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F. Denk . M. E. Walton . K. A. Jennings . T. Sharp .
M. F. S. Rushworth . D. M. Bannerman Differential involvement of serotonin and dopamine systemsin cost-benefit decisions about delay or effort Received: 27 April 2004 / Accepted: 30 September 2004 / Published online: 10 December 2004 Abstract Rationale: Although tasks assessing the role of Keywords Cost-benefit evaluation . Decision making .
dopamine in effort-reward decisions are similar to those Rat . Effort . Impulsivity . Serotonin . Dopamine .
concerned with the role of serotonin in impulsive choice in that both require analysis of the costs and benefits ofpossible actions, they have never been directly compared.
Objectives: This study investigated the involvement of serotonin and dopamine in two cost-benefit paradigms,one in which the cost was delay and the other in which it Many neurological patients have difficulties with decision was physical effort. Methods: Sixteen rats were trained making, particularly in situations in which they have to on a T-maze task in which they chose between high and evaluate different behavioural options on the basis of their low reward arms. In one version, the high reward arm was respective costs and benefits (Rahman et al. ). This is obstructed by a barrier, in the other, delivery of the high true not only of patients with lesions to parts of prefrontal reward was delayed by 15 s. Serotonin and dopamine cortex (Bechara et al. ; Rogers et al. Manes function were manipulated using systemic pCPA and et al. ), but also of patients who suffer from neuro- haloperidol injections, respectively. Results: Haloperidol- psychiatric disorders such as the frontal-variant of fronto- treated rats were less inclined either to exert more effort or temporal dementia (Rahman et al. ), unipolar and to countenance a delay for a higher reward. pCPA had no bipolar depression (Murphy et al. ) and substance effect on the performance of the rats on the effortful task, abuse (Rogers et al. London et al. ). Animal but significantly increased the rats’ preference for an models may help produce a better understanding of the immediate but smaller reward. All animals (drug treated neurobiological causes underlying these decision-making and controls) chose the high reward arm on the majority of problems. In the rat, cost-benefit evaluation can be trials when the delay or effort costs were matched in both studied with paradigms that offer the animal a choice high and low reward arms. Conclusion: A dissociation between a high reward obtainable at high cost and a low was found between the neurotransmitter systems involved reward obtainable at low cost. The type of cost involved in different types of cost-benefit decision making. While could be, for example, either increased physical effort or dopaminergic systems were required for decisions about both effort and delay, serotonergic systems were only Mesolimbic dopamine fibres projecting to the nucleus accumbens (NAc) have been implicated in effort-basedcost-benefit decision making. Blocking dopamine trans-mission using either systemic injections of the D2 an-tagonist, haloperidol, or following 6-hydroxydopamine F. Denk . M. E. Walton . M. F. S. Rushworth .
D. M. Bannerman (*) (6-OHDA) lesions of the NAc induced rats to shift their Department of Experimental Psychology, University of Oxford, behaviour towards choosing freely available lab chow over preferred food which was only obtainable by lever press- ing (Salamone et al. Cousins and Salamone ; e-mail: +44-1865-271444 Sokolowski et al. Moreover, on operant tasks using fixed ratio schedules, differences between 6-OHDA le-sioned animals and control animals were only found for higher fixed ratio schedules (e.g. FR5, FR16, FR64, but not Department of Pharmacology, University of Oxford, FR1: Aberman and Salamone ; Ishiwari et al. The lesioned animals were significantly less inclined to press the lever for reward when the ratio of required lever and Robbins ; Wade et al. though various tests presses to rewards was increased. The shift in preference of impulsivity may assess diverse cognitive processes towards lower ratio schedules was also observed when dif- ferences in the frequency of reinforcement on high and The present study compared the effects of blocking low ratio schedules were reduced, using a paradigm on either dopamine or serotonin function on two different which for both schedules the delivery of reward was in- versions of the T-maze task, both of which have been used termittent and of approximately the same reinforcement previously for studying decision making where the cost density (Salamone et al. ; Correa et al. is in terms of either increased effort or delayed reward Evidence for the involvement of dopamine in effort- (Thiebot et al. Bizot et al. Salamone et al. ; based cost-benefit evaluations has also been obtained using Walton et al. , The rat was given the choice a T-maze task. Rats were given the choice between a small between a high reward arm and a low reward arm. De- number of food pellets in one arm and a larger number of pending on the task, it either had to exert physical effort by food pellets in the other arm. Access to the high reward climbing a barrier to obtain the high reward or wait until a arm, however, could only be obtained after climbing a delay period of 15 s had elapsed. The two versions of the barrier. Blocking dopamine function using either system- T-maze task thus allowed decision making with both kinds ic haloperidol or following 6-OHDA depletions of NAc of cost (effort versus delay of reinforcement) to be com- led to rats choosing the low effort/low reward arm sub- pared using very similar experimental paradigms. Seroto- stantially more often than controls (Salamone et al. nin levels were manipulated using systemic injections of para-chlorophenyl-alanine methyl ester (pCPA), a seroto- Similar T-maze paradigms to those used for studying nin synthesis blocker. Dopamine function was blocked by effort-based decisions have also been employed in studies the D2 receptor antagonist haloperidol.
of impulsivity. The rat is again given a choice between alarger and a smaller reward, but this time, the cost as-sociated with the former is in terms of a delay before reward delivery. Serotonin has been implicated in delay-based cost-benefit decisions of this kind. Several studies have reported that drugs which directly or indirectly reduceserotonin function increase the frequency with which Sixteen male Lister hooded rats served as subjects through- animals choose an immediate small reward over a larger out the main series of experiments (1A, 1B, 2A and 2B).
delayed reward (e.g. Thiebot et al. Bizot et al. They were approximately 7 months old at the beginning of Conversely, administration of serotonin re-uptake inhibi- testing. All of the rats were experimentally naive prior to tors causes rats to choose the arm with the larger delayed training on the cost-benefit T-maze task. They were ex- reward more often than vehicle-injected controls (Bizot tensively familiarised with the barrier task (Experiment 1A) et al. Analogous studies using operant paradigms having served as the unoperated control group in another have also shown that manipulations of serotonin function experiment (see Walton et al., The animals were affect rats’ choices between small immediate and larger housed in pairs under standard conditions (12 h light/dark cycle, lights on between 7 a.m. and 7 p.m.). They were kept addition, rats with lesions of the dorsal and medial raphé at about 85% of their free-feeding weight throughout the nuclei, which represent the origins of the serotonergic study. Water was available ad libitum. Treatment and care of projections to the frontal cortex, were found to be less the animals was in accordance with the Principles of lab- inclined than sham lesioned animals to choose a larger oratory animal care and the United Kingdom Animals Sci- but delayed reward over a smaller, immediate reward An additional group of 12 male Lister hooded rats Taken together, these studies suggest a role for both served as subjects in a biochemical assay to determine the dopamine and serotonin in decision making. It remains to extent of the serotonin depletion following the pCPA be established, however, whether both neurotransmitter treatment schedule used in the behavioural studies.
systems are equally implicated in effort-based and delay-based cost-benefit decision making tasks using theseT-maze paradigms. The first aim of the present study therefore was to determine whether serotonin, in additionto its involvement in decisions where the cost is in terms The T-maze consisted of three wooden arms (a start arm of delay of reinforcement, is also important for decisions and two goal arms) which were 60 cm long, 10 cm wide about whether to exert increased effort for greater reward.
and 40 cm high. Metal food wells (3 cm in diameter, 1 cm Conversely, the second aim was to establish whether high) were placed at each end of the two goal arms, 3 cm dopamine, in addition to its role in effort-based decision from the wall. The maze was elevated 80 cm above floor making, is equally important for delay-based cost-benefit level and painted in a uniform grey colour. A video camera decision making using the T-maze task. There is evidence was mounted on the ceiling above the maze to allow consistent with a role for dopamine in aspects of impul- recording of the rats’ performance on certain days of sivity, and, more specifically, in delay discounting (Cole testing in order to obtain latency measurements. On forced trials a wooden block (30 cm high and 10 cm wide) was was then injected IP at a volume of 1 ml/kg 50 min before used to stop the animal from entering a particular goal the start of testing. Saline (0.9%; 1 ml/kg) was injected as Two different versions of the T-maze task were used pCPA (Sigma-Aldrich; Poole, UK) was injected IP at a (see Fig. ). Experiment 1 was concerned with cost-benefit dose of 300 mg/kg (dissolved in 0.9% saline at a volume decision making where the cost was in terms of increased of 10 ml/kg). Again, saline (0.9%; 10 ml/kg) served as the effort (Fig. A triangular wire mesh barrier was placed vehicle control. Each rat received two injections, 48 h and in the high reward goal arm so that the rat first had to 24 h before the start of testing. This regimen has been overcome a vertical side of 30 cm, before then descending repeatedly shown to reduce levels of serotonin and its down the slanted side towards the food (45 mg Noyes food metabolite 5-hydroxyindoleacetic acid (5-HIAA) by more pellets; Formula A/I; P.J. Noyes and Co., Lancaster, N.H., than 85% in frontal cortex and hippocampus (Castro et al.
USA). Performance was also assessed under conditions in ; Hajos et al. and for up to 7 days (Jakala et al.
which a second barrier with the same attributes was placed ). To verify this, an additional group of six animals similarly received two injections of pCPA (300 mg/kg) In experiment 2 the cost was in terms of delayed 24 h apart. A further six rats received saline vehicle reinforcement (see Fig. Four wooden guillotine doors injections. Twenty-four hours after the second injection were built into the maze. In each goal arm there was one (corresponding to the start of behavioural testing) the door just in front of the food well (10 cm from the end animals were killed and tissue samples from frontal cortex, wall of each goal arm) and one near the entrance of the striatum and hippocampus were removed and frozen for goal arm (10 cm from the junction of the start arm and the subsequent measurement of serotonin and 5-hydroxyin- goal arms). They were painted the same grey colour as doleacetic acid (5-HIAA) levels (for methods, see Hajos Based on previous findings (Walton et al., In all experiments, the rats were tested in batches of four haloperidol was administered at a dose of 0.2 mg/kg.
with an inter-trial interval of approximately 5 min. The Ampoules of Haldol (haloperidol dissolved in lactic acid location of the high reward arm was counterbalanced with and water at a concentration of 5 mg/ml; Janssen-Cilag respect to treatment groups, being always on the left for Ltd, High Wycombe, UK) were further diluted in 0.9% half of the animals and always on the right for the other saline to give a final concentration of 0.2 mg/ml. The drug half. The results were analysed with ANOVAs usingHuynh-Feldt corrections where appropriate.
Experiment 1A: haloperidol on the barrier task The rats were first trained on the barrier task. The animalswere given the choice between either climbing the barrierfor four food pellets in the high effort/high reward goalarm, or receiving two food pellets in the low effort/lowreward arm in which no barrier was present (Salamoneet al. ; Walton et al. As the rats hadbeen trained on this task 2 months previously as part of aseparate experiment, no lengthy habituation period wasrequired. Instead they were simply reminded of the pro-cedure by running them for several days on a series offorced trials, during which they had no choice of whicharm to enter because one of the goal arms was blocked.
The rats were pseudorandomly forced into either the highor low reward arm (five trials to each per day). Pre-drugtesting on the task proper then began. On each day oftesting the rats first received two forced trials (one to each Fig. 1 Diagram illustrating the experimental set-ups for both the side). They then received ten choice trials during which barrier (experiment 1) and delay (experiment 2) versions of the the number of times the rat chose the high reward arm was T-maze cost-benefit decision-making task. a On the barrier task recorded. This procedure in which two forced trials the rat had to choose between climbing a barrier for a four pellet preceded ten choice trials was used throughout the entire reward or no barrier for a two pellet reward. b On the delay task, the rat had to choose between an immediate reward of two pellets or alarger ten pellet reward which was delayed by 15 s Drug manipulations began as soon as all animals con- Experiment 2A: haloperidol on the delay task sistently chose the high reward on at least 75% of trials.
The effects of haloperidol on decision making were as- For the second set of experiments which examined deci- sessed using a within-subjects design. On test day 1, eight sion making when the cost was in terms of delayed rein- rats received haloperidol and eight received saline. The forcement, the animals could now choose between an assignment of animals to injection conditions was coun- immediate smaller reward and a delayed larger reward.
terbalanced with respect to pre-drug performance and the The spatial location of the high and low reward arms left/right orientation of the high/low reward arms. Twenty- remained unchanged, although the high reward arm now four hours after each injection day, the rats were retrained contained ten pellets and the low reward arm two pellets on the task. They received ten forced trials (five to both the (Thiebot et al. Bizot et al. ). When the rat chose high and low reward arms) and ten choice trials: at this the high reward arm, it was locked in the goal arm by point all animals were once again choosing the high re- means of the pair of sliding doors. After 15 s the sliding ward arm on at least 75% of the trials. On the following door adjacent to the food well was opened and the rat was day, a second test session was conducted but with the al- allowed to consume the reward. In contrast, when the rat location of animals to the drug and vehicle conditions now chose the low reward arm, the door adjacent to the food was opened as soon as the door at the entrance of the goal For the barrier control task, a second barrier was then arm was closed (i.e. as soon as the animal was fully inside added to the low reward arm. The rats could still choose between two food pellets in the low reward arm and four Several days were required to train the rats to this new food pellets in the high reward arm, but now there was a procedure so that they were choosing the delayed high 30 cm barrier in each arm (Walton et al. ). The rats reward option on the majority of trials. As in experiment 1, were run for 2 days on this two barrier task prior to the effects of haloperidol on the delay task were assessed receiving any drug treatments. The rats were again divided using a within-subjects design. After 2 days of drug free into two groups, counterbalanced according to perfor- testing on the task, half the animals were injected with mance and left/right orientation of the high/low reward haloperidol and half with saline. On the second day of arms. Haloperidol and vehicle were again administered drug testing the assignment of animals to drug and vehicle according to a within-subjects design. Performance of the groups was reversed. All rats received 1 day of drug free rats was videotaped in order to obtain latency measure- testing in between the 2 injection days, consisting of ten ments. The times taken to get (i) from the starting position forced and ten choice trials interleaved. Testing with hal- to the bifurcation of the maze (phase I), (ii) from there to operidol on the delay task began 2 weeks after the previous the top of the barrier (phase II), and (iii) from the top of the pCPA treatment. The assignment of animals to drug and barrier to the food (phase III) were recorded.
vehicle groups on the first day of drug testing was coun-terbalanced as before and with respect to previous pCPAor vehicle treatment.
A 15 s delay was then also introduced in the low reward arm (delay control task). The rats could still choose The animals were then re-trained on the single barrier task between two food pellets in the low reward arm and ten until they were again choosing the high reward arm on at food pellets in the high reward arm, but now there was an least 75% of trials. The effects of pCPA on decision equal delay in reinforcement in each arm. The rats making were assessed using a between subjects design.
received 2 days of drug-free testing prior to further drug The rats were newly assigned to groups according to pre- manipulations. As before, on the first day of drug testing drug performance and the left/right orientation of the high/ half the animals were injected with haloperidol and half low reward arms. Half of the animals received two with saline. On day 2 of drug testing, the assignment of injections of pCPA 24 h apart, the other half received animals to drug and vehicle groups was reversed.
saline. Testing on the single barrier task then began 24 hafter the second injection. The rats were tested for 2 dayson the single barrier task (days 1–2 post-pCPA; ten choice On the following day (day 3 post-pCPA), the barrier The rats then underwent 3 days of drug-free testing with control task was run. A second identical barrier was now a delay of 15 s in the high reward arm and immediate placed in the low reward arm. After two forced trials (one reinforcement in the low reward arm. As before, the to each of the high and low reward arm), the rats received effects of pCPA on decision making were assessed using 20 choice trials with barriers in both goal arms during a between-subjects design. Half of the animals received which preference for the high reward arm was recorded.
two injections of pCPA 24 h apart, the other half received Latency measurements were obtained as in experiment two injections of saline. The assignment of animals to pCPA and vehicle groups was identical to experiment 1B.
Testing on the single delay task then began 24 h after the second injection and the rats were tested for 3 con- 31.27; P<0.001], and a task×drug interaction [F(1,12)= secutive days (days 1–3 post-pCPA; ten choice trials per 8.06; P<0.05]. From Fig. it is clear that this is explained by a greater impairment on the barrier task as opposed to Several weeks later the rats were retrained as drug free the double barrier control task. Nevertheless subsequent animals on the single delay version of the task. Further analyses of simple main effects confirmed that there were injections of pCPA or saline were then administered, after significant impairments with haloperidol for both versions which the rats then received 3 days testing on the delay of the barrier task [F(1,12)>9.72; P<0.01]. Analysis of control task (days 1–3 post-pCPA injection) with a 15 s simple main effects also revealed an effect of task (single delay now introduced in the low reward arm as well as the barrier versus double barrier) for haloperidol treatment high reward arm. Animals were re-assigned to vehicle and [F(1,12)=18.99; P<0.005], although this did not quite reach pCPA groups according to a fully counterbalanced design statistical significance for vehicle injection [F(1,12)=4.46; on the basis of both prior drug history (previously pCPA or vehicle) and performance during the drug-free testing Analysis of the latency to complete trials revealed an interaction between drug treatment and the three phases oftrials [F(2, 24)=7.88, P<0.005]. Although haloperidolcaused a slight increase in time taken to climb the barrier (phase II), from Fig. (left panel) it is clear that halo-peridol particularly increased latencies in the first and last Experiment 1A: haloperidol on the barrier task The mean percentage of high effort/high reward armchoices obtained for haloperidol and saline groups on the barrier tasks is displayed in Fig. (experiment 1A). Whentested with just a single barrier in the high reward arm, Tissue levels of serotonin (pmol/mg tissue; mean±SEM) haloperidol injected animals chose the high effort/high in frontal cortex, hippocampus and striatum (2.81±0.59, reward arm significantly less often than saline treated 1.42±0.06 and 1.90±0.24, respectively) were reduced by animals. When a second barrier was then also placed in the 85–95% following pCPA treatment (0.18±0.01, 0.09±0.01 low reward arm, the haloperidol treated rats now showed a and 0.28±0.02, respectively). Levels of 5-HIAA (pmol/mg much stronger preference for the high reward arm (more tissue; mean±SEM) were similarly depleted in pCPA than 80% high reward arm choices), although still slightly treated animals (0.06±0.01, 0.06±0.01 and 0.10±0.01 for less so than the saline-injected controls. One animal frontal cortex, hippocampus and striatum, respectively) stopped running on the task during the pre-drug training relative to rats that had received saline injections (1.64± phase. In addition, two rats failed to run on the task after 0.35, 1.68±0.11 and 1.79±0.21, respectively).
haloperidol treatment. This analysis therefore includeddata from 13 subjects. An ANOVA revealed a main effectof task [single barrier versus double barrier control;F(1,12)=28.96; P<0.001], a main effect of drug [F(1,12)= Fig. 3 Mean latency (±SEM) on the barrier control task afterhaloperidol (left panel; experiment 1A) and pCPA (right panel;experiment 1B) injections. Only data from high reward trials aredisplayed. In the case of haloperidol, data from 2 days has been Fig. 2 Mean percentage of high reward arm choices (+SEM) for combined. I=phase I (time it took the animal from the start to the haloperidol (black bars) and saline (white bars) injected animals on choice point); II=phase II (time it took the animal from the choice the barrier task (left-hand side) and the barrier control task (right- point to the top of the barrier); III=phase III (time it took the animal hand side) (experiment 1A). Data were collapsed across days Figure shows the mean percentage of trials on which the rats chose the high effort/high reward arm, before andafter pCPA injection, on the barrier task. Serotonin deple-tion did not affect the frequency with which rats chose thehigh effort/high reward arm in preference over the loweffort/low reward arm. An ANOVA confirmed the absenceof any main effect of group or interactions involving group(P>0.20). The pCPA and saline groups also did not differwhen a second barrier was placed in the low reward arm(P>0.05). Furthermore, pCPA treatment had no effect onmean trial latencies during performance of the two-barrierversion of the task (P>0.20; Fig. right panel).
Experiment 2A: haloperidol on the delay task The effect of haloperidol on the delay task is displayed in Fig. 5 Mean percentage of high reward arm choices (+SEM) for Fig. Following injection of haloperidol, rats were less haloperidol (black bars) and saline (white bars) injected animals on likely to choose the delayed/high reward arm than con- the delay task (left-hand side) and the delay control task (right-hand trols. When reinforcement in the low reward arm was also side) (experiment 2A). Data were collapsed across days delayed by 15 s, the frequency with which haloperidoltreated rats chose the high reward arm was now muchhigher (greater than 80%), although as with the barrier task the drug treated animals still chose the high reward armless often than the controls. One haloperidol treated animal The effects of serotonin depletion on the delay task can failed to run during this stage of testing: the analysis be seen in Fig. pCPA treated rats chose the delayed/ therefore consists of data from 15 subjects. The ANOVA high reward arm less often than the saline controls. An revealed a main effect of task [single delay versus double ANOVA revealed a significant drug group×block inter- delay control; F(1,14)=19.19; P<0.005], a main effect of action [F(1,14)=4.64; P<0.05], as well as significant drug [F(1,14)=23.75; P<0.001], and a task×drug interac- main effect of block [pre-injection versus post-injection; tion [F(1,14)=6.43; P<0.05]. From Fig. it is clear that the F(1,14)=31.36; P<0.001], reflecting a small change in interaction is explained by a greater impairment on the performance across both groups after injection. Analysis single delay task than on the double delay control task.
of simple main effects confirmed that the pCPA and Nevertheless, analysis of simple main effects confirmed saline treated animals differed significantly post-injection that there were significant effects of haloperidol for both [F(1,19)=4.46; P< 0.05]. When a delay was also intro- versions of the delay task [F(1,14)>6.29; P<0.05]. Anal- duced in the low reward arm (Fig. both pCPA and saline ysis of simple main effects also revealed an effect of task groups showed an increased and equivalent preference for (single delay versus double delay control) for both ve- the high reward arm (P>0.10; saline versus pCPA for hicle [F(1,14)=9.33; P<0.01] and haloperidol treatment Fig. 4 Mean percentage of highreward arm choices (±SEM) forserotonin manipulations on thebarrier task (experiment 1B).
Depicted are 2 days of datacollected before pCPA injec-tions and data collected afterpCPA injections (two blocks often trials on the barrier task andtwo blocks of ten trials on thebarrier control task) Fig. 6 Mean percentage of highreward arm choices (±SEM) forserotonin manipulations on thedelay task (experiment 2B).
Depicted are 3 days beforepCPA injections (pre-injection)and 3 days after pCPA injections(post-injection, pCPA: filledcircles, vehicle: empty circles) Fig. 7 Mean percentage of highreward arm choices (±SEM) forserotonin manipulations on thedelay control task (experiment2B). Depicted are 3 days beforepCPA injections (pre-injection)and 3 days after pCPA injections based and delay-based decision making tasks were sen-sitive to dopamine receptor blockade. Animals that had The present study examined the roles of dopamine and received the D2 receptor antagonist haloperidol chose the serotonin in both effort-based and delay-based cost-benefit high effort/high reward arm significantly less often than decision making. The effects of manipulating the two vehicle injected controls, in agreement with the previous neurotransmitter systems were tested on two cost-benefit report of Salamone et al. (In addition, they also decision making tasks using the T-maze, one in which the chose the smaller but immediate reward more often than cost was effort (Salamone et al. ) and one in which controls in agreement with Wade et al. (). These re- the cost was delay (Thiebot et al. ). In agreement with sults therefore demonstrate a partial dissociation of the the previous report of Bizot et al. (), serotonin roles of serotonin and dopamine in cost-benefit decision depletion (in excess of 85% depletion) resulted in animals making. While serotonin is implicated when the cost is in being more likely to choose the smaller but immediate terms of delay but not when it is in terms of effort, do- reward, and less likely to choose the larger but delayed pamine is implicated in deciding about both effort and reward. In contrast, serotonin-depleted rats were as in- clined as controls to put in increased effort (climbing a 30cm barrier) for a larger reward (Table Both the effort- A role for serotonin in delay-based but not effort-based decision making Table 1 Overview of the findings from all the drug and taskmanipulations. Ticks indicate significant effect of drug administra-tion The results of the present series of experiments thereforesuggest a selective role for serotonin in decision making tasks where the animal has to choose between a smaller but immediate reward and a larger but delayed reward.
Importantly, when a 15 s delay was also introduced in the low reward arm, pCPA-treated rats increased their pref- erence for the high reward arm and were indistinguishable from the controls. This result argues strongly that the are perfectly capable of perceiving and discriminating effect of serotonin depletion is in terms of reducing animals’ tolerance of a delay for increased reward, andagainst the possibility that it is due to an effect of pCPA onsome other aspect of task performance such as memory for A more general role for dopamine in decision making the location of the high reward or appetite for reward pellets. Furthermore, the normal performance of the pCPAtreated rats on the barrier task also argues against an effect Rats that received haloperidol were more inclined to of the drug on some non-specific aspect of performance choose the low cost/low reward option on both versions of such as memory or appetite. Indeed, the dissociation the task, irrespective of whether the cost was in terms of between the effect of pCPA on the delay task and the lack effort or delay of reinforcement. These results are in agree- of an effect on the barrier task suggests that serotonin is ment with several previous studies which have implicated selectively involved in the ability of animals to tolerate a dopamine both in the ability to put in more effort to obtain a delay in order to obtain a larger reward. This implies greater reward (Salamone et al. Salamone and Correa that serotonin is involved in a specific aspect of decision ), and also the ability to withhold impulsive respond- making associated with a specific kind of cost, namely ing (Cole and Robbins ; Wade et al. Peterson et al. The effect of haloperidol on the barrier task is We cannot completely rule out the possibility that the unlikely to be due to the delay imposed by climbing the barrier task was simply less sensitive to serotonin depletion barrier, with latency data showing that its duration is neg- than the delay task. Nevertheless, a number of points argue ligible even in haloperidol injected rats. This also argues against this possibility. First, there is absolutely no sign of against a simple motor account. Furthermore, the perfor- even any marginal effect of pCPA treatment on the barrier mance of haloperidol treated rats on the two barrier task, task; the performances of both groups were almost iden- during which they demonstrated that they had retained the tical. It therefore seems extremely unlikely that the lack of ability to climb the barrier, also argues against such an an effect is due to insufficient power in the experiment.
Second, the absence of an effect of pCPA on the barrier task The role of dopamine in decision making tasks is not, is not because the dosing regimen used was ineffective. This however, entirely independent of the nature of the cost.
treatment schedule produced a greater than 85% reduction For example, it has recently been shown that dopamine in serotonin levels in frontal cortex, striatum and hippo- might be differentially involved in calculating the cost of campus, and was sufficient to disrupt performance on the physical work when it is concerned with the number of delay task. Third, the absence of an effect of pCPA on the lever presses that have to be performed, but not when it is barrier task is not because the barrier task itself is insuf- concerned with how much force is required in order to ficiently sensitive. In addition to the clear effects of halo- press the lever (Ishiwari et al. This raises the pos- peridol in the present study (see also Salamone et al. sibility that accumbens dopamine might be required for we have also shown dramatic effects after anterior cingulate putting in increased effort for increased reward but only in cortex lesions, using exactly the same apparatus and testing terms of sustained effort and not in terms of more forceful parameters (Walton et al. , It seems, therefore, that the crucial factor in terms of a role for serotonin is the It is also worth noting that although the frequency with nature of the cost associated with the task.
which haloperidol treated animals chose the high reward A selective role for serotonin specifically in delay- arm increased dramatically when the cost (either in terms related cost-benefit evaluations has been reported pre- of effort or delay) was subsequently equated in both the viously. Mobini et al. ) demonstrated that lesions high and low reward arms, the level of responding to the of the ascending serotonergic pathways affected choice high reward arm was still significantly lower than that behaviour between a small but immediate reward and a displayed by the controls. The reason for this is not larger but delayed reinforcement but not between small immediately obvious. One possibility is that haloperidol certain rewards and large uncertain rewards. Thus, like might have an effect on processing of reward value. It has effort-based cost-benefit decision making, serotonin does been demonstrated that orbitofrontal cortex lesions, for not seem to be necessary for choices concerned with the instance, can affect both the evaluation of a delay-based probability of reward delivery. There is, however, some cost and the sensitivity to the ratio of available rewards evidence that, under some circumstances, serotonin de- (Kheramin et al. ). Unfortunately, the nature of the pletion may also impair the perception and discrimination T-maze paradigm used here means that it is difficult to of reward magnitudes (Rogers et al. However, it establish whether haloperidol contributed to changes in the seems unlikely that the deficit following serotonin deple- perception of the relevant costs and benefits. Furthermore, tion on the delay task in the present study (experiment 2B) it could be that the effects of haloperidol on task perfor- is due to impaired perception and discrimination of reward mance may extend beyond decision making. A large body magnitudes. The fact that pCPA treated animals behaved of evidence indicates that haloperidol, along with other like controls and successfully selected the high reward arm anti-psychotics, may influence the reinforcing nature of on the majority of trials during both (i) the barrier tasks, stimuli (Wise Wise and Bozarth ; Mobini et al.
and (ii) the double delay task, suggests that these animals ) and impact on various motor processes (Horvitz Cole BJ, Robbins TW (1989) Effects of 6-hydroxydopamine lesions with this possibility, it is also worth noting that the halo- of the nucleus accumbens septi on performance of a 5-choiceserial reaction time task in rats: implications for theories of peridol injected rats were slower to complete running a selective attention and arousal. Behav Brain Res 33:165–179 trial on the two barrier version of the task than vehicle Correa M, Carlson BB, Wisniecki A, Salamone JD (2002) Nucleus injected controls (see also Cousins and Salamone accumbens dopamine and work requirements on interval Salamone et al. ). This is consistent with a number of Cousins MS, Salamone JD (1994) Nucleus accumbens dopamine demonstrations of the involvement of dopamine in wide depletions in rats affect relative response allocation in a novel ranging aspects of motivation and response initiation. Im- cost/benefit procedure. Pharmacol Biochem Behav 49:85–91 portantly, however, the highly significant interaction be- Cousins MS, Atherton A, Turner L, Salamone JD (1996) Nucleus tween drug treatment and task for both the effort and delay accumbens dopamine depletions alter relative response alloca- control versions (i.e. one barrier versus two barrier and one tion in a T-maze cost/benefit task. Behav Brain Res 74:189–197 Evenden JL (1999) Varieties of impulsivity. Psychopharmacology delay versus two delays) suggests that at least part of the effect of disrupting dopamine transmission is in terms of Evenden JL, Ryan CN (1996) The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice withvarying delays of reinforcement. Psychopharmacology 128:161–170 Evenden JL, Ryan CN (1999) The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and selectiveserotonergic drugs on response choice with varying delays of In conclusion, the present study demonstrates a clear dis- reinforcement. Psychopharmacology 146:413–421 Hajos M, Sharp T (1996) A 5-hydroxytryptamine lesion markedly sociation between the neurotransmitter systems involved reduces the incidence of burst-firing dorsal raphe neurones in in two different types of cost-benefit decision making.
While dopamine is important for decisions concerned with Hajos M, Richards CD, Szekely AD, Sharp T (1998) An elec- both effort and delay, serotonin is only crucial for eval- trophysiological and neuroanatomical study of the medial pre- uations concerned with delay. It is also possible that these frontal cortical projection to the midbrain raphe nuclei in therat. Neuroscience 87:95–108 different decision making processes depend on partially Horvitz JC, Ettenberg A (1988) Haloperidol blocks the response- dissociable neuroanatomical circuits (Cardinal et al. reinstating effects of food reward: a methodology for separating neuroleptic effects on reinforcement and motor processes.
Pharmacol Biochem Behav 31:861–865 Ishiwari K, Weber SM, Mingote S, Correa M, Salamone JD (2004) This study was supported by the MRC, with Accumbens dopamine and the regulation of effort in food- additional support from the Wellcome Trust (M.E.W.). D.B. was seeking behavior: modulation of work output by different ratio supported by a Wellcome Trust grant to J.N.P. Rawlins. The support or force requirements. Behav Brain Res 151:83–91 and encouragement of J.N.P. Rawlins is gratefully acknowledged.
Jakala P, Sirvio J, Jolkkonen J, Riekkinen P Jr, Acsady L, Riekkinen Treatment and care of the animals was in accordance with the P (1992) The effects of p-chlorophenylalanine-induced seroto- Principles of laboratory animal care and the United Kingdom nin synthesis inhibition and muscarinic blockade on the Animals Scientific Procedures Act (1986) under project licence performance of rats in a 5-choice serial reaction time task.
number PPL 30/1505 and personal licenses held by the authors.
Kheramin S, Body S, Mobini S, Ho MY, Velazquez-Martinez DN, Bradshaw CM, Szabadi E, Deakin JF, Anderson IM (2002)Effects of quinolinic acid-induced lesions of the orbital pre- frontal cortex on inter-temporal choice: a quantitative analysis.
Psychopharmacology 165:9–17 Aberman JE, Salamone JD (1999) Nucleus accumbens dopamine Liao RM, Fowler SC (1990) Haloperidol produces within-session depletions make rats more sensitive to high ratio requirements increments in operant response duration in rats. Pharmacol but do not impair primary food reinforcements. Neuroscience London ED, Ernst M, Grant S, Bonson K, Weinstein A (2000) Bechara A, Damasio AR, Damasio H, Anderson SW (1994) In- Orbitofrontal cortex and human drug abuse: functional imag- sensitivity to future consequences following damage to human Manes F, Sahakian B, Clark L, Rogers R, Antoun N, Aitken M, Bizot JC, Thiebot MH, Le Bihan C, Soubrie P, Simon P (1988) Robbins T (2002) Decision-making processes following dam- Effects of imipramine-like drugs and serotonin uptake blockers age to the prefrontal cortex. Brain 125:624–639 on delay of reward in rats. Possible implication in the behav- McQuade R, Sharp T (1995) Release of cerebral 5-hydroxytrypta- ioral mechanism of action of antidepressants. J Pharmacol Exp mine evoked by electrical stimulation of the dorsal and median raphe nuclei: effect of a neurotoxic amphetamine. Neuroscience Bizot J, Le Bihan C, Puech AJ, Hamon M, Thiebot M (1999) Serotonin and tolerance to delay of reward in rats. Psycho- Mobini S, Chiang TJ, Ho MY, Bradshaw CM, Szabadi E (2000a) Comparison of the effects of clozapine, haloperidol, chlorpro- Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt mazine and D-amphetamine on performance on a time-con- BJ (2001) Impulsive choice induced in rats by lesions of the strained progressive ratio schedule and on locomotor behaviour nucleus accumbens core. Science 292:2499–2501 in the rat. Psychopharmacology 152:47–54 Castro E, Tordera RM, Hughes ZA, Pei Q, Sharp T (2003) Use of Mobini S, Chiang TJ, Ho MY, Bradshaw CM, Szabadi E (2000b) Arc expression as a molecular marker of increased postsynaptic Effects of central 5-hydroxytryptamine depletion on sensitivity 5-HT function after SSRI/5-HT1A receptor antagonist co-ad- to delayed and probabilistic reinforcement. Psychopharmacol- Mobini S, Body S, Ho MY, Bradshaw CM, Szabadi E, Deakin JF, Salamone JD, Cousins MS, Bucher S (1994) Anhedonia or anergia? Anderson IM (2002) Effects of lesions of the orbitofrontal Effects of haloperidol and nucleus accumbens dopamine de- cortex on sensitivity to delayed and probabilistic reinforcement.
pletion on instrumental response selection in a T-maze cost/ben- efit procedure. Behav Brain Res 65:221–229 Murphy FC, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Salamone JD, Wisniecki A, Carlson BB, Correa M (2001) Nucleus Paykel ES, Sahakian BJ (2001) Decision-making cognition in accumbens dopamine depletions make animals highly sensitive mania and depression. Psychol Med 31:679–693 to high fixed ratio requirements but do not impair primary food Peterson JD, Wolf ME, White FJ (2003) Impaired DRL 30 per- reinforcement. Neuroscience 105:863–870 formance during amphetamine withdrawal. Behav Brain Res Sokolowski JD, Conlan AN, Salamone JD (1998) A microdialysis study of nucleus accumbens core and shell dopamine during Rahman S, Sahakian BJ, Hodges JR, Rogers RD, Robbins TW operant responding in the rat. Neuroscience 86:1001–1009 (1999) Specific cognitive deficits in mild frontal variant Thiebot MH, Le Bihan C, Soubrie P, Simon P (1985) Benzodia- frontotemporal dementia. Brain 122(Pt 8):1469–1493 zepines reduce the tolerance to reward delay in rats. Psycho- Rahman SJ, Sahakian BJ, Cardinal RN, Rogers RD, Robbins TW (2001) Decision making and neuropsychiatry. Trends Cogn Sci Wade TR, de Wit H, Richards JB (2000) Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Walton ME, Bannerman DM, Rushworth MF (2002) The role of rat Deakin JF, Sahakian BJ, Robbins TW (1999) Dissociable medial frontal cortex in effort-based decision making. J Neu- deficits in the decision-making cognition of chronic amphet- amine abusers, opiate abusers, patients with focal damage to Walton ME, Bannerman DM, Alterescu K, Rushworth MF (2003) prefrontal cortex, and tryptophan-depleted normal volunteers: Functional specialization within medial frontal cortex of the evidence for monoaminergic mechanisms. Neuropsychophar- anterior cingulate for evaluating effort-related decisions. J Neu- Rogers RD, Tunbridge EM, Bhagwagar Z, Drevets WC, Sahakian Walton ME, Croxson I-L, Rushworth MFS, Bannerman DM (2004) BJ, Carter CS (2003) Tryptophan depletion alters the decision- The Mesocortical dopamine projection to anterior cingulate making of healthy volunteers through altered processing of cortex plays no role in guiding effort-related decisions. Behav reward cues. Neuropsychopharmacology 28:153–162 Salamone JD, Correa M (2002) Motivational views of reinforce- Wise RA (1982) Neuroleptics and operant behavior: the anhedonia ment: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 137:3–25 Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K (1991) Haloperidol and nucleus accumbens dopamine Wogar MA, Bradshaw CM, Szabadi E (1993) Effect of lesions of depletion suppress lever pressing for food but increase free food the ascending 5-hydroxytryptaminergic pathways on choice consumption in a novel food choice procedure. Psychophar- between delayed reinforcers. Psychopharmacology 111:239–


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