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Research report

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Dopaminergic modulation of impulsive decision making in the rat insular cortex

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Tommy Pattij ∗ , Dustin Schetters, Anton N.M. Schoffelmeer Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

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h i g h l i g h t s • The agranular insular cortex is importantly involved in impulsive choice in rats. • Dopamine transmission in the insular cortex contributes to impulsive choice. • Infusion of a dopamine D1-like and not dopamine D2-like receptor antagonist in the agranular insular cortex modulates impulsive choice.

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Article history: Received 4 March 2014 Received in revised form 1 May 2014 Accepted 5 May 2014 Available online xxx

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Keywords: Cognition Decision making Dopamine Impulsivity Insular cortex Rat

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1. Introduction

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Neuroimaging studies have implicated the insular cortex in cognitive processes including decision making. Nonetheless, little is known about the mechanisms by which the insula contributes to impulsive decision making. In this regard, the dopamine system is known to be importantly involved in decision making processes, including impulsive decision making. The aim of the current set of experiments was to further elucidate the importance of dopamine signaling in the agranular insular cortex in impulsive decision making. This compartment of the insular cortex is highly interconnected with brain areas such as the medial prefrontal cortex, amygdala and ventral striatum which are implicated in decision making processes. Male rats were trained in a delay-discounting task and upon stable baseline performance implanted with bilateral cannulae in the agranular insular cortex. Intracranial infusions of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist eticlopride revealed that particularly blocking dopamine D1 receptors centered on the insular cortex promoted impulsive decision making. Together, the present results demonstrate an important role of the agranular insular cortex in impulsive decision making and, more specifically, highlight the contribution of dopamine D1-like receptors. © 2014 Published by Elsevier B.V.

Intolerance to delay of gratification, oftentimes referred to as impulsive decision making, is a prominent feature of several psychiatric disorders such as attention-deficit/hyperactivity disorder [1] and substance use disorders [2]. Accumulating evidence originating from delay discounting paradigms has stressed the importance of dopamine transmission in these processes. In these paradigms, which have been developed for both humans and laboratory animals, impulsive decisions are operationalized as

∗ Corresponding author at: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel.: +31 20 44 48089; fax: +31 20 44 48100. E-mail address: [email protected] (T. Pattij).

the preference for smaller-immediate over delayed-larger rewards when subjects are given the choice between both options [3]. For example, in healthy volunteers, treatment with the dopamine precursor l-dopa was found to promote choice for the sooner-smaller reward over larger-delayed reward [4]. In contrast, opposite findings have also been reported and increasing dopamine transmission in healthy volunteers via acute challenges with the psychostimulant and indirect dopamine agonist d-amphetamine [5] or the catechol-O-methyl transferase (COMT) inhibitor tolcapone [6] increased preference for the larger-delayed reward. These observations in humans are paralleled by preclinical studies in rats indicating that d-amphetamine promotes choice for the larger-delayed reward [7–9], whereas opposite effects of damphetamine on delay-discounting have also been found [10–12]. In addition, neurochemical and electrochemical studies in rats have indicated that performance in a delay discounting paradigms is associated with increments in dopamine efflux in the brain [13,14].

http://dx.doi.org/10.1016/j.bbr.2014.05.010 0166-4328/© 2014 Published by Elsevier B.V.

Please cite this article in press as: Pattij T, et al. Dopaminergic modulation of impulsive decision making in the rat insular cortex. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.05.010

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Together, the findings in humans and rats strongly point toward dopaminergic modulation of impulsive decision making, yet the direction seems variable and might perhaps be explained by, for instance, differences in trait impulsivity [15], altered dopaminergic tone through COMT polymorphisms [16], or interactions with other neurotransmitter systems such as serotonin [15,17]. In terms of contributions of dopamine receptor subtypes, both dopamine D1-like and dopamine D2-like receptors have been implicated in impulsive decision making [7,8]. Neuroimaging studies in humans have yielded further insights into the neural correlates of impulsive decision making and revealed increased activation patterns in the prefrontal cortex, including orbitofrontal cortex, insular cortex as well as the ventral striatum when subjects engage in delay-discounting paradigms [18–23]. Complementary to these neuroimaging data are the effects of excitotoxic lesions of similar brain regions in rats, including the ventral striatum and subregions of the orbitofrontal cortex, which were found to modulate impulsive decision making [24–28]. Based on such findings it has been postulated that the brain differentially codes smaller-immediate versus larger-delayed rewards, with areas such as the lateral orbitofrontal cortex and ventral striatum encoding immediate reward and more lateral prefrontal cortical areas including the insular cortex encoding delayed reward. Indeed, evidence from electrophysiological recordings in these aformentioned brain regions fits with this notion [29–32; for review, see 33]. Functionally, the insular cortex has been postulated to play a key role in maintaining homeostasis by monitoring and integrating interoceptive visceral and somatic feelings and translating these to conscious emotional perceptions [34,35]. Based on functional properties and relaying and processing information in a posterior to anterior manner, the insular cortex is divided into three main compartments, namely the posterior granular, dysgranular and anterior agranular insular cortex. In the rat brain, tract-tracing studies have demonstrated that each of these compartments has segregated reciprocal connections with other brain regions. The posterior granular and dysgranular insular cortices are primarily interconnected with visceral thalamic relay nuclei [36] and as such functionally implicated in monitoring and integrating interoceptive stimuli. The agranular insular cortex is largely interconnected with limbic structures including the medial prefrontal cortex, the amygdala and ventral striatum [36,37]. Thus, the integration and translation of interoceptive stimuli to emotional feelings and behavioral actions seems to be coded in the agranular insular cortex. Moreover, the rat agranular insular cortex is highly innervated in terms of dopaminergic fibers [38] and the insular cortex (including the agranular insula) contains higher densities of dopamine D1-like receptors compared to dopamine D2-like receptors across species [39–41]. Taken together, the purpose of the present study was to examine the importance of dopamine signaling – and preferential involvement of dopamine D1-like over dopamine D2-like receptors – in the agranular insular cortex in impulsive decision making. To this aim, rats were trained in a delay discounting paradigm and subsequently received micro-infusions of the dopamine D1-like receptor antagonist SCH23390 or dopamine D2-like receptor antagonist eticlopride in the agranular insular cortex.

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2. Materials and methods

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2.1. Subjects

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Sixteen male Wistar rats were obtained from Harlan CPB (Horst, The Netherlands). At the start of the experiments animals weighed approximately 250 g, and were housed two per cage in macrolon cages (42.5 cm × 26.6 cm × 18.5 cm; length × width × height) under

a reversed 12 h light/dark cycle (lights on at 7.00 p.m.) at controlled room temperature (21 ± 2 ◦ C) and relative humidity of 60 ± 15%. Animals were maintained at approximately 90% of their freefeeding weight, starting one week prior to the beginning of the experiments by restricting the amount of standard rodent food chow. Water was available ad libitum throughout the entire experiment. All experiments were conducted with the approval of the animal ethical committee of the VU University Amsterdam, The Netherlands, and all efforts were made to minimize animal suffering. 2.2. Delayed reward paradigm A detailed description of the operant boxes and delayed reward paradigm in our laboratory has been provided previously [7]. Briefly, rats were trained in operant boxes until baseline performance was achieved. In the final stages of training and during drug testing, a session was divided into 5 blocks of 12 trials, each block started with 2 forced choice trials. Each rat received a left forced and a right forced trial. The order of these was counterbalanced between subjects. In the next 10 free-choice trials, the animals had a free choice and both the left and right units were illuminated. Poking into one position resulted in the immediate delivery of a small reinforcer (1 food pellet), whereas a nose poke into the other position resulted in the delivery of a large, but delayed, reinforcer (4 food pellets). If an animal did not respond during the free-choice phase within 10 s, an intertrial interval was initiated and the trial was counted as an omission. The position associated with the small and large reinforcer was always the same for each individual, and counterbalanced for the group of rats. Delays for the large reinforcer progressively increased within a session per block of 12 trials as follows from 0, 5, 10, 20 to 40 s. Importantly, when animals chose the larger delayed reinforcer no cues were presented that signalled the delay period. Previous work has demonstrated that using cues bridging the delay period may modulate drug effects on impulsive decision making [10,42]. Responding into non-illuminated units during the test was recorded, but had no further programmed consequences. The behavioral measure to assess task performance, i.e. the percentage preference for the large reinforcer as a function of delay, was calculated as the number of choices for the large reinforcer/(number choices large + small reinforcers) × 100. Furthermore, we calculated the average number of omitted choice trials per block of 10 trials within a session as well as the latency to respond during freechoice trials. Animals were trained once daily from Monday until Friday, during the dark phase of the light/dark cycle. 2.3. Surgery Upon stable baseline performance in the delayed reward paradigm animals were prepared for cannulation surgery by terminating the food restriction and providing free access to food for three days prior to surgery. Bilateral placement of indwelling guide cannulae (Plastics One, Roanoke, VA, USA) occurred under inhalation anesthesia using a combination of oxygen (0.4 L/min), nitrous oxide (0.8 L/min) and isoflurane (1.75–2.5%; Pharmachemie BV, Haarlem, the Netherlands) in a stereotaxic instrument (David Kopf Instruments, Tujunga, CA, USA). Guide cannulae were positioned 1 mm above the agranular insula and anchored to the skull with four stainless steel screws and dental acrylic cement. The coordinates (in mm, relative to bregma) used for placement of intracranial cannulae were A/P +2.8, M/L ±4.2, D/V −5.8 ventral to the skull, calculated from [43]. Rats received 0.5 ml/kg of the analgesic Ketofen (1%; Merial, Amstelveen, the Netherlands) and 0.3 ml/kg of the antibiotic Baytril (2.5%; Bayer, Mijdrecht, the Netherlands) at the end of surgery. Following surgery, the animals were housed individually

Please cite this article in press as: Pattij T, et al. Dopaminergic modulation of impulsive decision making in the rat insular cortex. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.05.010

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and had ad libitum access to food for a week before retraining in the delayed reward paradigm.

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2.4. Infusion procedure

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Intracranial infusions were carried out when stable baseline performance was re-established. Initially, during a sham infusion session, animals were habituated to insertion of the injectors into the guide cannulae (31 gauge and extending 1 (±0.04) mm beyond the guide cannulae; Plastics One, model C316). During the infusion experiments, drugs were infused on Tuesdays and Fridays, with baseline training sessions in between during which no infusions were conducted. Rats were bilaterally infused with either saline, SCH23390 or eticlopride over a period of 2 min at a rate of 0.25 ␮l/min using 10 ␮l Hamilton syringes driven by a syringe infusion pump (Harvard Apparatus, South Natick, MA, USA). Following infusion, the injectors remained in place for an additional 60 s to allow diffusion of the drug, rats were placed in the operant cages and testing commenced 5 min later. The order of testing different doses of SCH23390 was saline – 0.3 ␮g/side – 1.0 ␮g/side – 0.1 ␮g/side and the order of testing different doses of eticlopride was saline – 0.3 ␮g/side – 1.0 ␮g/side – 0.1 ␮g/side. In between tests with SCH23390 and eticlopride lapsed one week. Furthermore, to assure whether findings on infusion days were attributable to drug effects and not explained by residual drug-induced changes in baseline performance, repeated measures ANOVAs were performed on the four baseline training sessions that immediately preceded drug infusion test sessions for SCH23390 and eticlopride separately.

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2.5. Assessment of cannulae placement

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Following completion of the behavioral procedures, animals were deeply anaesthetized using sodium pentobarbital (Ceva Sante Animale BV, Maassluis, the Netherlands; 60 mg/ml, i.p.). Subsequently, animals were perfused transcardially with 100 ml 0.9% NaCl, followed by 500 ml 4% paraformaldehyde in 0.1 M phosphate buffered saline (PBS, pH 7.2). Brains were removed rapidly and post-fixed for 1 h in the same fixative at room temperature, then stored in 5% sucrose in 0.1 M PBS at 4 ◦ C. Coronal sections of 40 ␮m were cut on a cryostat and subsequently stained with thionine for the determination of the infusion sites. Only animals with correct cannulae placements were included in the analyses.

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2.6. Drugs

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SCH23390 hydrochloride and S(−)-eticlopride hydrochloride (both Sigma Aldrich, St. Louis, MO, USA) were dissolved in sterile saline. Drug doses for eticlopride (0.1, 0.3 and 1.0 ␮g/side; calculated as salts) and SCH23390 (0.1, 0.3 and 1.0 ␮g/side; calculated as salts), were freshly prepared on each test day and were intracranially infused as described above. Drug doses of both SCH23390 and eticlopride were based on previous studies employing comparable instrumental cognitive paradigms in which similar doses were infused intracranially and were found to exert behavioral effects [42,44].

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2.7. Statistical analyses

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Data were analyzed using IBM SPSS Statistics version 20 (IBM Corporation, Armonk, NY, USA) and were subjected to repeated measures analysis of variance (ANOVA) with drug dose and delay to large reinforcer as within subjects variables. The homogeneity of variance across groups was determined using Mauchly’s tests for equal variances and in case of violation of homogeneity, Huynh–Feldt epsilon (ε) adjusted degrees of freedom and resulting more conservative probability values were depicted and used

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for subsequent analyses. In case of statistically significant main dose and dose × delay interaction effects, further paired comparisons were conducted against the vehicle dose using paired t-tests where appropriate. Furthermore, in keeping with previous results from our laboratory correlating D1 gene expression with impulsive decision making [45], Pearson’s correlation coefficients were also calculated in order to explore the relationship between the magnitude of effects of SCH23390 infusion and vehicle infusion on preference for the large reward. For this purpose, individual levels of impulsive choice were defined as the percentage choice for the large reward during the trials with intermediate delays (10 and 20 s) as described previously [45]. The level of probability for statistically significant effects was set at 0.05. Graphs were produced using GraphPad Prism version 5.02 for Windows (GraphPad Software, San Diego, CA, USA).

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3. Results

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3.1. Histological verification of cannulae placement

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Following histological analyses, correct placement of the cannulae in the insular cortex was verified for all animals. In particular, infusion sites were located in the dorsal and ventral parts of the agranular insular cortex (Fig. 1). Two animals were excluded from all analyses because infusion sites were positioned outside the borders of the agranular insular cortex. Furthermore, one animal died during the surgical procedure and was therefore excluded from the analyses. Therefore, in total n = 13 animals were included in all analyses.

3.2. Effects of intra-insular SCH23390 on impulsive decision making Stable baseline performance was achieved after approximately 30 sessions of training on the full delay range (delays: 0, 5, 10, 20 and 40 s) and animals were trained for an additional week on the task before surgery. The first intracranial vehicle infusion was carried out after 14 training sessions to re-establish baseline performance. Analysis of the four baseline training sessions that immediately preceded infusion sessions indicated that for SCH23390 performance did not shift in between tests with different drug doses [session: F(3,36) = 1.35, ε = 0.59, p = 0.28; session × delay: F(12,144) = 1.41, p = 0.17]. Infusion of SCH23390 into the insular cortex significantly increased impulsive decision making [Fig. 2A; delay: F(4,48) = 92.28, ε = 0.61, p < 0.001; dose: F(3,36) = 17.10, p < 0.001; dose × delay: F(12,144) = 2.29, ε = 0.65, p = 0.029]. Further comparisons revealed that 1.0 ␮g/side intra-insular SCH23390 significantly shifted the preference from the large delayed reward toward the small immediate reward compared to vehicle [dose: p < 0.001 and dose × delay: p = 0.038]. This dose of SCH23390 decreased the preference for the large reward compared to vehicle at both the 5 s delay and 10 s delay [p = 0.043 and p = 0.011, respectively] and not at any of the other delays. Although the omission rate was low during the free-choice trials, SCH23390 significantly altered omissions during free-choice trials [Fig. 2B; dose: F(3,36) = 6.83, p < 0.005]. Further comparisons revealed that only 1.0 ␮g/side intra-insular SCH23390 significantly increased omissions compared to vehicle infusion [p = 0.011]. Response latencies were not significantly altered by SCH23390 [dose: F(3,36) = 1.43, p = 0.25; values: vehicle, 0.71 ± 0.05 s; 0.1 ␮g/side, 0.77 ± 0.07 s; 0.3 ␮g/side, 0.82 ± 0.07 s; 1.0 ␮g/side, 0.87 ± 0.06 s]. A subsequent correlational analysis indicated that the effect of 1 ␮g SCH23390 on preference for the large reward negatively correlated with choice

Please cite this article in press as: Pattij T, et al. Dopaminergic modulation of impulsive decision making in the rat insular cortex. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.05.010

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effect of p = 0.06 which was close to statistical significance, we did conduct further comparisons between vehicle and the different eticlopride doses, yet none of the doses significantly differed from vehicle infusion. Similar to SCH23390, eticlopride also did alter omission rate during free-choice trials [Fig. 3B; dose: F(3,36) = 3.69, p = 0.020], yet further pairwise comparisons between any of three doses and vehicle failed to reach significance. Response latencies were not significantly altered by eticlopride [dose: F(3,36) = 0.18, p = 0.91; values: vehicle, 0.78 ± 0.07 s; 0.1 ␮g/side, 0.80 ± 0.12 s; 0.3 ␮g/side, 0.80 ± 0.06 s; 1.0 ␮g/side, 0.85 ± 0.13 s].

4. Discussion

Fig. 1. Schematic drawing of coronal sections depicting cannulae placement into the insular cortex at a level of 3.20 mm, 2.70 mm and 2.20 mm rostral to bregma. Triangles indicate the borders of the agranular insula (AI), including both the dorsal and ventral subregions. Drawings are adapted from [44].

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for the large reward under vehicle infusion [Fig. 2C; r = −.066, p = 0.014]. 3.3. Effects of intra-insular eticlopride on impulsive decision making To evaluate whether in the second set of experiments baseline impulsive decision making was changed, vehicle infusion data of SCH23390 were compared to those of eticlopride. There was no change in baseline impulsive decision making between both vehicle infusion days [day: F(1,12) = 0.25, p = 0.63; day × delay: F(4,48) = 0.69, ε = 0.74, p = 0.57]. Similar to SCH23390, analysis of the four baseline training sessions that immediately preceded infusion sessions showed that performance did not shift in between tests with different drug doses of eticlopride [session: F(3,36) = 0.84, p = 0.48; session × delay: F(12,144) = 1.07, ε = 0.75, p = 0.39]. In contrast to SCH23390, intra-insular infusion of eticlopride did not significantly affect impulsive decision making [Fig. 3A; delay: F(4,48) = 82.37, ε = 0.51, p < 0.001; dose: F(3,36) = 2.70, p = 0.060; dose × delay: F(12,144) = 1.57, p = 0.11]. In view of the main dose

To the best of our knowledge, this study is the first to demonstrate functional involvement of dopamine signaling in impulsive decision making in the rodent agranular insular cortex. We found that micro-infusions of the dopamine D1 receptor antagonist SCH23390 at a dose of 1 ␮g/side and not dopamine D2 receptor antagonist eticlopride into the agranular insular cortex in rats promoted choice for the smaller-immediate over larger-delayed reward in a delay-discounting task. As such the present data suggest that activation of dopamine Dl-like and not dopamine D2like receptors centered on the agranular insula contributes to the choice for delayed-larger reward over the immediate-small reward. This notion is in line with systemic pharmacological interventions revealing that blocking dopamine D1 receptors promotes impulsive decision making in a comparable delay discounting paradigm [7]. However, in a different delay discounting paradigm, the adjusting amount procedure, systemic administration of SCH23390 was not found to decrease the value of the delayed reward [8]. Possibly, this is explained by procedural differences such as the use of a tone as conditioned reinforcer in the latter study which may differentially impact drug effects in delay discounting procedures [10,42], or the sensitivity and structure of the adjusting amounting procedure which differs from the delayed reward paradigm [3]. In the current study, in addition to decreasing preference for the delayedlarger reward, intracranial infusion of SCH23390 was accompanied by an increment in omission rate in the task, perhaps indicative of altered motivation. Previous data indicate that both the dopamine antagonist ␣-flupenthixol and SCH23390 increase omissions and response latencies and decrease the number of completed trials in delay discounting tasks [7,8,10,45,46]. As such, dopamine D1 receptor antagonism in these tasks has been associated with altering the motivational value of food or the motivation to respond for conditioned reinforcers. Modulating the motivational value of food in a similar delay discounting task as in the present study was found to increase response latencies and omission rate, but did not affect choice [7]. Given the fact that the increment in omission rate by infusion of 1 ␮g/side SCH23390 here was modest and at the same time did not slow response speed, these observations do not preclude the interpretation that antagonism of dopamine D1 receptors centered on the agranular insular cortex modulates impulsive decision making. Neuroimaging data give rise to the notion that the insula and other lateral prefrontal cortical areas including the lateral orbitofrontal cortex are more implicated in processing intertemporal decisions following delay of reinforcement, whereas the ventral striatum, ventromedial orbitofrontal and medial prefrontal cortices are particularly engaged in decisions involving immediate reward [19–22,47]. This is further corroborated by electrophysiological recordings in rats and monkeys mirroring the notion that segregated regions are activated before or upon immediate and delayed reinforcement and point to a similar regional distribution [29–33]. Consistent with the idea that dorsolateral parts of the prefrontal

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Fig. 2. Effects of intra-insular infusion of different doses of the dopamine D1-like receptor antagonist SCH23390 on impulsive decision making (A) and omissions during the free-choice trials (B). Moreover, a correlational analysis indicated a negative correlation between the magnitude of infusion of 1 ␮g/side SCH23390 on choice for the large reward and baseline choice under vehicle infusion (C). Data are presented as mean ± SEM and * p < 0.05.

Fig. 3. Effects of intra-insular infusion of different doses of the dopamine D2-like receptor antagonist eticlopride on impulsive decision making (A) and omissions during the free-choice trials (B). Data are presented as mean ± SEM.

Please cite this article in press as: Pattij T, et al. Dopaminergic modulation of impulsive decision making in the rat insular cortex. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.05.010

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cortex process intertemporal choice, we found that dopamine D1 recepor blockade in the agranular insular cortex biased decisions toward immediate reinforcement compared to vehicle infusion. The fact that we did not find any effects of the dopamine D2 receptor antagonist at doses that previously have been shown effective in a comparable instrumental paradigm [44], might either indicate that these receptors are not implicated in processing intertemporal choice or might be explained by lower densities of this receptor subtype in the prefrontal cortex of rats [39]. Regardless, the current data implicate a role for dopamine transmission in the insular cortex in encoding delayed reinforcement and this may, for instance, be attributed to the role of dopamine in reward prediction. In view of this, support from empirical studies and computational models have converged upon midbrain dopamine neuronal activity as providing a key reward-prediction signal to guide value-based decisions including intertemporal choice [48–50]. In addition to coding reward-prediction signals, ascending mesocortical projections are also implicated in modulating executive cognitive functions such as working memory and decision making [51,52]. In support of the latter, dopamine transmission in various subregions of the prefrontal cortex has been strongly linked to impulsive decision making. First, compared to yoked controls active performance in a delay discounting task was found to lead to increments in DOPAC levels, a metabolite of dopamine, in the orbitofrontal cortex. Interestingly, in the medial prefrontal cortex both dopamine and DOPAC levels were found to be increased regardless of active task performance [14]. Thus, these findings point toward an important role of dopamine efflux in the orbitofrontal cortex in guiding decision making involving reward of different magnitudes and/or the time to obtain these rewards, whereas dopamine efflux in the medial prefrontal cortex might code for obtaining reward irrespective of active task performance. Moreover, we have previously demonstrated that the expression of dopamine D1-like receptors in the medial prefrontal cortex positively correlates with impulsive decision making. In high impulsive rats displaying a larger preference for the immediatesmaller reward, dopamine D1-like gene expression levels in the medial prefrontal cortex were higher compared to low impulsive individuals [45]. In turn, in that study intracranial infusions of dopamine D1 receptor ligands in this brain region were found to modulate impulsive decision making. Building upon these aforementioned studies, the current data highlight the importance of dopamine D1 receptor modulation centered on the agranular insular cortex in impulsive decision making. Interestingly, a correlational analysis in the current study further confirms this notion and indicated that the magnitude of the effects of SCH23390 on impulsive decision making was baseline-dependent. Although the sample size is relatively small (n = 13), in animals displaying higher preference for the delayedlarger reward under vehicle infusion, the effects of SCH23390 in promoting impulsive choice were more pronounced. In our earlier study [45], involvement of these dopamine receptor subtypes in delay discounting was interpreted on the basis of their involvement in working memory and contribution to optimizing delay-period activity of prefrontal cortical neurons [52,53]. Indeed, this might be a plausible explanation since recent human studies indicating that these behavioral phenomena might be interrelated [54,55]. To date, to our knowledge, such an interrelationship between working memory and intertemporal choice has not been investigated in rats using similar paradigms employed in the current study [but see, 56]. Therefore, this urges for future work examining the commonality between working memory and intertemporal choice in rats and the contribution of dopamine D1 receptors. Interestingly, accumulating evidence indicates that impulsive decision making and drug addiction are closely interrelated. Not

only does prolonged substance use result in heightened levels of impulsivity across different classes of drugs of abuse [2,57], impulsivity may also predict the susceptibility to become drugdependent and the likelihood to maintain abstinence in drug addiction [58]. In view of this interrelationship and the involvement of the insular cortex in impulsive decision making, it is interesting that in human smokers acquired damage to the insula was found to promote abstinence from smoking and to reduce the urge to smoke [59]. Also, neuroimaging data demonstrate that cigarette craving in smokers is associated with increased activity in the insular cortex [60]. Preclinical work has further stressed the importance of the insular cortex in nicotine reinforcement and shown that temporary inactivation of the granular insular cortex reduces the rewarding properties of nicotine in rats [61]. Moreover, blocking dopamine D1 and not dopamine D2 receptors in the agranular insular cortex also strongly reduces volitional nicotine self-administration in rats indicating the importance of activation of insular dopamine D1 receptors in nicotine reward [62]. In the present study, we demonstrate that the insula and particularly dopamine D1 receptor involvement in this brain region in impulsive decision making. Together with previous work demonstrating that impulsive decision making predicts relapse to nicotine-seeking behavior in rats [63] and successful abstinence in human tobacco smokers [64,65], this may suggest that the insular cortex is a crucial brain region linking disturbances in higher-order cognitive processes, such as decision making, to reward processing possibly via dopamine D1 receptor-mediated mechanisms. Of course other brain regions, such as for instance the ventral striatum and orbitofrontal cortex, and dopamine function in these regions contribute to both delay discounting and reward processing [66–68] and further studies are clearly warranted to what extent these observations are explained by divergent or shared mechanisms. Taken together, the present data extend human neuroimaging findings demonstrating involvement of the insular cortex in processing intertemporal choice [23]. In particular, the preference for the smaller-immediate over larger-delayed reward appears to be modulated by insular dopamine D1-like and not dopamine D2like receptors. As such, further unraveling the neural correlates of impulsive decision making may improve our understanding of psychiatric disorders in which intertemporal choice is disturbed such as attention-deficit/hyperactivity disorder and substance use disorders.

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