [5CSRTT] and 1B [DRT]. Impulsive Action and Nicotine SA 5CSRTT. Under stable baseline performance, the proportion of premature responses amounted to 23 ⫾ 2% in the upper quartile and to 13 ⫾ 1% in the lower quartile of the population of rats [F (1,14) ⫽ 19.24, p ⬍ .001; Figure 2]. Likewise, highimpulsive rats made more perseverative responses [high: 22 ⫾ 3 and low: 10 ⫾ 2 responses; F (1,14) ⫽ 13.27, p ⬍ .005]. Accurate choice was lower in high-impulsive rats [F (1,14) ⫽ 14.25, p ⬍ .005]; however, in-depth analyses indicated that this did not result from reduced attentional capacities, because the total number of correct stimulus detections was comparable across
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Figure 1. Trait impulsivity. (A) Premature responding (%) in low- and highimpulsive rats during baseline testing (means of five consecutive 5-choice serial reaction time task [5CSRTT] sessions) and re-test performance 4 weeks later. (B) Impulsive choice (mean % large reward for 10- and 20-s delays) in low- and high-impulsive rats during baseline testing (five consecutive delayed reward task [DRT] sessions) and re-test performance 4 weeks later. Depicted are individual values (lower quartile: Œ, upper quartile: ) and group means (⫺), ␣ ⬎ .75.
groups [F (1,14) ⫽ .008, p ⫽ NS] and high-impulsive rats only made more incorrect responses [F (1,14) ⫽ 48.9, p ⬍ .001]. No group differences were detected for omissions, correct response latencies, or magazine latencies (data not shown), indicating that there were neither large differences in motivation nor motor activity between high- and low-impulsive rats. Nicotine SA. Rats readily acquired nicotine SA behavior (Figure 3A), and the number of active responses was relatively high during session 1 and did not increase further over sessions, presumably resulting from a long history of instrumental conditioning. Nonetheless, high-impulsive rats made significantly more active responses during acquisition [impulsivity: F (1,14) ⫽ 6.26, p ⬍ .05]. In contrast, responding on the inactive hole tended to decrease over sessions in both groups similarly [session: F (9,123) ⫽ 1.90, p ⫽ .06]. Upon stable nicotine intake after 10 FR1 sessions, response requirements were progressively increased over sessions to FR25 (between-sessions progressive ratio, PR). As a result in both
Figure 2. Stable baseline responding for 5 days in the 5-choice serial reaction time task (5CSRTT) in the lower and upper quartile of rats on the basis of their impulsive action in this paradigm. Depicted is the percentage ⫾ SEM of premature responses in the lower quartile □ and the upper quartile of the population. *p ⬍ .001.
Figure 3. Nicotine self-administration (SA) in the lower and upper quartile of rats screened on impulsive action in the 5-choice serial reaction time task (5CSRTT). Continuous lines symbolize active responses, whereas dashed lines represent inactive responses; lower quartile (Œ) and upper quartile (). (A) Active and inactive responses during acquisition of nicotine SA. (B) Number of active responses (lines) and infusions (histograms) during between-sessions progressive ratio responding for nicotine. (C) Extinction of nicotine SA behavior. (D) Conditioned-cued reinstatement of nicotine seeking behavior compared with nose poking behavior during the last extinction session, active responses () and inactive responses (□). Data represent means ⫾ SEM. *p ⬍ .05.
groups active responses increased over ratios; however, the number of active responses was higher in high-impulsive rats for all response requirements [Figure 3B; ratio: F (7,90) ⫽ 7.32, p ⬍ .001; impulsivity: F (1,14) ⫽ 5.39, p ⬍ .05]. With increasing response requirements, the number of nicotine infusions decreased with high-impulsive rats earning more nicotine rewards [ratio: F (7,90) ⫽ 23.74, p ⬍ .001; F (1,14) ⫽ 4.42, p ⬍ .05]. Likewise, inactive responding decreased over ratios with no differences between groups [ratio: F (7,90) ⫽ 4.18, p ⬍ .001]. After PR responding, rats were subjected to four additional FR3 sessions. During the last FR3 session, high- and low-impulsive individuals displayed equal numbers of active responding (low: 41 ⫾ 6 and high: 32 ⫾ 5). Then, extinction training commenced for 14 subsequent sessions (Figure 3C). In the absence of nicotine and nicotine-associated stimuli, responding in the active hole significantly decreased [session effect: F (13,158) ⫽ 14.30, p ⬍ .001]. High-impulsive rats showed stronger resistance to extinction of nicotine seeking [session ⫻ impulsivity: F (13,158) ⫽ 1.79, p ⬍ .05], but further ANOVAs revealed no significant group differences in individual extinction sessions. Presentation of nicotine-associated cues robustly reinstated responses into the active hole [cue: F (1,14) ⫽ 17.95, p ⬍ .001]. Nonetheless, both high- and low-impulsive rats made comparable numbers of active responses during the conditionedcued reinstatement test (Figure 3D). Finally, low-impulsive indiwww.sobp.org/journal
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viduals displayed a small increase in inactive responses during reinstatement testing [cue ⫻ impulsivity: F (1,14) ⫽ 5.00, p ⬍ .05]. Impulsive Choice and Nicotine SA DRT. As shown in Figure 4, both low- and high-impulsive rats delay-dependently decreased their preference for a delayed, large reward [delay: F (4,52) ⫽ 61.81, p ⬍ .001]. Impulsive choice differed between groups in a delay-dependent manner [delay ⫻ impulsivity: F (4,52) ⫽ 5.28, p ⬍ .01]. Further ANOVAs indicated that for the no-delay condition there was no group difference in the preference for the large reward; however, starting from the 5-s delay high-impulsive rats discounted the large reward more. Furthermore, the total numbers of omissions to start a trial did not differ between high- and low-impulsive individuals (high: 9.7 ⫾ 1.4 and low: 9.5 ⫾ .7). Nicotine SA. Nicotine SA was readily acquired (Figure 5A), and the number of active responses was already high for the first session and did not further increase with repeated training. Highand low-impulsive rats self-administered equal amounts of nicotine during the acquisition phase. Inactive responding was stable during acquisition and was not different between both groups. After 10 FR1 sessions, rats were subjected to a betweensessions PR experiment (Figure 5B), and this resulted in increments in active responses [ratio: F (7,91) ⫽ 9.41, p ⬍ .001], and moreover, high-impulsive rats made more active responses on FR20 and FR25 [ratio ⫻ impulsivity: F (7,91) ⫽ 5.53, p ⬍ .001]. The number of nicotine infusions decreased significantly when response requirement increased, and these decrements were more pronounced in low-impulsive individuals for FR20 and FR25 [ratio: F (7,91) ⫽ 51.72, p ⬍ .001; ratio ⫻ impulsivity: F (7,91) ⫽ 4.62, p ⬍ .001]. In addition, inactive responses decreased with increasing ratios [ratio: F (7,91) ⫽ 4.17, p ⬍ .01] and were not affected by the level of impulsivity. After PR testing rats received three additional FR3 sessions. By the last FR3 session, both groups displayed equal numbers of
Figure 5. Nicotine self-administration (SA) in the lower and upper quartile of rats screened on impulsive choice in the delayed reward task (DRT). Continuous lines symbolize active responses, whereas dashed lines represent inactive responses; lower quartile (Œ) and upper quartile (). (A) Active and inactive responses during acquisition of nicotine SA. (B) Number of active responses (lines) and infusions (histograms) during between-sessions progressive ratio responding for nicotine. (C) Extinction of nicotine SA behavior. (D) Conditioned-cued reinstatement of nicotine seeking behavior compared with nose poking behavior during the last extinction session, active responses () inactive responses (□). Data represent means ⫾ SEM. *p ⬍ .05; **p ⬍ .01.
active (low: 30 ⫾ 5, and high: 33 ⫾ 5) and inactive (low: 5 ⫾ 2, and high: 4 ⫾ 1) responses. Hereafter, nicotine SA was extinguished during 12 subsequent sessions (Figure 5C). Active responses rapidly declined in the absence of nicotine and nicotine-associated stimuli [session: F (11,142) ⫽ 21.40, p ⬍ .001], whereas high-impulsive rats were more resistant to extinction [session ⫻ impulsivity: F (11,142) ⫽ 4.18, p ⬍ .02]. The number of inactive responses decreased similarly across both groups [session: F (11,142) ⫽ 3.38, p ⬍ .02]. Presentation of nicotineassociated cues robustly reinstated responding into the active hole [cue: F (1,11) ⫽ 28.61, p ⬍ .001], and high-impulsive rats made considerably more active responses [Figure 5D; cue ⫻ impulsivity: F (1,11) ⫽ 7.17, p ⬍ .05]. No significant group differences were observed for the number of responses into the inactive hole.
Figure 4. Stable baseline responding for 5 days in the delayed reward task (DRT) in the lower quartile (Œ) and upper quartile () of rats on the basis of their impulsive choice in this paradigm. Plotted is the percentage choice for the delayed, large reward as a function of the delay between choice and delivery of the large reward. Data are expressed as means ⫾ SEM. *p ⬍ .05; **p ⬍ .01; ***p ⬍ .001.
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In Vitro Dopamine Release 5CSRTT. An upper and lower quartile was selected as described before [premature responses low-impulsive rats: 7 ⫾ 1% and high-impulsive rats: 19 ⫾ 1%; F (1,18) ⫽ 243.33, p ⬍ .001]. Control [3H] dopamine release (in low-impulsive rats) amounted to 6.9 ⫾ .3 (mPFC), 2.6 ⫾ .1 (DS), 1.9 ⫾ .1 (Acb shell), and 3.3 ⫾ .2 (Acb core) of total tissue tritium, respectively. As shown in Figure 6A, dopamine release in the Acb shell was
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mine reactivity in the DS was not affected by impulsivity level [F (1,30) ⫽ .26, p ⫽ NS].
Discussion Our study, by combining advanced animal models of impulsivity and nicotine addiction, is the first to demonstrate that poor impulse control might enhance the vulnerability to nicotine SA and that sub-dimensions of impulsivity predict vulnerability to distinct stages of nicotine seeking behavior. Thus, impulsive action mainly reflects a pre-existing vulnerability to initiation and maintenance of nicotine taking, whereas impulsive choice seems primarily related to an inability to inhibit nicotine seeking during abstinence together with an enhanced sensitivity to nicotineassociated cues that precipitate relapse. The different dimensions of impulsivity have a trait-like nature and might originate from differences in reactivity of accumbens and prefrontal dopaminergic nerve terminals.
Figure 6. Electrically evoked release of [3H] dopamine in the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens shell (Acb shell), and core (Acb core) of the lower and upper quartile of rats on the basis of their impulsive action in the 5-choice serial reaction time task (5CSRTT) (A) or impulsive choice in the delayed reward task (DRT) (B). Data of the upper quartile of rats () are expressed as percentage of the release measured in the lower quartile (□). Values represent means ⫾ SEM of four to five experiments. In each brain region evoked [3H] dopamine release was confined to the stimulation period and the next 10-min fraction collected. *p ⬍ .05; **p ⬍ .01; ***p ⬍ .001.
significantly increased in high- compared with low-impulsive rats [F (1,38) ⫽ 4.56, p ⬍ .05]. In contrast, a reduction in dopamine release was found in the Acb core for high- compared with low-impulsive rats [F (1,38) ⫽ 58.06, p ⬍ .001]. No differences in dopamine reactivity were detected in the mPFC or DS [F (1,38) ⫽ .85, p ⬍ .05 and F (1,38) ⫽ .74, p ⫽ NS; respectively]. DRT. An upper and lower quartile was selected as described before, and impulsive choice was again significantly different between groups in a delay-dependent manner [delay ⫻ impulsivity: F (4,90) ⫽ 19.02, p ⬍ .001]. Control [3H] dopamine release (in low-impulsive rats) amounted to 5.0 ⫾ .3 (mPFC), 2.0 ⫾ .1 (DS), 2.2 ⫾ .1 (Acb shell), and 2.8 ⫾ .3 (Acb core) of total tissue tritium, respectively. As shown in Figure 6B, dopamine release in the mPFC [F (1,30) ⫽ 6.05, p ⬍ .02], Acb shell [F (1,30) ⫽ 25.70, p ⬍ .001], and Acb core [F (1,30) ⫽ 6.58, p ⬍ .02] was significantly reduced in high- as compared with low-impulsive rats. Dopa-
Impulsivity and Nicotine SA Impulsive action was associated with higher levels of nicotine SA during the entire acquisition phase. When response requirements were gradually increased, impulsive rats consistently reached higher nicotine intake levels throughout all tested ratio requirements compared with their more self-controlled counterparts, which is generally interpreted as an increased motivation to obtain a particular reinforcer (30,31). Importantly, in the absence of differences on measures reflecting motivation and motor activity in the 5CSRTT, such as omissions and response latencies, the differences in nicotine SA are likely to be caused by disturbances in inhibitory control. This notion is further substantiated by the fact that the number of inactive responses in the nicotine SA paradigm did not differ between individuals selected on the basis of impulsive action and that the observed differences were limited to specific stages of nicotine taking and seeking. Finally, trait impulsivity on the 5CSRTT has been shown to be inversely related to the level of spontaneous locomotor activity (10), indicating that impulsivity rather than hyperactivity underlies the higher rates of nicotine SA. Collectively, high-impulsive rats responded differently as compared with their low-impulsive counterparts in stages where nicotine was available (i.e., when responding was reinforced by nicotine). In the absence of nicotine, extinction responding was only slightly elevated in high-impulsive rats, a short-lived effect, because responding returned to comparable levels within two sessions. One might have predicted that extinction behavior would have been more affected by impulsive action as high motor impulsive rats have difficulties in inhibiting their response. It should be kept in mind, however, that animals were not confronted with the nicotine-associated cues during extinction and therefore were not challenged to respond prematurely. Also, no differences were found between high- and low-impulsive rats when nicotine-associated cues were presented again and nicotine seeking behavior was successfully reinstated. These findings indicate that pre-existing differences in impulsive action predicts sensitivity in particular to the primary reinforcing effects of nicotine but not the secondary reinforcing properties of nicotineassociated cues, the latter being powerful stimuli for relapse to nicotine seeking after abstinence. Impulsive choice predicted vulnerability to other stages of nicotine taking and seeking behavior in our model compared with impulsive action. Similar to impulsive action, there were no large differences in overall levels of activity that might have contributed to these findings. During acquisition of nicotine SA, www.sobp.org/journal
306 BIOL PSYCHIATRY 2008;63:301–308 the number of nicotine infusions was similar in high- and low-impulsive rats. Likewise, during the between-sessions PR experiment, both groups earned similar amounts of nicotine infusions when response ratios were increased up to FR15, possibly indicating that, in contrast to impulsive action, impulsive choice did not affect the reinforcing strength of nicotine. Nonetheless, high-impulsive rats maintained higher levels of responding when response requirements were further increased (FR20 and FR25). This might suggest that rats more prone to impulsive choice are more motivated to self-administer nicotine when response rates are high. Conversely, these higher response rates under increased task demands might also relate to the observed much stronger resistance to extinction when nicotine was no longer available and suggests that impulsive choice is associated with enhanced nicotine seeking behavior after abstinence. In agreement with this view is the finding that, upon re-exposure to nicotine-associated cues, high-impulsive rats showed a more robust reinstatement of nicotine seeking. Collectively, these results suggest that impulsive decision making might increase the risk to relapse after smoking cessation. In addition to the current findings, previous preclinical studies have shown a similar relationship between poor impulse control and increased vulnerability to self-administer other substances of abuse, such as cocaine (9,10) as well as alcohol (32). Together, these findings imply that disturbances in impulse control might be considered as general risk factors for the initiation of addictive behavior. Importantly, although evidence is still limited, clinical studies have indeed confirmed the existence of a relationship between poor impulse control and subsequent drug use. For instance, elevated trait impulsivity has been shown to correlate with a higher probability of experimenting with cigarettes and its progression to regular tobacco use as well as the failure to quit smoking (33). In addition, it has been demonstrated recently that impulsive choice as measured on a neuropsychological test of decision making predicts early relapse in drinking behavior in alcohol-dependent subjects (34). Interestingly, in line with these latter findings, decreased activation of, for example, the dorsolateral prefrontal cortex during performance in a decision-making task has been shown to reliably predict the propensity to relapse in previous methamphetamine users (35). The fact that these relationships can now be studied in animal models (present study) paves the way for the development of novel therapeutic strategies. Further insight in the neurobiological substrates of the multiple forms of impulsivity might lead to new pharmaceutical targets for the improvement of impulse control. Impulsivity and Dopamine Function The two sub-dimensions of impulsivity were associated with distinct differences in depolarization-induced dopamine release in terminal areas of the mesocorticolimbic dopamine system. Because the neurochemical analyses were performed 1 week after the animals were last tested in the impulsivity paradigms and brains were collected from animals in resting conditions, the differences in reactivity of the dopamine nerve terminals can be considered as a trait characteristic. In this respect, it is important to note that we (present study) and others have shown that trait impulsivity in 5CSRTT represents a stable subtype that can be dissociated behaviorally and pharmacologically from other subtypes such as attentive and inattentive subtypes (36). Collectively, these and our data support the idea that impulsivity is not a unitary concept and that various dimensions of impulsivity might have a different neural basis. Although firm conclusions on www.sobp.org/journal
L. Diergaarde et al. a causal relationship of such in vitro findings with the observed behavioral characteristics should be drawn with care, our findings seem in line with recent observations on the role of dopamine function in the Acb and mPFC in measures of impulsivity. A role of dopamine in impulsive action as measured in the 5CSRTT has been clearly demonstrated (17,26) with a particular role of Acb dopamine release (18,37). In this respect, we demonstrated that amphetamine-induced increments in premature responding were particularly sensitive to dopamine D2 receptor blockade in the core but not shell of the Acb. A role of mPFC dopamine in premature responding is less clear cut, and in fact, dopamine efflux in the mPFC seemed not to be related to premature responding in the 5CSRTT (38). Interestingly, our neurochemical analyses revealed that impulsive action was associated with a reduction in electrically evoked release of dopamine from Acb core slices, whereas no differences were observed in the mPFC and the dorsal striatum. In line with the idea that in particular a dys- or hypofunctional dopamine system in Acb might represent a vulnerability factor for both impulse action and addictive behavior are the recent observations by Dalley et al. (10) showing that reduced dopamine D2 receptor function was related to increased cocaine SA in rats displaying high rates of impulsive action. A role of dopamine in impulsive choice has been demonstrated in both animal (2,27) as well as in human (39) versions of delay discounting procedures. With respect to the neuroanatomical substrates involved, Acb core (15) lesions increased impulsive choice in rats, whereas lesioning the mPFC was without effect. Human studies, however, highlight a role of the mPFC, because several studies have demonstrated that patients with PFC damage showed increased impulsive choice on several decision-making tasks (14,40). Our neurochemical data revealed that impulsive choice was associated with reduced dopamine reactivity in both Acb shell and core regions and an attenuated responsiveness of mPFC dopamine terminals. As mentioned earlier, activation patterns within the prefrontal area during performance in a decision-making task has been shown to reliably predict the propensity to relapse in previous methamphetamine users (35). Such relationships are supported by the fact that there is a considerable overlap in the brain regions regulating impulse control and those mediating the reinforcing properties of drugs and drug-associated stimuli, including those of nicotine. Similar to other drugs of abuse, accumbal dopamine plays an important role in the reinforcing properties of nicotine (41,42), and smoking-induced dopamine release in the ventral striatum has recently been demonstrated in humans (43). In particular, selective increases in Acb shell dopamine transmission have been demonstrated upon intravenous nicotine (self-)administration in rats (44,45). In addition, besides its postulated role in impulsivity, the mPFC seems a critical relay station within the neural circuitry mediating conditioned-cued relapse to drug seeking in rats (46). Similarly, human brain imaging studies have demonstrated the involvement of the PFC in cue reactivity in nicotine-deprived smokers and detoxified cocaine users (13,47,48). In conclusion, the strong interrelationship between impulsivity and motivational processes as presented in this study might have its origin in mesocorticolimbic dopamine systems known to play crucial roles in Pavlovian conditioning, relapse to drug seeking, and impulse control (25). In this respect, our neurochemical data are only a first step in unraveling the neurobiological origins of individual differences in distinct measures of impulsivity. Another neurotransmitter system of interest in this
L. Diergaarde et al. respect is the serotonergic system and in particular its interaction with the dopamine system (49). Other candidate brain regions that warrant further analysis, because they have been strongly implicated in impulse control, include the basolateral amygdala, orbitofrontal cortex (50), and subthalamic nucleus (51,52). Our experimental design did not permit the determination of the extent to which impulsive choice and impulsive action would correlate. On the basis of the fact that both the behavioral (i.e., nicotine SA data) and neurochemical profiles of impulsive rats screened on the 5CSRTT and rats screened by means of the DRT differ to a large degree, we speculate that this correlation would be rather low. Also, Winstanley et al. (53), with central serotonin depletion in non-selected rats reported little inter-relationship between action and choice impulsivity. Whether this also holds true for innate impulsivity remains to be established. Concluding Remarks Our data, translated to the human situation, would imply that impulsive action heightens the risk of smoking initiation and promotes continued smoking, whereas impaired decision making (impulsive choice) seems primarily related to failure to quit smoking and enhanced sensitivity to smoking-relating cues that precipitate relapse. These distinct measures of impulsive behavior were associated with specific dopamine imbalances in (fronto)striatal circuitry that might well be responsible for the observed differences in vulnerability to nicotine SA and relapse. Therefore, pharmacological and behavioral interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and continued tobacco abuse or, alternatively, lead to successful smoking cessation. Drs. Diergaarde and Pattij contributed equally to this study. We thank Dr. J.W. Dalley for helpful comments on our manuscript; G. Wardeh, R. Binnekade, H. Raasø, J. de Kieviet, and A. Sah for excellent technical support; and Dr. M.M. van Gaalen for MED programming. The authors do not have any conflicts to disclose. Supplementary materials cited in this article are available online. 1. Evenden JL (1999): Varieties of impulsivity. Psychopharmacology 146: 348 –361. 2. Winstanley CA, Eagle DM, Robbins TW (2006): Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies. Clin Psychol Rev 26:379 –395. 3. Bickel WK, Odum AL, Madden GJ (1999): Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology (Berl) 146:447– 454. 4. Mitchell SH (1999): Measures of impulsivity in cigarette smokers and non-smokers. Psychopharmacology (Berl) 146:455– 464. 5. Spinella M (2002): Correlations between orbitofrontal dysfunction and tobacco smoking. Addict Biol 7:381–384. 6. Skinner MD, Aubin HJ, Berlin I (2004): Impulsivity in smoking, nonsmoking, and ex-smoking alcoholics. Addict Behav 29:973–978. 7. Robbins TW (2002): The 5-choice serial reaction time task: Behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380. 8. Evenden JL, Ryan CN (1996): The pharmacology of impulsive behaviour in rats: The effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 128:161–170. 9. Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005): Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine selfadministration in female rats. Psychopharmacology 178:193–201. 10. Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DE, Laane K, et al. (2007): Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270.
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