ORIGINAL INVESTIGATION

Noradrenergic α2A-receptor stimulation in the ventralhippocampus reduces impulsive decision-making

Andrew R. Abela & Yogita Chudasama

Received: 17 May 2013 /Accepted: 19 August 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractRationale Guanfacine, an α2A-adrenergic receptor agonist, iscurrently in use for treatment of a variety of psychiatricdisorders that are associated with impulsive decision-making(e.g., attention-deficit hyperactivity disorder; ADHD). In an-imals and humans, the behavioral effects of adrenergic agentsare presumed to involve neuromodulation of the prefrontalcortex, consistent with the demonstrated actions of dopami-nergic agents. However, recent experimental work has shownthat the ventral hippocampus (vHC) contributes to decision-making and impulse control, raising the possibility that thehippocampus may be an important site of action for thesedrugs.Objective The purpose of this study was to examine the effectof local vHC infusions of guanfacine and other neuropharma-cological agents on behavioral decisions that involve a trade-off between reward size and delay.Methods Different cohorts of rats were implanted with bilat-eral guide cannulae targeting the vHC. We examined theanimals’ behavior in a touchscreen version of a delaydiscounting task following intra-vHC infusions of: (a)guanfacine (α2A-adrenergic receptor agonist), (b) SCH23390 (dopamine D1 receptor antagonist), and (c) muscimol/baclofen (GABAA/B agonists).Results Guanfacine led to a dose-dependent reduction in im-pulsive decision-making, increasing the animals’ tolerance fordelay in exchange for a larger reward. By contrast, infusion ofSCH 23390 had no behavioral effects. Consistent with previ-ous lesion studies, reversible pharmacological inactivationwith muscimol/baclofen increased impulsive decision-making.

Conclusions These data provide the first evidence thatguanfacine, a commonly used treatment for ADHD, mayderive its clinical benefits through hippocampal stimulation,via α2A-adrenergic receptors.

Keywords Rat . Delay discounting . Prefrontal cortex .

Noradrenaline . Dopamine . Reward

Introduction

Impulsive behaviors underlie a range of cognitive and socialproblems, contributing to episodes of violence, gambling,credit card binges, deviant sexual behavior, and substanceabuse. A central aspect of impulsive behavior is an aversionto waiting, where the immediacy of an expected reward isfavored over any delay, even if the delayed option offers asubstantially greater payoff. In laboratory settings, the “delaydiscounting” paradigm allows one to systematically studyhow this trade-off can influence choice behavior in humansor animals (Winstanley 2011). Decision-making is influencedby the cerebral level of neurotransmitters such as noradrena-line (NA) and dopamine (DA). For example, after receiving asystemic injection of the α2A-adrenergic receptor agonistguanfacine, monkeys are more likely to select an option thatincurs a long delay but delivers a large reward (Kim et al.2012). Clinically, medications such as atomoxetine and meth-ylphenidate that increase levels of NA and DA in the brain(Bymaster et al. 2002; Swanson et al. 2006) likewise improvetolerance for delayed rewards (Robinson et al. 2008; Shielset al. 2009).

Several lines of evidence, in animals and humans, suggestthat the prefrontal cortex contributes significantly to this formof decision-making. Damage to prefrontal regions often di-minishes tolerance for delay, biasing behavior toward choiceswith immediate payoff (Mar et al. 2011; Rudebeck et al. 2006;

A. R. Abela :Y. Chudasama (*)Department of Psychology, McGill University,Montreal, QC H3A 1B1, Canadae-mail: yogita.chudasama@mcgill.ca

PsychopharmacologyDOI 10.1007/s00213-013-3262-y

Sellitto et al. 2010; but see Fellows and Farah 2005). Quitenaturally, the effects of systemic drugs have been linked toprefrontal circuitry with noradrenergic stimulation of thisregion providing a clinical framework for understanding thebeneficial effects of guanfacine in decision-making (Arnsten1996; Kim et al. 2012). Nonetheless, despite the evidenceimplicating both the prefrontal cortex and the noradrenergicsystem in delay discounting (e.g., Mar et al. 2011; Kim et al.2012), there is no direct evidence that the prefrontal cortexmediates the effect of systemic guanfacine described above. Infact, when guanfacine is infused directly into the medial ororbital prefrontal cortex of rodents, there is no apparent effecton delay discounting behavior (Pardey et al. 2012; see alsoMorrow et al. 2004), suggesting that prefrontal α2A-receptorstimulation contributes little to the observed behavioral ef-fects. In contrast, local prefrontal infusions of the DA D1

antagonist SCH 23390 disrupts delay tolerance, causing ratsto opt more often for the small, immediate reward instead ofthe large, delayed reward alternative (Loos et al. 2010; Pardeyet al. 2012). Thus, while both noradrenergic and dopaminergicdrugs affect choices in the delay-discounting task when ap-plied systemically, only the dopaminergic effects have beenlinked directly to the prefrontal cortex.

One potential target of these drugs is the hippocampus,which in rats and humans is replete with both noradrenergic(α2A) and dopaminergic (D1) receptors (Camps et al. 1990a;Happe et al. 2004; Unnerstall et al. 1984). Like the prefrontalcortex, the hippocampus receives ascending NA and DA inputfrom brainstem nuclei (Foote et al. 1983; Gasbarri et al. 1994;Pickel et al. 1974; Scatton et al. 1980). Moreover, hippocam-pal lesions, like prefrontal lesions, consistently decrease rats’tolerance for delayed rewards (Abela and Chudasama 2013;Cheung and Cardinal 2005; Mariano et al. 2009; McHughet al. 2008). The vHC sends strong, excitatory projectionsdirectly to the prefrontal cortex (Swanson 1981; Thierryet al. 2000), suggesting that these two regions may interactto support executive function. Thus, the behavioral influenceof the ascending transmitter systems may in some cases reflectlocal neuromodulation in the vHC, rather than the prefrontalcortex (Abela et al. 2013; Howland et al. 2008; Seamans et al.1998). Unlike the prefrontal cortex, where the effects of manyneurochemical manipulations have been characterized (forreview, see Robbins and Arnsten 2009), the behavioral effectsof manipulating such systems in the vHC remain largelyunexplored.

In this study, we examine, for the first time, the effects oflocal guanfacine infusion in the vHC on delay discountingbehavior. We report that guanfacine increased rats’ tolerancefor delay, thus enabling them to maximize their long-termgains by choosing the large reward option. For comparison,we also assessed the effects of the DA D1 antagonist SCH23390, which, while known to affect performance on this taskwhen infused in the prefrontal cortex, had no effect in the

vHC.We further show that temporary inactivation of the vHCwith muscimol/baclofen increased rats’ choices for the small,immediate rewards, in accordance with previous lesion stud-ies. Together, these data suggest that noradrenergic stimula-tion of the vHC may underlie the efficacy of guanfacine, acommonly used treatment for impulse control disorders,underscoring the contribution of the vHC to executivebehavior.

Methods and materials

Subjects

Male Long-Evans rats (Charles River, LaSalle, QC, Canada)weighing 200–225 g at the start of behavioral training weremaintained at 85 % of their free-feeding weight. All animalswere housed in pairs in a temperature-controlled room(22 °C), under diurnal conditions (12 h light/12 h dark). Allexperimental procedures were approved by the McGill Uni-versity Animal Care Committee, in accordance with theguidelines of the Canadian Council on Animal Care.

Apparatus

Four touchscreen testing boxes (Lafayette Instruments, Lafa-yette, IN, USA) were used, each comprising a standard oper-ant chamber and a touchscreen as described previously (Abelaand Chudasama 2013). In brief, computer graphic stimuliwere presented on a black background on the touchscreen(see Fig. 1). A black Plexiglas mask (approximately 1.5 cmfrom the surface of the display) served to restrict the rat’saccess to the display except through response windows(2.05″L×2.05″H). Sucrose pellets served as food reward(Ren’s Pets Depot, ON, Canada). Magazine entries weredetected by photocells located at the entrance of the foodmagazine. The apparatus and online data collection for eachchamber were controlled using the Whisker control system(Cardinal and Aitken 2010).

Surgery and cannulae implantation

Rats were anesthetized with isoflurane gas. Bilateral 22-guagestainless steel guide cannulae (HRS Scientific, QC, Canada)were implanted into the vHC using standard stereotaxic pro-cedures (incisor bar −3.0 mm). The guide cannulae werecarefully lowered through craniotomies at the following coor-dinates: anterior–posterior, −5.6 mm; medial-lateral, ±5.0 mm;and dorso-ventral, −7.2 mm from dura (Paxinos and Watson2005). Sterile obdurators flush with the end of the guide can-nulae prevented occlusion.

Psychopharmacology

Behavioral procedure

Following habituation to the testing chamber, rats were trainedto make a nosepoke touch response to a white square (2″×2″)that was presented in either the left or right response window.When rats were able to make 50 touch responses, and therebyobtain 50 reward pellets within a 20-min session, they wereready for surgery. Following cannulae implantation and post-operative recovery, rats were retrained to touch the screen untilthey reached the same preoperative criterion. Rats were thenready to be tested on the delay discounting task.

In the delay discounting task, rats chose between twoidentical white squares located on the left and right side of atouchscreen monitor. Their position indicated differences inreward size and delay (see Fig. 1). Responses to the leftstimulus resulted in the immediate delivery of a small, onepellet reward. Responses to the right stimulus resulted in thedelivery of a large, four pellet reward, but after a delay. Theside on which the large reward stimulus was presented (left orright) was counterbalanced between subjects, and remained inthe same location for each rat. Each session consisted of fourblocks of 12 trials. Each block began with two ‘forced choice’trials in which either the left or the right stimulus waspresented to demonstrate the outcome associated with thestimulus. The remaining ten trials were ‘free choice’ trials in

which the rats could choose between both stimuli. Each triallasted for 70 s regardless of the rat’s choice of stimulus. Ratswere initially trained to discriminate between the two rewardsizes when there were no delays until they were choosing thelarge reward >80 % of the time (∼2 days). Thereafter, thedelay to delivery of the large reward was progressively in-creased in each block within a session (0, 8, 16, and 32 s).Trial onset was signaled by illumination of the food magazineand houselight. A nosepoke entry into the food magazinetriggered the presentation of the stimuli on the touchscreen,which remained on the touchscreen for 10 s. Choice behaviorwas measured as the total number of choices of the largereward per delay (maximum of ten responses). Failures tomake a response within 10 s were recorded as omissions,and the box returned to its intertrial interval (ITI) state whenall lights were extinguished until the next trial. The responselatency was the time from stimulus presentation to the time therat made a response. Following a response, and after theanimal had retrieved the food reward, the chamber went intoan ITI state until the next trial. During the delay period, thefood magazine was illuminated. The time between pelletdelivery and pellet collection was the magazine latency. Ratswere tested for approximately 15 days and stable discountingbehavior was confirmed with a main effect of delay and nomain effect of session.

Microinfusion procedure

Rats were first adapted to three mock infusions to minimizestress associated with the procedure. Rats were gently re-strained, the obdurators were removed and replaced with a28-guage injector extending 1 mm beyond the tip of the guidecannula. Drug or saline was administered in a volume of0.5 μL infused bilaterally at a rate of 0.25 μL/min over2 min. Injectors were left in place for another 2 min to allowfor diffusion. Rats were placed inside their home cage for10 min before behavioral testing. Two days separated drugtest days: 1 day of no testing and a second day of baselinetesting with no infusion.

Drug preparation and experimental design

All drugs were purchased from Sigma-Aldrich, Canada, anddissolved in 0.9 % saline. Rats were assigned to two cohorts.Rats in cohort 1 (n =14) were first tested on the standard delaydiscounting task following a counterbalanced bilateral infu-sion of saline, or a 0.3 μg/side dose of a muscimol/baclofencocktail to temporarily inactivate the vHC. The rats were thenrestabilized on baseline performance for 2 days. Second, inorder to determine if delay discounting behavior followingvHC inactivation reflected an aversion to delayed rewards orinstead a failure to remember the amount of reward after thedelay, the effect of vHC inactivation (or saline infusion) was

Fig. 1 Schematic diagram depicting (a) the events in one trial of thedelay discounting task, and (b) a photograph of a rat performing the task.In a , the visual stimuli used in the task are shown, displayed as they wereon a touchscreen in the experiments

Psychopharmacology

re-examined in an equal delays procedure. That is, the deliv-ery of the small and large reward was delayed by the sameamount and the delay was progressively increased in eachblock within a session. All other task parameters remainedthe same. Third, after two baseline training days, the ratswere tested again on the standard delay discounting taskfollowing bilateral infusion of saline or guanfacine (0.0025,0.005, and 0.01 μg/side) in a counterbalanced order. Thesedoses were based on a recent demonstration that localizedinfusion of the medium (0.005 μg) dose of guanfacine inthe medial prefrontal cortex affects inhibitory control (Bariet al. 2011). The low and high doses were determined ashalf and double the medium dose, respectively. One impor-tant reason for using a repeated measures design for eachexperiment described above was to guard against slightdrift in the baseline, potentially caused by mechanicaldamage, so we could assess the effects of guanfacinedirectly against vehicle within the same animal. Moreover,all animals returned to their baseline level of performancebefore receiving a drug infusion thus controlling for anyshifts in the relative value of the two reward options.Finally, rats in cohort 2 (n =10) received counterbalancedinfusions of saline or SCH 23390 (0.25, 0.5, and 1 μg/side), similar to doses previously reported (e.g., Zeeb et al.2010).

At the conclusion of all behavioral testing, the rats wereperfused transcardially with 0.9 % saline followed by 10 %formaldehyde in 0.9 % saline. The brains were cut into 40-μmsections on a cryostat and stained with cresyl violet to verifycannulae placement. Data from five rats were excluded fromanalysis due to inaccurate cannulae placements (cohort 1, n =3; cohort 2, n =2). Thus the final number of rats in cohort 1that received muscimol/baclofen was 11. Two rats then losttheir cannulae leaving a sample size of nine rats in cohort 1that received guanfacine. In cohort 2, a total of eight ratsreceived infusion of SCH 23390.

Data analysis

Data for each variable were subjected to a repeated measuresanalysis of variance (ANOVA) using PASW Statistical Soft-ware, version 20 (SPSS Inc, Chicago, IL, USA). Homogeneityof variance was assessed by Mauchly’s sphericity test. Whenthis requirement was violated for a repeated measures design,the F term was tested against degrees of freedom correct byGreenhouse–Geisser to provide a more conservative p valuefor each F ratio. Where F ratios were significant at p <0.05,group means were compared at each delay using the Fisher’sleast significant difference (Fisher’s LSD) test. The within-subject factor was drug treatment at two levels for the vHCinactivation study (saline vs muscimol/baclofen), four levelsfor the guanfacine and SCH 23390 infusion studies (saline,

low dose, medium dose, and high dose of drug), and delay atfour levels (0, 8, 16, and 32 s).

Results

Figure 2 shows the position of the cannula tips within thevHC, and a representative photomicrograph illustrating thelocation of the cannula in the vHC region. For all rats includedfor analysis, all cannulae tips were located within the vHC inthe range of −4.68 and −5.80 mm anterior–posterior frombregma. Following cannulae placement, the rats were trainedon a touchscreen version of a delay discounting task. In thistask, rats made decisions that involved a trade-off betweenreward size and delay. Specifically, rats chose between onestimulus that resulted in the immediate delivery of a small, onepellet reward, and another stimulus that delivered a large,four-pellet reward, but after a delay. When rats showed stablediscounting behavior, we examined their choices followingintra-vHC infusions of: (a) guanfacine (cohort 1, n =9), and(b) SCH 23390 (cohort 2, n =8), or (c) muscimol/baclofencocktail (cohort 1, n=11; see Drug preparation and experimentaldesign). In all cases, the infusions were compared to that ofsaline within the same animals. We investigated the effects ofthese agents parametrically by keeping a fixed volume (0.5 μL)but varying the dose. In the following sections, we describe theresults of these three manipulations.

Infusion of guanfacine into the vHC increases toleranceto delay

Bilateral infusion of guanfacine into the vHC prompted rats tomake choices leading to longer waiting times but whichresulted in larger rewards. This effect, which was stronglydose-dependent, is shown in Fig. 3. Specifically, as the delayto large reward delivery was increased incrementally within asession, the guanfacine infusion increased rats’ responses tothe stimulus leading to the large, delayed reward, relative tothe control saline infusions (F (3,21)=10.912, p <0.001). Thisincreased tolerance for delay was true only for the medium,0.005 μg dose (F (3,21)=144.828, p <0.00001; see Fig. 3b),and was observed at all but the 0 s delay (Fisher’s LSD, 8 s, p<0.05; 16 s, p <0.01; 32 s, p <0.001). At the low (0.0025 μg)and high (0.01 μg) doses, the effect of guanfacine did notdiffer from saline at any delay (Fisher’s LSD, all p >0.05).Importantly, performance was otherwise normal, as the ani-mals were not impaired in terms of the number of omittedtrials (F (3,21)=0.664, p >0.05), latency to respond (F (3,21)=0.260, p >0.05), or latency to collect food reward (F (3,21)=0.792, p >0.05). Thus local infusion of guanfacine into thevHC affected behavior in a manner consistent with the sys-temic effects of the drug as observed in the clinic (Hunt et al.1995; Sallee et al. 2009; Scahill 2001).

Psychopharmacology

Infusions of SCH 23390 into the vHC has no effecton tolerance to delay

In contrast to the effects of guanfacine, bilateral infusion ofSCH 23390 into the vHC had no effect on rats’ preference forthe large, delayed reward at any dose (Fig. 4, F (3,21)=0.591,p >0.05). In line with normal behavior, the rats shifted theirpreference to the small, immediate reward with increasingdelay (F (3,21)=12.871, p <0.001), with no influence of thedrug (F (3,21)=0.591, p >0.05) and no interaction betweendose and delay (F (9,63)=0.508, p >0.05). All other measuredvariables were in the normal range, including the number ofomitted trials (F (3,21)=1.288, p >0.05), speed of response(F (3,21)=0.669, p >0.05), and the latency to collect food re-ward (F (3,21)=0.406, p >0.05). Thus despite the presence ofDA D1 receptors in the hippocampus (Boyson et al. 1986;Dubois et al. 1986; Savasta et al. 1986), and the knowninfluence of SCH 23390 on delay discounting following in-fusion into the prefrontal cortex (Loos et al. 2010; Pardey et al.2012), its local infusion into the vHC had nomeasurable effecton rats’ behavior.

Inactivation of the vHC decreases tolerance for delay

We also investigated whether bilateral infusion of the GABAagonists muscimol and baclofen into the vHC would affectchoice performance in the delayed discounting task. Such aresult might be predicted based on previous work involvingpermanent excitotoxic hippocampal lesions (Abela andChudasama 2013; Cheung and Cardinal 2005; Mariano et al.

Fig. 2 Reconstruction of the cannulae placements for each rat in cohort 1(black circle) and cohort 2 (white triangle) superimposed on coronalsections of the rat brain, with a representative photomicrograph of oneplacement. Rats in cohort 1 received infusions of a muscimol/baclofencocktail followed by three doses of guanfacine. Rats in cohort 2 receivedinfusions of SCH 23390. Numbers indicate the location of sectionsrelative to bregma according to the atlas of Paxinos and Watson (2005)

Fig. 3 The effect of guanfacine infused into the vHC on delaydiscounting. Guanfacine infused into the vHC at a medium dose(0.005 μg/side) increased the number of large, delayed reward choicesmade by rats relative to a low dose (0.0025 μg/side), high dose (0.01 μg/side), and saline (a). The large reward choice preference produced by

each dose of guanfacine is shown for the 8, 16, and 32 s delays (b). Alldata shown are mean (±SEM) percentage choice of the large reward.★p<0.05 relative to saline, *p <0.05 relative to the low and high dose, andsaline, at that particular delay

Psychopharmacology

2009; McHugh et al. 2008). Consistent with this hypothesis,we found that inactivation significantly reduced selection of thelarge reward option, indicating an unwillingness to accept adelay (F (1,10)=9.989, p <0.05; see Fig. 5a). There was also asignificant drug × delay interaction (F (3,30)=2.979, p <0.05)with vHC inactivation only affecting the rats’ choice behaviorfor the longer delays (Fisher’s LSD, 8 s, p <0.05; 16 s, p <0.0001; 32 s, p <0.001). All other aspects of performance (i.e.,speed of responding, number of omissions, and latency tocollect food reward) were normal (all, p >0.05).

Finally, we used reversible inactivation as an opportunity tounderstand the rats’ behavior in the task more generally.Specifically, we asked whether or not the observed behavioralchanges with local administration were more closely related tothe perception/memory of the delay or reward, or instead tothe internal preferences of the animal. To address this ques-tion, we tested the same cohort of rats (cohort 1) under anadditional condition in which the delays were always equal.The rats’ response therefore indicated their selection of thelarge reward in the absence of any trade-off. Under theseconditions, the rats chose the stimulus leading to the largereward albeit less so as the delay increased to 32 s (as shown inFig. 5b). Consequently, a repeated measures ANOVA re-vealed a main effect of delay (F (3,27)=10.249, p <0.0001).Importantly, the behavioral pattern was statistically indistin-guishable following vHC inactivation (F (1,9)=0.138, p >0.05)indicating that the rats’ capacity to associate a choice responseand its reward outcome was unaffected (see also Rudebecket al. 2006). Nevertheless, the animals’ bias for the largereward declined with the long delay, suggesting that at verylong delays the waiting time is too long for the difference inreward size to reliably influence the decision.

Discussion

We demonstrate, for the first time, that noradrenergic modu-lation of the vHC plays a critical role in decision-making.Specifically, we show that local stimulation of α2A-adrenergicreceptors in the vHC increased rats’ willingness to wait for alarge reward, thereby reducing their propensity to make whatare sometimes called “impulsive choices”. That vHC inacti-vation produced the opposite result of making rats moreimpulsive in their choices is consistent with previous lesionstudies, highlighting the important contribution of the vHC todecision-making. Moreover, the apparent lack of involvementof the DA D1 receptor system in the same task is consistentwith the notion that the primary site of dopamine action fordelay discounting is in the prefrontal cortex (Loos et al. 2010;Pardey et al. 2012). Together, these data provide the firstevidence that stimulation of α2A-adrenergic receptors in thevHC contributes to the beneficial effects of systemically ad-ministered guanfacine on impulsive decision-making.

Mechanisms of guanfacine action

Our results demonstrate that adrenergic modulation in thevHC affects behavior. Guanfacine is a selective α2A-adrener-gic receptor agonist. In the rodent hippocampus, these recep-tors are most principally located on presynaptic terminals(McCune et al. 1993; Nicholas et al. 1993; Scheinin et al.1994), although some are also located in the postsynapticmembrane of somas and/or dendrites. The presynaptic recep-tors are thought to act as autoreceptors that control noradren-ergic release (Dubocovich 1984; Langer 1980; Milner et al.1998). It is known that α2A-adrenergic receptor stimulation

Fig. 4 The effect of SCH 23390 infused into the vHC on delaydiscounting. SCH 23390 infused into the vHC at three doses (low,0.25 μg/side; medium, 0.5 μg/side; and high, 1 μg/side) had no effecton the number of large reward choices made by rats (a). The large reward

choice preference produced by each dose of guanfacine is shown for the8, 16, and 32 s delays (b). All data shown are mean (±SEM) percentagechoice of the large reward

Psychopharmacology

has the effect of reducing cyclic adenosine monophosphateintracellular signaling by activating Gi proteins. In locuscoeruleus terminals located in the hippocampus, presynapticα2A-adrenergic receptor stimulation might thus lead to a localdecrease in noradrenaline release (Schoffelmeer et al. 1985,1986; Schoffelmeer and Mulder 1983). Thus, one possibilityis that the beneficial effect of both local and systemic deliveryof guanfacine is a reduction of NA levels in the vHC.Distinguishing between this presynaptic interpretation andalternative interpretations will require administration with ag-onists and antagonists selective for other adrenergic receptorsubtypes. The selectivity of the agent is critical to establish themechanism of action. For example, less selective agents suchas clonidine provide results that are more difficult to interpret.In delay discounting, systemic administration of clonidineproduces the opposite effect of guanfacine, even though bothare α2A receptor agonists (van Gaalen et al. 2006). However,unlike guanfacine, clonidine has high affinity for several otherreceptors including α1, α2B, α2C, ß-adrenergic, histaminergic,imidazoline, and possibly dopaminergic receptors (Brownet al. 1990; Cornish 1988; Sastry and Phillis 1977; Uhlénet al. 1995; Uhlén and Wikberg 1991). This broad stimulationleads to a number of effects that are absent or less intense withguanfacine, including sedative and hypotensive side effects(Arnsten et al. 1988; Balldin et al. 1993; Hunt et al. 1990;Morrow et al. 2004).

Dopaminergic versus noradrenergic contributions to delaydiscounting

Our finding that only the medium dose of guanfacine promot-ed selection of the large delayed reward demonstrates the

neuromodulatory role of NA in decision-making. This isconsistent with the evidence that systemic noradrenergic ago-nists have a nonmonotonic influence on behavioral perfor-mance with peak efficiency at intermediate concentrations.This relationship is sometimes described as an ‘inverted U’shaped function (Robbins and Arnsten 2009). In contrast tothe effects of guanfacine, DA D1 receptor antagonism in thevHC using SCH 23390 had no observable effect on delaydiscounting. This was true at all of the doses tested, despite thefact that DA D1 receptors are distributed throughout the hip-pocampus in rats and primates (Bergson et al. 1995; Campset al. 1990b; Savasta et al. 1986). Evidently, DA D1 receptorantagonism in the vHC has minimal if any impact on delaydiscounting. This result stands in distinction to previous find-ings in the prefrontal cortex, where local infusion of DA D1

antagonists led to an increase in delay discounting, causing abias toward immediate reward (Loos et al. 2010; Pardey et al.2012; Zeeb et al. 2010). Together with the guanfacine results,these data suggest that this type of decision-making dependson both DA D1 receptor activity in the prefrontal cortex andα2A-adrenergic receptor activity in the vHC. As there was noobserved role for DA D1 modulation in the hippocampus (thisstudy) or α2A-adrenergic receptor activity in the prefrontalcortex (Morrow et al. 2004; Pardey et al. 2012), there appearsto be a pharmacological double dissociation between the twostructures in the context of decision-making.

How to conceive of the interaction between hippocampaland prefrontal areas is at present unclear but a topic of activeresearch (Chudasama et al. 2012; Prasad and Chudasama2013). Delay discounting is affected by manipulation not onlyof these areas but also the nucleus accumbens (Cardinal et al.2001) and the amygdala (Winstanley et al. 2004).While human

Fig. 5 Effect of vHC inactivation with a muscimol/baclofen cocktail onthe standard delay discounting task (a) and the equal delays procedure(b). vHC inactivation significantly reduced the number of large reward

choices made by rats when it was delayed (a), but not when the smallreward option was delayed as well (b). All data shown are mean (±SEM)percentage choice of the large reward. ★p <0.05 relative to saline

Psychopharmacology

neuroimaging studies have identified multiple brain regionsthat support different aspects of decision-making (for review,see Peters and Büchel 2011), a more complex picture emergeswhen we consider pharmacological mechanisms that are regionspecific. Take for example the action of atomoxetine, a selec-tive NA reuptake inhibitor used clinically to treat ADHD. Likeguanfacine, systemic administration of this agent has beenshown to decrease delay discounting in rats (Robinson et al.2008). Guanfacine, in stimulating α2A-receptors on the presyn-aptic membrane of noradrenergic neurons, is thought to exertits largest effect by decreasing NA release and thereby lowersthe overall amount of NA transmission. This effect is essen-tially the opposite of that expected by atomoxetine, whichincreases NA levels by a transporter reuptake mechanism.Thus, the systemic effects of atomoxetine may act throughdifferent neural circuits, such as those in the prefrontal cortex.Our results showing reduced impulsive choices followingtargeted vHC infusions of guanfacine suggest that at least someof the beneficial effects of noradrenergic drugs used for neuro-psychiatric illnesses associated with prefrontal dysfunction(e.g., Arnsten and Li 2005; Chamberlain et al. 2007; Harmeret al. 2003), may instead be mediated by the hippocampus.

Unchanged aspects of cognition following hippocampalinactivation

Our demonstration that local pharmacological manipulationof the hippocampus affects delay discounting adds to thegrowing conception that the hippocampus contributes todecision-making (Peters and Büchel 2010). Consistent withour inactivation findings, several studies have shown robustincreases in delay discounting in rats with hippocampal le-sions (Abela and Chudasama 2013; Cheung and Cardinal2005; Mariano et al. 2009; Rawlins et al. 1985). Our dataextend this work in several important ways. Specifically, itshows that the shift in choice behavior following hippocampalinactivation is not due to perceptual deficits, poor discrimina-tion of reward value, or the inability to make associations.Inactivation of the vHC had no specific effect on rat’s choiceswhen both the small and large rewards were equally delayed.Under these conditions, the vHC did not play a role in the rats’selection of the large reward indicating that the animals weresensitive to time and understood the relative size of theexpected future reward (Kim and Zauberman 2009;Zauberman et al. 2009). It also demonstrates that vHC-inactivated rats were willing to wait for the large reward, anddid not respond for the small reward because they wereimpulsive.

The vHC inactivation also had no effect on zero-delay trials,where their performance was indistinguishable from controls.The results suggest that vHC inactivation affects decision-making related to the promise of a future payoff, a notion thatis consistent with the hippocampus being concernedwith future

events (Johnson et al. 2007; Peters and Büchel 2010; Schacteret al. 2007; van der Meer et al. 2010). Note that this link withtime stands in distinction to the prefrontal cortex. Recently, weshowed a double dissociation between the two areas, with vHCdamage affecting choices involving time but prefrontal damageaffecting choices involving uncertainty (Abela and Chudasama2013; see also Stopper et al. 2012). Furthermore, none of theanimals in the present study were affected with respect to theirmotor or motivational status, since the latency to respond orcollect and consume food was normal. Together, these dataargue an important role for the hippocampus in decision-making especially when evaluating the potential outcome of adecision over long time scales. That α2A-adrenergic receptorstimulation in the vHC enabled normal rats to make betterchoices (i.e., choose the large reward option at long delays)further supports the notion that the vHC has the capacity tooptimize long-term gains.

Potential role of stress

Theα2A-adrenergic receptor is closely associated with stress. Infact, systemic administration of yohimbine, an α2A receptorantagonist increases stress in rats and humans as measuredthrough autonomic physiological responses (Johnston andFile 1989; Stine et al. 2002). It also leads to impulsive behaviors(Sun et al. 2010; Swann et al. 2005). Thus one interpretation ofthe effects of guanfacine in the current study is that it amelio-rates stress through stimulation of adrenergic receptors in thevHC. Furthermore, the stress response is associated with sig-nificant increases in noradrenaline in the hippocampus (Adellet al. 1988; Glavin et al. 1983; Tanaka et al. 1982, 1983). Byreducing noradrenergic tone through presynaptic mechanismsas described above (Milner et al. 1998; Schoffelmeer et al.1985), guanfacine acting in the vHC may serve to attenuatethe stress response during the stressful wait for the large reward.In fact, stress may be an integral part of the delay discountingtask itself. That is, the level of stress experienced while waitingfor the large reward might mediate the rate at which largerewards are discounted. In this interpretation, guanfacine ad-ministration promotes the rats’ selection of larger rewards bycounteracting the stress associated with waiting. Note that thisinterpretation appears contrary to results from a recent studyshowing that stress affects decisions associated with increasedeffort but not with increased delay (Shafiei et al. 2012), thusfurther investigation of the specific relationship between stress,guanfacine, and decision-making is warranted.

Clinical implications

The cognitive-enhancing effect of guanfacine demonstratedhere may relate to the successful use of noradrenergic stimu-lants in relieving impulsive-like symptoms of ADHD andrelated disorders. The site of action of these drugs is presumed

Psychopharmacology

to be in the prefrontal cortex, but never the hippocampus.Decision-making deficits are observed in patients with condi-tions that affect the hippocampus such as Alzheimer’s disease,amnesia, and epilepsy (Gupta et al. 2009; Gutbrod et al. 2006;Kwan et al. 2012; Labudda et al. 2009; Sinz et al. 2008). Ourdata suggest that the vHC under the modulatory control of thenoradrenergic system represents a critical component of thebroader neural circuitry that supports decision-making.

Acknowledgments This work was supported by grants from the Ca-nadian Institute of Health Research (CIHR) and the Canadian Foundationfor Innovation (CFI). Yogita Chudasama is a member of the Center forstudies in Behavioral Neurobiology (CSBN) at Concordia University inMontreal. We thank Shivani Bhat for help with behavioral testing andhistology.We are very grateful to DavidA. Leopold for helpful commentson the manuscript.

Financial disclosures The authors report no biomedical financial in-terests or potential conflict of interests.

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