Paychopharmacalogy 2009) 204108112 DOF 10.1007ScED 4814412 ORIGINAL INVESTIGATION The adenosine Az, antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure Allison M. Mott +Erie J. Nunes + Lyndsey E. Collins « Russell G. Port + Kelly S. Sink + Jorg Hockemeyer + Christa E, Miiller - John D. Salamone Roocivad: 15 August 2008 / Accepted: 9 December 2008 Published online: 9 January 2009 © Springer Verig 2009 Abstract Rationale Mesolimbic dopamine (DA) isa critical compo- nent of the brain circuitry regulating behavioral activation and effortselated processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food- reinforced tasks with high response requirements. and instead select less effortfil food-seeking behaviors. Objective Previous work showed that adenosine Ao, ‘antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice. The present work used a T-maze choice procedure to assess the effects of adenosine A>, and A, antagonism, ‘Materials and medhods With this task, the two ams of the nmuve have different reinforcement densities (four vs. two food pellets), and a vertical 44 om barter is positioned in the arm with the higher density, presenting the animal with an effortaelated challenge, Untreated rats strongly prefer the arm with the high density of food reward and clim the barrier in order to obtain the food. A.M, Mott-E.J. Nuxs*L, E Collins °R. G. Pat“. S Sink J.D, Salmon Daparment of Psychology, University of Connecticut, Stems, CT 06266-1000, USA J. Hockemeyer “C, E, Mille Phemmzeisches Insinut, Phamaeuische Chic 1, Universitit Born, Bonn, Germany J.D, Salamone (=) Division of Bechuvioral Neuroscience, Department of Psycholeuy, Univesity of Comacticut Stony CT 06249-1000, USA ‘omni: jon salamone@uccmnad Results Haloperidol produced a dose-related (0.0S-0.15 mg/kg i.p.) reduction in the number of trials in which the nats chose the high-barrier am, Co-administration of the adenosine Az, receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg ip), but not the Ay antagonist 8-cyclopenty- 1,3+dipropybxanthine (0.75, 1.5, and 3.0 mekg ip), reversed the effects of haloperidol on effortelated choice and latency, Conclusions Adenosine Azx and D2 receptors interact regulate effortelated decision making, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anereia that can be observed in depression, parkinsonism, and other disorders, Keywords Reinforcement -Motivation Behavioral economics-Reward. A, receptor Activation «DPCPX- Psychomotorslowing « Anergia Introduction Motivational stimuli often have activating effects, and soak directed behavior ffequently is characterized by a high degree of activity, vigor, or persistence in work output (Salamone and Corea 2002), These activational aspects of motivation are adaptive because they enable organisms t ‘overcome work-related response costs that separate them from significant stimuli (Salamone et al. 1997, 2007; Salamone and Conea 2002; Van den Bos et al. 2006). ‘Conversely, lack of behavioral activation can be malaclap= tive; in humans, symptoms such as psychomotor slowing, ‘anergia, and fatigue are fundamental aspects of depression, as well as other psychiatric and neurological disorders emyttenaere et al, 2005; Salamone et ale 2006, 2007; D springer104 Paychophamacology (2009) 204: 03-112 ‘Yurgelun-Todd etal, 2007; Capuron etal. 2007; Majer etal 2008). Brain dopamine (DA), particularty in the nacleus ‘accumbens, appears to be one of the critical components of the brain circuitry controlling effort-related behavioral processes and behavioral activation (Salamone et al. 1997, 2005, 2007; Barbano and Cador 2007; Phillips etal. 2007; Robbins and Everitt 2007). Nucleus accumbens DA. depletions make rats very sensitive to ratio requirements in operant leverspressing schedules (Sokolowski_ and Salamone 1998; Corea et al. 2002; Mingote et al, 20085), Moreover, DAvdepleted rats show alterations in response allocation in tasks that measure effort-related choice behavior (Salamene et al. 2007). Same studies in this area have used a concurrent fixed ratio 5 (FRSY/chow feeding procedure to study effortelated choice (Salamone et al 1991, 2002, 2007), With this task, rats have the option of responding on a FRS lever-pressing schedule for a highly preferred food (high carbohydrate food pellets) or ‘approaching and consuming a less preferred food (standard rodent chow) that is freely available in the chamber. Low= to-moderate doses of DA antagonists that act on either DI ‘or D? family receptors suppress lever pressing for food but actually increase chow intake (Salamone et al, 1991, 20025, ‘Cousins et al, 1994; Koch et al, 20005 Sink et al, 2008), Nocleus accumbens is the DA teminal region most closely associated with these effects of impaired DA. transmission (Cousins et al. 1993; Sokolowski and Salamone 1998; Koch et al. 2000; Nowend et al. 2001). Furthermore, the effects of interference with DA transmission were shown to dlffer substantially from those produced by pre-feeding to reduce food motivation (Salamone et al. 1991) and by appetite-suppressant drugs with various neurochemical profiles, including amphetamine (Cousins et al, 1994), fenfluramine (Salamone et al, 2002), and cannabinoid CBI antagonists (Sink et al, 2008). Additional studies in this area have employed a Fmaze task to assess effortlated choice behavior (Salamone et al, 1994; Cousins et al. 1996; Walton et al. 2003; Denk et al, 2005; Schweimer et al. 2005; Floresco and Ghods- Sharifi 2007). In this task, two ams of the maze can have lfferent reinforcement densities (@.g., four vs. two food pellets, or four vs. zero), andl under some conditions, a vertical barrier can be placed in the am with the higher reward density to vary task difficulty, When there is no baicr present, untreated rats preferred the high reward density am, and neither haloperidol nor accumbens DA cepletion altered arm prefirence when no barrier was in the mmuve (Salamone et al. 1994), Under conditions in which the an with four food pellets was partially blocked with the barrier, but the other am contained no pellets (i, the ‘nly way to get food was to climb the bamier), rats with accumbens DA depletions were relatively slow but still chose the high-density am, climbed the barrier, and D springer ‘consumed the food (Cousins et al, 1996), Nevertheless, DA manipulations dramatically altered choice behavior ‘when the high-density am (four pellets) had the barrier in place, and the am without the barrier had an altemative sourte of food (two pellets). Under these conditions, rats ‘treated with DA antagonists or accumbens DA depletions showed decreased choice of the high-density am. and increased choice of the low-density am (Cousins et al 1996; Salamone et al, 1994; Denk et al. 2005), (Other brain areas and transmitters in addition to nucleus accumbens DA also are involved in effertelated processes (42s prefrontal cortex, amygdala, and ventral pallidal Y= ‘aminobutytic acies see Walton et al. 2006; Denk et al. 20055, Schweimer et al. 2005; Floresoo and Ghods-Sharfi 2007; Salamone etal. 2007; Farmar et al. 2008), anc recent studies have focused upon the purine nucleoside adenosine (Farrar et al, 2007; Font et al. 2008; Mingote et al. 2008). Adenosine ‘Aga receptors are heavily concentrated in striatal areas, including the caudate/putamen and nucleus accumbens Gchiffinann et al. 1991; DeMet and Chicz-DeMets 2002; Faré et al, 2004), The is considerable evidence of a functional interaction between striatal and accumbens DA. D2 receptors and adenosine Ax, receptors (Fink et al 1992; Femé 1997; Hillion et al, 2002; Fuxe et al, 2003). This interaction offen has been investigated in relation to neo= striatal motor functions involved in parkinsonism (Femé et al. 1997, 2001, 2008; Hauber and Munkel 1997; Svenningsson etal, 1999; Huber etal, 2001; Warts etal, 2001; Morelli and Pinna 2002; Comea et al. 2004; Pinna et al. 2005; [Shiwari et al. 2007; Salamone et al, 20082,5). However, researchers also have identified functions of adenosine Ao. receptor transmission related to cognition (Takahashi et al 2008) and aspects of motivation (O”Neill and Brown 2006; Fararetal.2007; Fontet al, 2008; Mingote etal, 2008), Farar et al, 007) demonsirated that systemic injections of the ‘adenosine Aq antagonist MSX-3 reversed the haloperidol induced shift in choice behavior seen in rats responding on the ‘operant concurrent choice task. “The present work was undertaken to examine the role of DAVadenosine A>x receptor interactions in effort-related, choice behavior by assessing the ability of an adenosine ‘Aaa receptor antagonist to reverse the behavioral impaire ment in Fmaze performance induced by the DA antagonist haloperidol, Unlike the concurrent choice task, which studies response allocation between fee operant lever Pressing and chow intake (@.gm Farr et al, 2007), the T= maze task allows for assessment of discrete choices on a triakby-trial basis. For these studies, one aim of the maze ‘contained a high density of food reinforcement (four pellets), and the other am contained a low density of food reinforcement (two pellets). Response costs were different in the two ams duc to the presence of a large vertical barrier located in the highlensity am of the maze.Psychophurmacology 009) 24:1 05-112 10s Experiment 1 studied the effects of different doses of haloperidol (Veh, 0.05, 0.10, and 0.15 mgkg ip.) on T= maze performance in order to identify the dose of haloperidol to be used for the subsequent reversal studies. Experiment 24 assessed the ability of the adenosine Ao. ‘antagonist MSX-3 (0.75-3.0 mgkg isp.) to reverse the effects of 0.15 mg/kg haloperidol on Tsmaze perfomance. In onder to compare the effects of antagonists that act on different adenosine receptors, experiment 3A. studied the ability of the adenosine Ay antagonist &-cyclopentyl13- ipropylxanthine (DPCPX; 0.75-3.0 make isp.) to reverse the effects of 0.15 mgdkg haloperidol, Additional control studies (2B and 3B) assessed the effects of injections of the high doses of MSX-3 and DPCPX on T-maze performance in the absence of haloperidol. ‘Materials and methods Subjects Adult male, drug-naive, Sprague-Dawley rats (Harlan Sprague-Dawley, Indianapolis, IN, USA) were housed in a colny maintained at 23°C at with 12-h lighvidark cycles, (ights on at 0700 hours). The rats (N=20) weighed 290— 340 gaat the beginning of the study and were fooxl-90% choice of the barrier ‘um out of 30 trials) a final wire mesh barrier 44 om) was introduced halfway between the start am door and the D springer106 Paychophamacology (2009) 204: 03-112 food dish, Rats were trained on the high-barier choice procedure until they selected the high-density am greater than 90% of tials per session, After successfil completion of high-barier taining, drug testing commenced. For alll rug studies, including the baseline days between drug ‘treatments the high barrier was present in the high-censity ‘um, and no barrier was present in the low-density am, Experimental design All experiments used a within group design, with all rats receiving their ip, drug treatments in the study in a randomly varied order (one treatment per week; no treatment sequence repeated across different animals in the experiment), Baseline training sessions with no drug treatments were conducted four additional days per week. Experiment 1: Effect of haloperidol on T-maze perform= ance Rats were trained before drug testing as described above, Rats (7=5) received i. injections of tartaric acid vehicle, 0.05 mykg haloperidol, 0.1 mg/kg haloperidol, and 0.15 mg/kg haloperidol (all injections 50 min before testing), All rats were tested for 30 trials The observer recortled the number of high- and low-density choices, as ‘well asthe respanse latency (start door opening to food dish area). Experiment 2: Ability of MSX-3 10 reverse the effects of haloperidol Trained rats (n=9) received the flowing treat- mants in experiment 2A: tartaric acid vehicle (50 min before testing) plus saline vehicle ip. Q0 min before testing), 0.15 mg/kg haloperidol ip. (50 min before testing) plus saline vehicle ip. 20 min before testing), 0.15 make, haloperidol i. (50 min before testing) plus 0.75 make, MSX-3 ip. (20 min before testing), 0.15 mgkg haloperidol ip. (50 min before testing) plus 1.5 mg/kg MSX-3 ip. 20 min before testing), and 0.15 mykg haloperidol ip. 60 min before testing) plus 3.0 melkg MSX-3 ip. (20 min before testing) and were tested for 30 trials, The observer recorted the number of high- and low-density choices, as ‘well asthe respanse latency (start door opening to food dish area). For experiment 2B, a group of rats (7=5; the same rats that had completed experiment 1) received injections of cither saline or 3.0 mykg MSX-3 Gps 20 min before testing). Experiment 3: Ability of DPCPX to reverse the effects of haloperidol An additional group of wained rats (7=6) received the flowing treatments in experiment 3A: tartaric acid vehicle (50 min before testing) plus saline vehicle ip. (20 min before testing), 0.15 mg/kg haloperidol ip. (50 min before testing) plus saline vehicle ip. @0 min before testing), 0.15 mg/kg haloperidol ip. (50 min before testing) D springer plus 0,75 mg/kg DPCPX ip, (20 min before testing), (15 mg/kg haloperidol ip. (50 min before testing) plus 1.5 mg/ kg DPCPX ip. 20 min before testing), and 0.15 mekg, haloperidol i:p. (50 min before testing) plus 3.0 mekg, DPCPX i.p. (20 min before testing), and all rats were tested for 30 trials. As with experiment 2, the observer recorded the number of high- and low-density choices and the response latency (start door opening to food lsh area), For experiment 3B, another group of rats (n=6; the see rats that had completed experiment 3) received injections of cither saline or 30 mg/kg DPCPX (ips 20 min before testing). Statistical analyses In these experiments, there were no differences between animals that had the high-density am to the left as opposed to those trained on the right, so these data were combined for further analyses. The total number of high-density arm. selections (ie., barrier crossings) was analyzed with repeated measures analysis of variance (ANOVA); selec- tions of the low-density am were not statistically analyzed because no animals failed to make a choice, and thus they are simply the miror image of the high-density arm data, In experiment 1, repeated measures ANOVA was conducted ‘on four treatment levels. For experiments 2A and 3A, repeated! measures ANOVA was conducted for each of the five uvatment levels (tartaric acid vehicle plus saline vehicle, 0. 15 mg/kg haloperidol plus saline vehicle, and 0.15 mg/kg haloperidol plus cach dose of MSX-3 or DPCPX), Paired comparisons were performed using non- ‘xthogonal planned comparisons that employed the overall enor term (Keppel 1991); for experiment 1, the three haloperidol conditions were compared with vehicle, and for experiments 2 and 3, the data for the haloperidol plus vehicle treatment condition were contrasted with the other four treatments. The f test was used for analyses of experiments 2B and 3B, Results Experiment 1: Effects of haloperidol ‘The data for selection of the high-density arm (ie. crossing the barrier) for experiment I are shown in Fig. 1. Repeated measures ANOVA indicated that there was an overall significant effect of haloperidol treatment [F(3,12)=31.46, P=0.001, Planned comparisons revealed that haloperidol produced a significant decrease in high-density arm selection compared 10 vehicle-treated control rats at both, the 0.10 and 0.15 mgkg dose (p<0.01). Furthermore,Psychophurmacology 009) 24:1 05-112 wor Erect of Haloperidok Choice Banter Crossings 8 + 2 Veh 005 O10 ais Dose Haloperidal (maka) Fig. 1 Effect of ip, administration of the DA antguonist haloperidol ‘nam choice in the maze. Mean (4SEM) number of bauer am choices after weament with vehicle or various doses of haloperdal are shown (Fp<0.01, differnt ficm vehicle). Regression analysis, revealed tht there was @ significant near elation berwaan das and am choice [F(,19=927, p<0001; r°=0.84] haloperidol induced a sinificant increase in the selection of the low reinforcement density arm of the T-Maze (data not shown} and all haloperidol-ireated rats consumed every pellet that was present in their chosen arm on each trial. There were no tials in which vehicle or haloperidol-reated rats failed 10 choose one of the two anns of the maze. Experiment 2: Reversal with MSX-3 ‘The data on high-density am selection (ie., barrier cross+ ings) for rats treated with MSX-3 and haloperidol are shown in Fig, 2a, Repeated measures ANOVA indicated that there was an overall significant effect of drug treatment on am choice [F(4, 32)=37.64, p<0.001], Haloperidok vehicle treated rats showed a. significant decrease in the selection of the number of barrier crossings as compared to vehicle-vehicle-treated rats (non-orthogonal planned com- parisons; <0.001). Co-administration of MSX-3 with haloperidol produced a significant dose-elated increase in selection of the high-density ann with the barrier relative to haloperidol plus vehicle-treated rats (planned comparisons; P<0.01). Mean run latencies for haloperidol anc) MSX-3 ‘conadministration are shown in Fig. 2b, Repeated measures ANOVA indicated an overall significant effect of drug ‘treatment on run latency [/(4,32)=4.59, p<0.01], Admin- istration of haloperidol caused a significant increase in response latency as compared to vehicle-vehicle-reated rats (non-orthogonal planned comparisons; p<0.001). Additionally, non-orthogonal_ planned comparisons indi= cated that a significant decrease in latency compared to haloperidol-vehicle-treated rats occurred upon co- administration of MSX-3 in a dose-dependent manner (075 mekg MSX-3, <0.001; 15 and 3.0 meke MSX- 3, p=0.05). Experiment 2B assessed the effects of the high dose of MSX-3 on maze performance in the absence of haloperidol (Table 1}. There was no significant effect on «um choice produced by MSX-3 (/=1.0, d/=4,n.s.)and also no significant effect on latency ('=2.4, d/4, ns.). Howe ever, four of the five animals did show slight decreases in latency after MSX-3 injection relative to saline injection. Experiment 3: DPCPX plus haloperidol ‘The mean (#SEM) number of high-density am selections ve. barrier crossings) for ras treated with DPCPX ancl haloperidol are shown in Fig, 3a, Repeated measures ANOVA indicated that there was an overall significant effect of drug treatment on am choice [F(4,20)=38.1, p< 0.001], Haloperidol plus vehicle-treated rats showed a significant decrease in the selection of the highdensity ‘am as compared to vehicle-vehicle-treated rats (planned ‘comparisons, 7<0.001). However, co-administration of DPCPX with haloperidol did not reverse the effects of haloperidol; in fact, treatment with 3.0 mg/kg DPCPX plus haloperidol significantly reduced selection of the barrier ‘am relative to haloperidol plus vehicle (p<001). Mean run latencies for haloperidol and DPCPX co-administration are shown in Fig, 3b, Repeated measures ANOVA indicated an ‘overall significant effect of drug treatment on run latency [A4.20)=4.27, p<0.05}, The planned comparison between haloperidol plus vehicle and vehicle-vehicle control approached significance (p=0.065); however, subsequent non-parametric analysis with the Wilcoxon test did show a significant difference (p=0.05). In addition, non-orthogonal planned comparisons indicated that there was a sienificant increase in latency compared tothe haloperidol plus vehicle ‘treatment condition in animals administered haloperidol plus 30 mekg DPCPX. In experiment 3B (Table 1), DPCPX ‘without haloperidol had no significant effect on arm choice (E12, df=5,ns,) 0 on latency (1-24, df=5, ns). Five of the six animals showed slightly longer latencies after injec- tions of DPCPX than they did after injections of vehicle, Table 1 Results of conmol experimen involving adminisuation of MSXG3 and DPCPX in the absence af haloperidal Experimant 2B: MSX3 Bair crossings Vehicle: 280 30 mgkg MSX3: 055) 286 (20.24) Avergenm bieney() Vide 367 30 mule MS: 029) 3.336024) Experiment 38: DPCPX Bari crossines Wthide: 25 30 mwky DPCPX: 20) 17235) Avergze nm bieney (6) hide: 42630 mak DACPX: 4066) 552097) Daa shown as mean (#SEM) foreach measure D springer108 Paychophamacology (2009) 204: 03-112 MSX-3 and Haloperdot Choice Banter Crossings 8 * 4 2B se be I CChotce Latency Vere Hen FETS HON Drug Treatment (HP and MSX-3) Fig,2_a Eftsofthadnnsine Aoy amit MSX3 on Fnac am che in rats coadiminsorad halopandol. Mean (2SEM) number of buaier am choices afer teament with vehicle cr hakperdel ps ‘ats doses of MSX3 are shown. Veh (chide pls vec), HAL? ‘eh (15 meg haloparol pls vehice), HALOS M (QS make Talepridel pus 0.75 meks, MSX), HAL/S M (1S make halperda ps1 Smekg MSX3}, HALO M (15 mekg heeparidol plus 30 mark MSX).»<001 fire fem vehi, lamed compara: "pO, dfn fem veick pls Helopeko, peed companisen, b Eos of the aknasine zy anagsnist MSX3 on nun Tangy in rls coudhinisted hecperkol, Mian (SEM) un ak (Gc, ave aces 2) tials exprosad in some) afr treatment wih ‘ehide or halkperiel ps varius doses of MSX=3 are shen. Veh (chick ps vehick), HALAth (0.1 make habbo! pis vec, HALAL7S M (0.1 mek haloper plus 075 mekg MSX=), HAL! 15 M ul mekg habpadl pos 15 mekg MSX3) HALO M (Oe gig: halbpandhl plus 30 marke MSX-3} "2-00, eiixet fom \chidovehiee plamed comparison, "/p<001, fer fem veicke us lope, planed comerscn Discussion ‘Consistent with previous findings, administration of the DA ‘antagonist haloperidol produced a significant decrease in selection of the high reward density Tsmaze am that ‘contained the barrier (Salamone et al. 1994; Cousins et al. 1996; Denk et al. 2005). Correspondingly, haloperidol ‘administration also increased the selection of the lowe density T-maze am. 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