PBB-72188; No of Pages 10 Pharmacology, Biochemistry and Behavior xxx (2015) xxx–xxx

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Article history: Received 31 January 2015 Received in revised form 5 May 2015 Accepted 9 May 2015 Available online xxxx

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Keywords: Dopamine D1 receptor Nucleus accumbens Behavioral activation Motivation Depression Fatigue Anergia

Dept. of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA Department of Psychiatry, Yale School of Medicine, 300 George ST., Suit 901, New Haven, CT 06511, USA d Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain e Pfizer Research Institute, Eastern Point Road, Groton, CT 06340, USA b c

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Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists. © 2015 Published by Elsevier Inc.

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1. Introduction

In a complex environment with concurrent access to multiple reinforcers, and diverse paths for obtaining them, organisms often must make decisions based upon cost/benefit analyses (Aparicio, 2007; Williams, 1988). Several variables influence these choices, with one of the most important being interactions based upon work requirements and reinforcement value (Hursh et al., 1988; Salamone, 2010a, 2010b; Salamone and Correa, 2002, 2012; Salamone et al., 2003, 2007; Walton et al., 2006). Effort-based decision-making is typically studied using tasks that offer a choice between high effort instrumental actions leading to more highly valued reinforcers vs. low effort options leading to less valued reinforcers. In rodents, effort-related decision making is regulated by a distributed circuit that includes prefrontal/anterior cingulate cortex, basolateral amygdala, ventral pallidum and nucleus accumbens (Caginard et al., 2006; Farrar et al., 2008; Floresco and

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Samantha E. Yohn a, Jessica L. Santerre a,b, Eric J. Nunes a,c, Rouba Kozak e, Samantha J. Podurgiel a, Mercè Correa a,d, John D. Salamone a,⁎

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The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists

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⁎ Corresponding author at: Division of Behavioral Neuroscience, Dept. of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA. E-mail address: [email protected] (J.D. Salamone).

Ghods-Sharifi, 2007; Font et al., 2008; Ghods-Sharifi and Floresco, 2010; Hauber and Sommer, 2009; Mingote et al., 2008; Nunes et al., 2013a, 2013b; Salamone and Correa, 2012; Salamone et al., 1997, 2007; Walton et al., 2003). Furthermore, interference with dopamine (DA) transmission can affect the relative allocation of behavior in animals responding on tasks that assess effort-based choice behavior, biasing animals towards lower effort alternatives (Floresco et al., 2008; Hauber and Sommer, 2009; Salamone et al., 2003, 2007). In addition to being relevant for understanding the basic neuroscience of motivation, studies of effort-related decision making also are clinically relevant. Recent clinical studies have shown that alterations in effortrelated choice behavior (i.e., increased selection of low-effort alternatives) are shown by people with major depression (Treadway et al., 2012a), as well as schizophrenics with a high level of negative symptoms (Barch et al., 2014; Gold et al., 2013). In view of studies linking DA transmission to effort-related decision making in humans (Treadway et al., 2012b; Wardle et al., 2011), it is reasonable to suggest that drugs that act upon DA transmission are useful for investigating effort-related motivational functions that are relevant for psychopathology, including studies with animal models.

http://dx.doi.org/10.1016/j.pbb.2015.05.003 0091-3057/© 2015 Published by Elsevier Inc.

Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

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Adult male, drug-naïve, Sprague-Dawley rats (Harlan SpragueDawley, Indianapolis, IN, USA) were housed in a colony maintained at 23 °C with 12-h light/dark cycles (lights on at 0700 h). The rats (n = 56) weighed 300–350 g at the beginning of the study and were food-restricted to 85% of their free-feeding body weight for the initial training. They were fed weighed amounts of supplemental chow to maintain the food restriction, and were allowed modest growth over the course of the experiment; ad libitum water was available in their home cages. Animal protocols were approved by the University of Connecticut Institutional Animal Care and Use Committee and followed NIH guidelines.

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2.2.1. Concurrent FR5/chow-choice procedure Behavioral sessions were conducted in operant conditioning chambers (28 × 23 × 23 cm, Med Associates, Georgia, VT, USA) during the light period. Rats were initially trained to lever press on a continuous reinforcement schedule (30 min sessions, during 5 days) to obtain 45 mg pellets (Bioserve, Frenchtown, NJ, USA), and then were shifted to the FR5 schedule (30 min sessions, 5 days/week) and trained for several additional weeks until reaching baseline targets for number of lever presses (i.e., consistent responding ≥ 1200 lever presses). Animals needed to consistently reach baseline criteria for the course of approximately one week before being introduced to the concurrent FR5/chowfeeding choice procedure. In this task, weighed amounts of laboratory chow (Laboratory Diet, 5P00 Prolab RHM 3000, Purina Mills, St. Louis, MO, USA; typically 20–25 g, 4–5 large pieces) were concurrently available in the chamber during the 30 min FR5 session. At the end of the session, rats were immediately removed from the chambers, lever pressing totals were recorded, and amount of chow consumed was determined by weighing the remaining food and spillage.

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2.2.2. T-maze barrier choice task Food-restricted rats were trained on the T-maze apparatus during the light period. The start arm was an enclosed box (29 × 21 × 21 cm), and the test arms were a rectangular box (99 × 32 × 59 cm). The start arm, test arms, and maze walls were made of Plexiglas, and the floor was wire mesh; a stainless steel guillotine door separated the start arm from the choice arms. For each experiment, there was a high density (HD) arm and a low density (LD) arm based upon the number of food pellets (45 mg each, Bioserve, Frenchtown, NJ, USA), which were located in small glass dishes placed against the far walls of the arms. The HD arm had 4 pellets, while the LD arm contained 2 pellets. Half the rats had the HD arm located consistently in the left arm of the maze, while the other half had the HD arm in the right arm. Rats were trained in several different phases. There was one week of initial training, which allowed free access to both arms of the maze upon exiting the start arm. During initial training no barrier was present, and rats consumed pellets in both high- and low-density arms of the maze before being returned to the start arm. For all subsequent training conditions, the rats were removed after entering the goal area of one arm of the maze. Each animal was trained for 30 trials per day. If an animal failed to leave the start arm after 2 min, the animal would have a “null” trial. Beyond this initial training, two different behavioral procedures were used: 4–2 barrier condition (barrier obstructing HD arm 4 pellets/LD arm 2 pellets), and 4–0 barrier condition (barrier obstructing HD arm 4 pellets/LD arm 0 pellets). The first two experiments compared the effects of ecopipam in rats tested on the 4–2 and 4–0 barrier conditions; all subsequent T-maze experiments used only the 4–2 condition. The training procedures for the 4–2 condition proceeded as follows: after completion of the initial training phase,

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A number of tasks have been used in rodents for assessing effortrelated decision making, including operant tasks that offer animals choices between lever pressing for a more preferred food on ratio schedules vs. approaching and consuming a less preferred reinforcer (Cagniard et al., 2006; Randall et al., 2012; Salamone et al., 1991, 2007; Schweimer and Hauber, 2005), effort discounting (Floresco et al., 2008; Bardgett et al., 2009), and a T-maze task that uses a vertical barrier to provide an effort-related challenge (Cousins et al., 1996; Mai et al., 2012; Mott et al., 2009; Salamone et al., 1994; Yohn et al., 2015). Using multiple tasks in both rats and mice, it has been shown that antagonists of DA D2 family receptors can alter effort-related choice, biasing animals towards the low effort alternative (Cousins et al., 1994; Denk et al., 2005; Pardo et al., 2012; Randall et al., 2012; Salamone et al., 1991, 1994; Sink et al., 2008). Moreover, much is known about the characteristics of the effects of D2 antagonism on effort-related choice, including details about the anatomical connections and signal transduction mechanisms involved (Farrar et al., 2010; Santerre et al., 2012), and the ability of adenosine A2A antagonists to reverse the effects of D2 antagonism in rodents tested on both operant and T-maze choice procedures (Farrar et al., 2007, 2010; Mott et al., 2009; Nunes et al., 2010; Pardo et al., 2012; Salamone et al., 2009; Worden et al., 2009). In contrast, relatively less is known about the role of DA D1 receptor transmission. Systemic or intra-accumbens administration of the D1 antagonist SCH 23390 decreased lever pressing and increased chow intake in rats tested on the concurrent fixed ratio (FR)5/chow feeding choice task (Cousins et al., 1994; Nowend et al., 2001). In addition, local administration of SCH 23390 into anterior cingulate cortex altered effort-based decision making as measured using the T-maze barrier task (Schweimer and Hauber, 2006). However, one problem with these early studies was the use of SCH 23390 as the D1 antagonist, because this drug also binds with high affinity to 5-HT 2A and 5-HT2C receptors (Alburges et al., 1992). More recent studies have employed SCH 39166 (ecopipam), which is highly selective for DA D 1 receptors and has relatively low affinity for 5-HT receptors (Alburges et al., 1992), and administration of low doses of ecopipam was shown to shift choice behavior from lever pressing to chow intake in rats tested on the FR5/chow feeding choice task (Sink et al., 2008; Nunes et al., 2010). The main focus of the present studies was related to the actions of DA D1 agonists, in terms of their ability to reverse the effects of reduced D1 transmission on effort-related choice behavior. It is critical to study agonist/antagonist interactions in pharmacology, because it demonstrates the interaction between drugs that act upon the same receptor binding site. Furthermore, D1 agonists are undergoing preclinical assessment for their effects related to various clinical targets, including aspects of cognition, motivation, and depressive symptoms (Acheson et al., 2013; Francis et al., 2014; Goldman-Rakic et al., 2004; Rajagopal et al., 2014; Roberts et al., 2010). Thus, the present studies assessed the effects of the D1 agonists SCH 38393, SCH 81297, and A77636, which vary in terms of chemical family (benzazepine and isochroman) and degree of partial vs. full agonism, to determine if they could reverse the effects of the D1 antagonist ecopipam on FR5/chow feeding choice performance. Moreover, the effort-related effects of ecopipam were assessed using the T-maze barrier choice task, and the ability of D1 agonists to reverse the effects of ecopipam, as well as the catecholamine depleting agent tetrabenazine (Yohn et al., 2015), were determined using this procedure. This task was employed because it involves a different type of behavioral activity than the operant procedure (i.e., locomotion and climbing vs. lever pressing), and also because it is a discrete-trial task that involves an explicit choice between two different instrumental behaviors (Salamone et al., 1994). Tetrabenazine was used in the final experiment because this drug depletes DA, and reduces postsynaptic DA signaling at both D1 and D2 family receptors (Nunes et al., 2013b). Recent studies have shown that tetrabenazine can alter effort-related decision making (Nunes et al., 2013b; Randall et al., 2014; Yohn et al., 2015).

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2.3. Pharmacological agents and dose selection

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Different groups of rats were used for each experiment. All experiments used a within-groups design in which each rat received all doses of drug or vehicle treatments in their particular experiment in a randomly varied order (one treatment per week; no treatment sequence repeated across different animals in the experiment). Baseline training sessions (i.e.: non-drug) were conducted four days per week in both, the operant choice procedure (experiments 1–3) and the T-maze barrier choice task (experiments 4–7). Experiment 1: Ability of the dopamine D1 receptor partial agonist SKF38393 to reverse the effects of ecopipam on the concurrent FR5/chow feeding procedure. Rats were trained prior to testing described above. Rats (n = 12) simultaneously received IP injections of the following treatments 20 min prior to testing: ecopipam vehicle plus SKF38393 vehicle, 0.2 mg/kg ecopipam plus SKF38393 vehicle, 0.2 mg/kg ecopipam plus 0.25 mg/kg SKF38393, 0.2 mg/kg ecopipam plus 0.5 mg/kg SKF38393, or 0.2 mg/kg ecopipam plus 1.0 mg/kg SKF38393. Immediately after the 30 min session, rats were removed from the chambers, total lever presses were recorded, and chow consumed was calculated. Experiment 2: Ability of dopamine D1 receptor agonist SKF81297 to reverse the effects of ecopipam on the concurrent FR5/chow-feeding procedure. Trained rats (n = 6) were administered the following IP treatments simultaneously 20 min prior to testing: ecopipam vehicle plus SKF81297 vehicle, 0.2 mg/kg ecopipam plus SKF81297 vehicle, 0.2 mg/kg ecopipam plus 0.025 mg/kg SKF81297, 0.2 mg/kg ecopipam plus 0.05 mg/kg SKF81297, 0.2 mg/kg ecopipam plus 1.0 mg/kg SKF81297, or 0.2 mg/kg ecopipam plus 2.0 mg/kg SKF81297. Experiment 3: Ability of the dopamine D1 receptor agonist A77636 to reverse the effects of ecopipam on the concurrent FR5/ chow-feeding procedure. Trained rats (n = 8) received the following IP treatments over the course of six weeks; A77636 was administered 60 min before the session and ecopipam 20 min before the session: A77636 vehicle plus ecopipam vehicle, saline vehicle plus 0.2 mg/kg ecopipam, 0.25 mg/kg A77636 plus 0.2 mg/kg ecopipam, 0.5 mg/kg A77636 plus 0.2 mg/kg ecopipam, 1.0 mg/kg A77636 plus 0.2 mg/kg ecopipam, or 2.0 mg/kg A77636 plus 0.2 mg/kg ecopipam. Experiments 4–5: Effect of the DA D1 receptor antagonist ecopipam on T-maze performance in the 4–2 barrier and 4–2 no barrier conditions. Rats were trained using the 4–2 barrier condition as described above. Rats (n = 8) received IP injections of saline, 0.1, 0.2, or 0.3 mg/kg ecopipam 20 min before testing. All rats were tested for 30 trials. The observer recorded the number of HD and LD arm choices, as well as the response latency (start door opening to food dish area). For experiment 5, an additional group of rats (n = 8) was trained for several weeks prior to drug testing using the 4–2 no barrier condition as described above. Rats received IP injections of saline, 0.1, 0.2, or 0.3 mg/kg ecopipam 20 min before testing. Experiment 6: Ability of the dopamine D1 receptor partial agonist SKF38393 to reverse the effects of ecopipam on T-maze performance. Trained rats (n = 8) received the following IP treatments simultaneously 20 min before testing: saline vehicle plus saline vehicle 0.3 mg/kg ecopipam plus saline vehicle, 0.3 mg/kg ecopipam plus 0.25 mg/kg SKF38393, 0.3 mg/kg ecopipam plus 0.5 mg/kg SKF38393, or 0.3 mg/kg ecopipam plus 0.75 mg/kg SKF38393 and were tested for 30 trials. Experiment 7: Ability of the dopamine D1 receptor agonist SKF81297 to reverse the effects of tetrabenazine on T-maze performance. Trained rats (n = 6) received the following treatments: IP TBZ 90 min before testing and SKF81297 20 min before testing: TBZ vehicle plus SKF81297 vehicle, 0.75 mg/kg tetrabenazine plus SKF81297 vehicle, 0.75 mg/kg tetrabenazine plus 0.025 SKF81297, 0.75 mg/kg tetrabenazine plus 0.05 SKF81297, or 0.75 mg/kg plus 0.01 SKF81297 and were tested for 30 trials.

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The DA D1 receptor antagonist SCH 39166 (ecopipam; (6aS-trans)11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d] naph227 tha[2,1-b]azepin-12-ol hydrobromide) was obtained from Tocris 228 (Ellisville, MO, USA). Ecopipam was used because it binds to dopamine 229 Q10 D1 receptors with high affinity and selectivity (Tice et al., 1994). 230 Ecopipam was dissolved in 0.9% saline also used as the vehicle control. 231 The benzazepine DA D1 receptor partial agonist SKF38393 (Phenyl232 2,3,4,5-tetrahydro-(1H)–3-benzazepine-7,8-diol hydrobromide) 233 was obtained from Tocris (Ellisville, MO, USA), was dissolved in 234 0.9% warmed saline and heated at low temperature on a hot235 plate until it went into solution. Saline was also used as the vehicle 236 control. The benzazepine D 1 receptor full agonist SKF81297 (6237 Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine 238 hydrobromide) and the isochroman D1 agonist A77636 (3-Adamantyl239 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hy240 drochloride hydrate), were purchased from Sigma Aldrich (Milwaukee, 241 WI, USA). Both were dissolved in a vehicle solution of 0.9% warmed sa242 line. Vehicle control injections in both experiments were also 0.9% sa243 line. Tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 244 11b hexahydrobenzo[a]quinolizin-2-one), the VMAT-2 inhibitor, was 245 purchased from Tocris Bioscience (Bristol, UK). Tetrabenazine was dis246 solved in a vehicle solution of 0.9% saline (80%) and DMSO (20%). 247 1 N HCl/mL volume was then added to adjust the pH and get the drug 248 completely into solution. The final pH of the tetrabenazine solution 249 was 3.5–4.0. The 20% DMSO/saline vehicle solution was administered 250 as the vehicle control. 251 The doses of ecopipam (SCH 39166) used for the T-maze barrier 252 choice and FR5/chow feeding choice tasks (0.1, 0.2, 0.3 mg/kg) were se253 lected based upon previous research and extensive pilot studies 254 (Clifton, 1995; Nunes et al., 2010; Sink et al., 2008; Worden et al., 255 2009). The 0.3 mg/kg dose of ecopipam was used in the T-maze barrier 256 choice task for reversal studies because it produced the most robust ef257 fect without disrupting general behavior. In the FR5/chow feeding 258 choice procedure, the 0.2 mg/kg dose of ecopipam was chosen based 259 upon previous data showing that it produced the most robust effect de260 creasing lever pressing while subsequently increasing chow consump261 tion (Nunes et al., 2010; Sink et al., 2008; Worden et al., 2009). The 262 highest dose of SKF38393 (1.0 mg/kg) was established based on previ263 ous results indicating that higher doses have been reported to substan264 tially suppress locomotion (Eilam et al., 1991). The 0.75 mg/kg dose of 265 tetrabenazine, which was used for the T-maze barrier choice task, was 266 based on previous work from our laboratory (Nunes et al. 2013; 267 Randall et al., 2014; Yohn et al., 2015). In summary, the doses to be 268 used were selected based upon pilot studies, and were designed to char269 acterize the effective doses of each drug. All drugs were administered 270 through intraperitoneal injections (IP).

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rats were trained to select between the HD arm and LD arm with no barrier in place. Then, rats were trained for one week with a small plastic barrier (11.3 cm) in the high-density arm. Next, animals were trained for several weeks with a medium-sized (23.4 cm) wire mesh barrier. Upon successful completion of the medium barrier training (i.e., N85% selection of HD arm), a final wire mesh barrier (44 cm) was placed halfway between the start arm door and the glass food dish. Rats were trained on the high barrier for the remainder of their sessions and incorporated into the test phase once successfully making 26 or greater HD arm selections. Rats in experiment 2 (4–0 condition) received the same number of weeks of training, but with no barrier in the HD arm. For most baseline days, rats did not receive supplemental feeding; however, over weekends and after drug tests, animals received supplemental chow in their home cage. The observer recorded per trial the number of HD and LD arm choices as well as latency. Latency was defined as the amount of time it takes an animal to leave the start arm and have its head enter the glass dish containing pellets.

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Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

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SKF38393 vs. Ecopipam

Experiment 1: Ability of the dopamine D1 receptor partial agonist SKF38393 to reverse the effects of ecopipam on the concurrent FR5/ chow-feeding procedure. The D1 partial agonist, SKF38393, produced a partial reversal of the effects of ecopipam in animals tested on the FR5/chow feeding choice test (Fig. 1). There was an overall significant effect of drug treatment on lever pressing [F(4,44) = 47.238, p b 0.001]. Planned comparisons showed that ecopipam produced a significant reduction in lever pressing compared to vehicle control conditions (p b 0.01). Co-administration of SKF38393 with ecopipam significantly increased lever pressing compared to ecopipam plus vehicle; 0.5 mg/kg SKF38393 plus ecopipam significantly increased lever pressing relative to ecopipam plus vehicle (p b 0.01). There was also an overall significant effect of drug treatment on chow intake [F(4,44) = 15.13, p b 0.001]. Ecopipam significantly increased chow consumption compared to vehicle-vehicle control (planned comparisons, p b 0.01). Co-administration of 0.05 mg/kg SKF38393 plus ecopipam significantly decreased chow consumption relative to ecopipam-vehicle (planned comparison, p b 0.05). Experiment 2: Ability of dopamine D1 receptor agonist SKF81297 to reverse the effects of ecopipam on the concurrent FR5/chow-feeding procedure. SKF81297 partially attenuated the effects of ecopipam on the concurrent lever pressing/chow feeding task. The overall treatment effect for lever pressing was statistically significant [F(5,25) = 32.303, p b 0.001; Fig. 2]. Planned comparisons revealed that ecopipam significantly decreased lever pressing compared to the vehicle-vehicle treatment (p b 0.01). SKF81297 produced a modest reversal of the suppression of lever pressing induced by ecopipam, with 0.05 mg/kg SKF81297 being significantly different from ecopipam-vehicle (planned comparisons, p b 0.01). The overall treatment effect for chow consumption was also statistically significant [F(5,25) = 18.948, p b 0.001]. Planned comparisons revealed that ecopipam significantly increased chow consumption compared to vehicle animals (p b 0.01). Chow consumption was significantly reduced at 0.05 mg/kg SKF81297 plus ecopipam compared to ecopipam alone (planned comparison, p b 0.01). Experiment 3: Ability of the dopamine D 1 receptor agonist A77636 to reverse the effects of ecopipam on the concurrent FR5/ chow-feeding procedure. In the A77636/ecopipam experiment repeated measures ANOVA demonstrated that there was an overall significant

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In experiments 1–3, total number of lever presses and gram quantity of chow intake from the 30 min session were analyzed using repeated measures ANOVA. A computerized statistical program (SPSS 14.0 for Windows) was used to perform all analyses. When there was a significant ANOVA, non-orthogonal planned comparisons using the overall error term were used to assess the differences between each treatment and the control condition. The number of comparisons was restricted to the number of treatments minus one (Keppel, 1991). In experiments 4–7, there were no differences between animals that had the HD arm to the left as opposed to those trained on the right, so these data were combined for further analyses. The total number of HD arm selections was analyzed with repeated measures analysis of variance (ANOVA). Data for selection of the LD arm were not statistically analyzed because no animals failed to make a choice, and thus they are simply the mirror image of the HD arm choices. The average latency across trials in the T-maze was analyzed with repeated measures ANOVA. For the effect size calculations partial eta-squared was used (ηρ2). In order to determine if latency acted as a mediator variable in the T-maze experiments (i.e., if it largely explained the effects of ecopipam on arm choice), partial correlations were performed to determine the relation between dose of ecopipam (including vehicle, which was 0 mg/kg) and arm choice when latency was controlled for, as well as the relation between dose of ecopipam and latency when controlling for choice.

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Fig. 1. Effects of the DA D1 agonist SKF38393 in combination with 0.2 mg/kg ecopipam. (A) Mean (±SEM) number of lever presses (FR5 schedule) during the 30 min session after treatment with vehicle or ecopipam plus various doses of SKF38393. (B) Mean (±SEM) intake of lab chow (in grams) after treatment with vehicle or ecopipam plus various doses of SKF38393 are shown. VEH/VEH (vehicle plus vehicle), ECO/VEH (0.2 mg/kg ecopipam plus vehicle), ECO/0.25 (0.2 mg/kg ecopipam plus 0.025 mg/kg SKF38393), ECO/0.5 (0.2 mg/kg ecopipam plus 0.5 mg/kg SKF38393), ECO/1.0 (0.2 mg/kg ecopipam plus 1.0 mg/kg SKF38393). (A) Mean (±SEM) number of lever presses (FR5 schedule) during the 30 min session. (B) Mean (±SEM) gram quantity of chow intake. ##p b 0.01, ecopipam different from vehicle/vehicle, planned comparison; *p b 0.05, different from ecopipam plus vehicle, planned comparison; **p b 0.01, different from ecopipam plus vehicle, planned comparison.

effect of drug treatment on lever presses [F(5, 35) = 11.387, p b 0.001; Fig. 3]. Ecopipam significantly lowered lever pressing compared to vehicle control (planned comparison, p b 0.01). Planned comparisons also revealed that co-administration of A77636 produced a significant increase in lever pressing relative to ecopipam vehicle-treated animals only at the 0.5 mg/kg dose (p b 0.05). There was also a significant effect of drug treatment on chow consumption [F(5,35) = 7.406, p b 0.001]. Ecopipam significantly increased chow intake compared to vehicletreated animals (planned comparisons, p b 0.01). Planned comparisons also revealed that co-administration of A77636 at the three highest doses significantly reduced chow consumption relative to ecopipam vehicle-treated animals (p b 0.05 at 0.5 mg/kg and 1.0 mg/kg of A77636, and p b 0.01 at the 2.0 mg/kg dose of A77636). Experiments 4–5: Effect of the dopamine D1 receptor antagonist ecopipam on T-maze performance in the 4–2 barrier and 4–2 no barrier conditions. Systemic administration of ecopipam significantly decreased high-density arm selection (i.e., barrier crossings) as shown in Fig. 4. Repeated measures ANOVA indicated that there was an overall significant effect of ecopipam treatment [F(3,21) = 9.984, p b 0.001]. Planned comparisons revealed that ecopipam produced a significant decrease in HD arm selection compared to vehicle-treated control rats at both the 0.2 and the 0.3 mg/kg dose (p b 0.01). Furthermore, ecopipam

Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

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significantly increased selection of the LD arm of the T-maze (data not shown) and all ecopipam rats consumed every pellet that was present in their chosen arm on each trial. There were no trials in which vehicle or ecopipam-treated rats failed to choose one of two arms of the maze. The effect size analysis on arm selection indicated a strong effect size (ηρ2 = 0.804). Repeated measures ANOVA also indicated that there was an overall significant effect of ecopipam treatment on latency [F(3,21) = 5.336; p b 0.007]. Planned comparisons revealed that ecopipam produced a significant increase in average latency times (sec) at the 0.2 and 0.3 mg/kg dose (p b 0.05 for the 0.2 mg/kg dose of ecopipam, p b 0.01 for the 0.3 mg/kg dose of ecopipam; Table 1). The latency effect also displayed a strong effect size (ηρ2 = 0.972). Although latency and arm choice were both affected by ecopipam, there was no significant correlation between arm choice and latency at the highest dose of ecopipam (0.3 mg/kg, r = −0.32, n = 8, n.s.). In order to determine if latency acted as a mediator variable for the effect of ecopipam on arm choice across the vehicle and ecopipam treatments, partial correlations were performed to determine the relation between dose of ecopipam and arm choice when latency was controlled for, and the relation between dose of ecopipam and latency when controlling for choice. These analyses showed that there was a statistically significant

U

421

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E

Fig. 2. Effects of the DA D1 agonist SKF81297 in combination with 0.2 mg/kg ecopipam. (A) Mean (±SEM) number of lever presses after treatment with vehicle or ecopipam plus various doses of SKF81297 are shown. (B) Mean (±SEM) intake of lab chow (in grams) after treatment with vehicle or ecopipam plus various doses of SKF81297 are shown. VEH/VEH (vehicle plus vehicle), ECO/VEH (0.2 mg/kg ecopipam plus vehicle), ECO/0.025 (0.2 mg/kg ecopipam plus 0.025 mg/kg SKF81297), ECO/0.5 (0.2 mg/kg ecopipam plus 0.05 mg/kg SKF81297), ECO/1.0 (0.2 mg/kg ecopipam plus 1.0 mg/kg SKF81297), ECO/2.0 (0.2 mg/kg ecopipam plus 2.0 mg/kg SKF81297). ##p b 0.01, ecopipam different from vehicle/vehicle, planned comparison; **p b 0.01, different from vehicle plus ecopipam, planned comparison.

Fig. 3. The effects of the DA D1 agonist A77636 on ecopipam-induced changes in the performance on the concurrent lever pressing/chow feeding procedure. (A) Mean (±SEM) number of lever presses after treatment with vehicle or ecopipam plus various doses of A77636 are shown. (B) Mean (± SEM) intake of lab chow (in grams) after treatment with vehicle or ecopipam plus various doses of A77636 are shown. VEH/VEH (vehicle plus vehicle), ECO/VEH (0.2 mg/kg ecopipam plus vehicle), ECO/0.25 (0.2 mg/kg ecopipam plus 0.25 mg/kg A77636), ECO/0.5 (0.2 mg/kg ecopipam plus 0.5 mg/kg A77636), ECO/1.0 (0.2 mg/kg ecopipam plus 1.0 mg/kg A77636), ECO/2.0 (0.2 mg/kg ecopipam plus 2.0 mg/kg A77636). ##p b 0.01, ecopipam different from vehicle/vehicle, planned comparisons; *p b 0.05, different from vehicle plus ecopipam, planned comparisons; **p b 0.01, different from vehicle plus ecopipam, planned comparisons.

relation between dose of ecopipam and arm choice even when latency was controlled for in the partial correlation (r = − 0.49, df = 29, p b 0.005). However, there was no significant correlation between dose and latency when arm choice was controlled for (r = 0.27, df = 29, p N 0.1). This pattern of effects indicates that latency is not serving as a mediator of the effect of ecopipam on choice. For experiment 5, repeated measures ANOVA revealed there was not a significant effect of ecopipam on HD arm selection (i.e., barrier crossings) when no barrier was obstructing the HD arm [F(3,21) = 1.988, p N 0.05, n.s.] as shown in Fig. 5. Effect size estimates through use of partial eta-squared revealed that there was a weak effect size (ηρ2 = 0.221). Although ecopipam had no significant effect on arm choice, there was a significant effect on latency [F(3,21) = 8.493; p b 0.001]. Planned comparisons showed that the 0.2 and 0.3 mg/kg doses of ecopipam significantly increased latency as compared to vehiclecontrol (p b 0.05; Table 1). Experiment 6: Ability of the dopamine D1 receptor partial agonist SKF38393 to reverse the effects of ecopipam on T-maze performance. The DA D1 agonist, SKF38393, significantly increased HD arm selection

Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

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S.E. Yohn et al. / Pharmacology, Biochemistry and Behavior xxx (2015) xxx–xxx

30

25

** **

15 10 5 0 0.1

VEH

0.2

0.3

**

25

** 20

** ##

15 10 5 0

Dose Ecopipam (mg/kg)

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496

C

E

R

478 479

R

476 477

O

474 475

C

472 473

N

470 471

U

468 469

t1:3 t1:4 Q1 t1:5 t1:6 Q2

Fig. 5. Effects of the DA D1 agonist SKF38393 on T-maze arm choice in rats co-administered ecopipam. Mean (±SEM) number of barrier arm choices after treatment with vehicle or ecopipam plus various doses of SKF38393 are shown. VEH/VEH (vehicle plus vehicle), ECO/VEH (0.3 mg/kg ecopipam plus vehicle), ECO/0.25 (0.3 mg/kg ecopipam plus 0.25 mg/kg SKF38393), ECO/0.5 (0.3 mg/kg ecopipam plus 0.5 mg/kg SKF38393), ECO/0.75 (0.3 mg/kg ecopipam plus 0.75 mg/kg SKF38393). ## p b 0.01, different from VEH/VEH, planned comparisons; **p b 0.01, different from ECO/VEH, planned comparisons.

R O

Table 1 Latency (mean ± SEM; in seconds) to reach goal area. ECO (ecopipam).

466 467

Treatment (mg/kg IP)

P

t1:1 t1:2

464 465

ECO/ 0.75

498

4. Discussion Consistent with previous studies (Nunes et al., 2010; Sink et al., 2008), the DA D1 receptor antagonist ecopipam altered response allocation in rats tested on the concurrent FR5/chow feeding choice task, decreasing FR5 lever pressing reinforced by high carbohydrate pellets, but increasing chow intake (experiments 1–3). These effects of ecopipam do not resemble those produced by manipulations that affect primary food motivation, such as devaluation of the food reinforcer by pre-feeding (Randall et al., 2012; Salamone et al., 1991), or administration of appetite suppressant drugs (Cousins et al., 1994; Salamone et al. 2002; Sink et al., 2008). Furthermore, in rats responding on the T-maze barrier choice task, administration of ecopipam produced a significant decrease in selection of the HD arm that was obstructed by the barrier, but increased selection of LD arm without the barrier (experiment 4). Although ecopipam affected arm selection when the barrier was present, it had no effect on arm choice when no barrier was present (experiment 5). Thus, ecopipam did not affect discrimination of reinforcement magnitude or left vs. right, nor did it alter preference for the higher density of reinforcement, or impair reference memory. Across both the lever pressing and T-maze tasks, ecopipam-treated rats remained directed towards the acquisition and consumption of food; in each case, administration of ecopipam suppressed the tendency to work for food by lever pressing or climbing the barrier, but led animals to select an alternative path to obtain food. These results indicate that the effects of ecopipam on tasks involving effort-related choice are similar to those produced by blockade of DA D2 receptors (Sink et al., 2008; Worden et al., 2009; Mott et al., 2009; Nunes et al., 2010; Pardo et al., 2012) and nucleus accumbens DA depletions (Salamone et al., 1991, 1994; Cousins et al., 1996; Nunes et al., 2013b). Furthermore, these findings are consistent with the hypothesis that DA systems are important for instigating and maintaining instrumental behavior

T

497

when co-administered with ecopipam as shown in Fig. 5. Repeated measures ANOVA indicated that there was an overall significant effect of drug treatment on arm choice [F(4,28) = 54.126; p b 0.001]. Ecopipam-vehicle-treated rats showed a significant decrease in HD arm selection (i.e., barrier crossings) as to vehicle-vehicle-treated control rats (planned comparisons, p b 0.01). Co-administration of SKF38393 with ecopipam produced a significant increase in HD arm selection with the barrier compared to the ecopipam plus vehicle control condition; all doses of SKF38933 when given in conjunction with ecopipam significantly increased HD arm selection (planned comparisons; p b 0.01). The ecopipam treatment effect was marked by a strong effect size (ηρ2 = 0.783). Repeated measures ANOVA also indicated that there was a significant effect of drug treatment on run latency [F(4,28) = 2.704; p b 0.05; Table 2]. Administration of ecopipam caused a significant increase in average response latency (sec) as compared to vehicle-vehicle treated rats (planned comparisons, p b 0.05). However, although co-administration of SKF38393 reversed arm choice, planned comparisons showed that latency was not significantly reversed by SKF38393 as compared to control conditions. The drug treatment effect on latency was very weak (ηρ2 = 0.005) in terms of effect size. Experiment 7: Ability of the dopamine D1 receptor agonist SKF81297 to reverse the effects of tetrabenazine on T-maze performance. The data on high-density arm selections (i.e., barrier crossings) for rats treated with tetrabenazine and SKF81297 are shown in Fig. 6. Repeated measures ANOVA indicated that there was a significant effect of drug treatment on arm choice [F(4,28) = 4.789; p b 0.05]. Tetrabenazine plus vehicle-treated rats showed a significant decrease in the selection of the number of barrier crossings as compared to vehiclevehicle treated rats (planned comparisons, p b 0.01). Co-administration of 0.05 mg/kg SKF81297 with tetrabenazine produced a significant increase in the selection of the HD arm relative to tetrabenazine plus vehicle-treated rats (planned comparisons, p b 0.01). There was a large effect size between drug treatment and arm-selection (ηρ2 = 0.559). Repeated measures ANOVA showed that there was not a significant overall effect of drug treatment on run latency [F(4,28) = 1.99; n.s.; Table 3], and that the effect size on the latency measure was low (ηρ2 = 0.066).

462 463

ECO/ 0.5

D

461

ECO/ 0.25

E

Fig. 4. Effect of IP administration of the DA D1 antagonist ecopipam on arm choice in the T-maze. Mean (±SEM) number of barrier arm choices after treatment with vehicle or various doses of ecopipam are shown (**p b 0.01, different from vehicle, planned comparisons).

ECO/ VEH

O

VEH/ VEH

F

20

HD Arm Selections

HD Arm Selections

SKF38393 vs. Ecopipam

4-2 barrier 4-2 no barrier

30

4–2 barrier 4–2 no barrier

VEH

0.1 ECO (mg/kg)

0.2 ECO (mg/kg)

0.3 ECO (mg/kg)

2.762 (±0.141) 1.75 (±0.197)

3.525 (±0.428) 2.237 (±0.277)

7.263 (±1.468)* 3.76 (±0.570)*

8.834 (±1.99)* 3.759 (±0.495)*

#p b 0.05, different from VEH.

Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

499 500 501 502 503 504 505 506 507 Q11 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528

S.E. Yohn et al. / Pharmacology, Biochemistry and Behavior xxx (2015) xxx–xxx t2:1 t2:2 t2:3

VEH/VEH

t2:5

ECO/SKF38393 4.262 (±0.457)

t2:6 t2:7

Table 3 t3:1 Latency (mean ± SEM; in seconds) to reach goal area. TBZ (tetrabenazine); SKF81297 t3:2 doses are in mg/kg. t3:3

Table 2 Latency (mean ± SEM; in seconds) to reach goal area. Eco (ecopipam); SKF38393 doses are in mg/kg.

t2:4

ECO/VEH

ECO/0.25

ECO/0.5

ECO/0.75

9.46 (±1.448)#

10.14 (±1.542)

9.409 (±2.162)

9.738 (±1.65)

VEH/VEH TBZ/SKF81297 4.195 (±0.235)

Ecopipam different from VEH/VEH. # p b 0.05.

20 15 10 5

**

##

0 VEH/ VEH

TBZ/ VEH

TBZ/ 0.025

TBZ/ 0.05

TBZ/ 0.1

Treatment (mg/kg IP) Fig. 6. Effects of the DA D1 agonist SKF81297 on T-maze arm choice in rats co-administered with the VMAT-2 inhibitor tetrabenazine. Mean (±SEM) number of barrier arm choices after treatment with vehicle or tetrabenazine plus various doses of SKF81297 are shown. VEH/VEH (vehicle plus vehicle), TBZ/VEH (0.75 mg/kg tetrabenazine plus vehicle), TBZ/0.025 (0.75 mg/kg tetrabenazine plus 0.025 mg/kg SKF81297), TBZ/0.05 (0.75 mg/kg tetrabenazine plus 0.05 mg/kg SKF81297), TBZ/0.1 (0.75 mg/kg tetrabenazine plus 0.01 mg/kg SKF81297) ##p b 0.01, different from vehicle/vehicle, planned comparisons; **p b 0.01, different from tetrabenazine plus vehicle, planned comparisons.

TBZ/0.025

TBZ/0.05

TBZ/0.1

t3:4

5.629 (±0.314)

5.196 (±0.327)

5.602 (±0.380)

t3:5

No significant differences.

t3:6

several studies have failed to find a robust correspondence between intrinsic activity effects for stimulating adenylate cyclase activity and behavioral effectiveness in measures of feeding, locomotion, grooming, circling, drug discrimination, and self-administration, across different D1 family agonists. Several factors, including the specific signal transduction mechanism, the tissue, and receptor concentration in the target area influence whether a drug acts like a partial or full agonist. There are several possible explanations of why D1 agonists showed an inverted-u shaped dose response curve in these studies. One possible explanation is that at high doses, D1 agonists are breaking through the blockade produced by ecopipam, but are not restoring normal levels of food-reinforced lever pressing because of appetite suppressant effects. Previous studies have shown that selective DA D1 agonists can exert anorectic effects at moderate doses, leading to a reduction in meal size and meal duration (Clifton, 1989; Cooper et al., 1990, 2006; Rusk and Cooper, 1989; Terry and Katz, 1992; 1994; Terry et al., 1994). While that explanation seems applicable to the effects of A77363, because higher doses of that drug in combination with ecopipam led to low levels of both lever pressing and chow intake compared to ecopipam alone (Fig. 3), this explanation does not fit the pattern of results seen with SKF38393 and SKF81297 (Figs. 1B and 2B). It also is possible that higher doses of the D1 agonists are altering preference for the high carbohydrate pellets, or inducing activities that are incompatible with lever pressing. Finally, another possible explanation is that D1 agonists are displacing ecopipam off D1 receptors, but are not restoring the normal pattern of phasic DA signaling that depends upon the release of endogenous DA. Based upon unpublished observations, we have observed that very high doses of drugs that stimulate DA transmission, such as bupropion, can disrupt performance in tetrabenazinetreated rats. Furthermore, it is worth noting that inverted-u shaped dose response curves also were reported to occur in studies focusing on the cognitive effects of D1 agonists (Goldman-Rakic et al., 2004; Roberts et al., 2010; Floresco, 2013). Thus, it appears that moderate levels of D1 transmission are necessary for the normal pattern of performance on the concurrent FR5/chow feeding choice task and the T-maze barrier choice procedure, while either low or high levels of D1 transmission are disruptive (see also Floresco, 2013). Moreover, while D1 antagonism clearly alters response allocation, the agonist/antagonist studies indicate that it is difficult to completely restore the normal pattern of behavior by co-administration of an agonist with an antagonist. The final experiment assessed the ability of the D1 agonist SKF81297 to reverse the effects of tetrabenazine on T-maze performance. Tetrabenazine is an inhibitor of the vesicular monoamine transporter2 (VMAT-2), which induces a blockade of vesicular storage. At low doses (i.e., 1.0 mg/kg or less), the greatest effects of tetrabenazine are on depletion of DA in the nucleus accumbens and neostriatum (Pettibone et al., 1984; Tanra et al., 1995; Guay, 2010; Nunes et al., 2013b). Administration of 0.75 mg/kg tetrabenazine reduced extracellular DA in accumbens core by 75%, and altered DA-related signal transduction as measured by DARPP-32 expression in a manner consistent with a reduction of both D1 and D2 receptor transmission (Nunes et al., 2013b). Recent studies have shown that administration of 0.75 mg/kg tetrabenazine can alter effort-related choice behavior in rats tested on the T-maze barrier choice task, without affecting arm choice, discrimination of the reinforcer, or climbing of the barrier (Yohn et al., 2015). As described above, the D1 agonist SKF81297 was able to reverse the effects of tetrabenazine on T-maze performance.

559

O

R O

P

D

E

T

C

E

R

R

25

U

HD Arm Selections

30

N C O

SKF81297 vs. Tetrabenazine

TBZ/VEH 5.187 (±0.621)

F

529

(Salamone and Correa, 2002, 2012; Berridge and Robinson, 2003; 530 Robbins and Everitt, 2007; Nicola, 2010; Howe et al., 2013; McGinty 531 et al., 2013; Nunes et al., 2013a; Floresco, 2015), and for regulating sen532 sitivity to the work-related response requirements of an instrumental 533 task (Salamone and Correa, 2002, 2012; Salamone et al., 2007, 2012; 534 Hosking et al., 2014). In addition, the present results are consistent 535 with previous studies showing that mice with genetic inactivation of 536 the DA D1 receptor show poor motivation to perform instrumental 537 tasks (Wall et al., 2011). 538 The effects of ecopipam on effort-related choice behavior were 539 partially attenuated by co-administration of D1 agonists. SKF38393, 540 SKF81297, and A77636 were all able to significantly increase lever 541 pressing and decrease chow consumption in ecopipam-treated rats 542 relative to ecopipam plus vehicle. The magnitude of the reversal of the 543 effect of ecopipam by D1 agonists was generally moderate; the mean 544 numbers of lever presses at doses that produced the largest reversal ef545 fects were about half those of control levels of responding. Moreover, 546 the dose-response curves for the effects of D1 agonists on lever pressing 547 in ecopipam-treated rats generally had a biphasic (i.e., inverted-u) 548 shape, with moderate doses producing statistically significant reversals 549 of the effects of ecopipam. In rats tested on the T-maze task, SKF38393 550 also was able to reverse the effects of ecopipam, and increase selection 551 of the HD arm with the barrier in ecopipam-treated rats. As with the 552 lever pressing studies, this reversal effect showed an inverted-u shaped 553 dose-response curve. Thus, even though SFK38393 is a partial agonist at 554 D1 receptors, it was able to partially attenuate the effects of ecopipam in 555 a manner that was comparable to that shown by the full agonists 556 SKF81297 and A77636. With D1 agonists, partial vs. full agonism has 557 typically been defined in terms of cellular studies of c-AMP production 558 Q12 (Vermeulen et al., 1994). Nevertheless, as stated by Desai et al. (2003),

7

Please cite this article as: Yohn, S.E., et al., The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists, Pharmacol Biochem Behav (2015), http://dx.doi.org/10.1016/j.pbb.2015.05.003

560 561 562 563 564 565 566 567 568 569 570 571 572 573 Q13 574 Q14 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615

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that contain both D2 and A2A receptors and project from accumbens core to lateral ventral pallidum (Ferre et al., 1997; Farrar et al., 2008; Mingote et al., 2008; Smith et al., 2013). Considerable evidence implicates this component of the GABAergic ventral striatopallidal pathway in behavioral activation and effort-related processes (Mingote et al., 2008; Farrar et al., 2008, 2010; Salamone et al. 2010). Yet despite the co-localization of adenosine A1 receptors with DA D1 receptors on accumbens substance P-positive medium spiny neurons, the behavioral effects of D 1 antagonism are not reversed by A1 antagonists (Collins et al., 2010; Nunes et al., 2010). Furthermore, the contribution of D1 receptors in nucleus accumbens core or shell, the striatal output pathway mediating D1 related effects, and the relative involvement of anterior cingulate cortex (Schweimer and Hauber, 2006), remain uncertain. Future research should focus on identifying the specific neural circuitry mediating the effort-related effects of DA D1 antagonists, and also should employ tests of effort-related decision making to further evaluate the potential clinical utility of D 1 agonists for the treatment of motivational symptoms of depression and other disorders (Nunes et al., 2013a,2013b; Sommer et al., 2014; Randall et al., 2014; Francis et al., 2014).

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This work was supported by grants to J.S. from the National Institute of Mental Health (MH094966) and Pfizer, and to Merce Correa from Fundació Bancaixa/ U. Jaume I. (P1.1B2010-43). Many thanks to Christian Thompson for his assistance.

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Thus, restoration of D1 receptor transmission was able to partially restore T-maze performance in DA-depleted rats. 618 In addition to measuring arm selection in the T-maze, response la619 tencies were also recorded. Drug effects on response latencies were 620 somewhat mixed. Although ecopipam increased response latencies in 621 experiments 4–6, the relation between arm choice and response latency 622 was not consistent. In experiment 5, in which no barrier was present, 623 ecopipam increased latency but did not affect arm choice. In experiment 624 6, SKF38393 attenuated the effects of ecopipam on arm choice, but did 625 not reverse the effects on latency. Also, in experiment 7, there were 626 no effects of tetrabenazine or SKF 81297 on response latency, despite 627 robust effects on choice. This dissociation between T-maze arm choice 628 and run latency is consistent with the results of previous studies 629 (Salamone et al., 1994; Bardgett et al., 2009; Yohn et al., 2015). More630 over, these observations are consistent with previous studies involving 631 locomotor activity. For example, 0.2 mg/kg ecopipam suppressed loco632 motor activity (Collins et al., 2010), while 0.75 mg/kg tetrabenazine 633 Q15 did not (Podurgiel et al., 2015), even though both treatments affect 634 effort-related choice. In order to determine if the effects of ecopipam 635 on arm choice in experiment 4 were mediated by changes in latency, 636 partial correlation analyses were performed. These analyses showed 637 that there was a statistically significant relation between dose of 638 ecopipam and arm choice even when latency was controlled for in the 639 partial correlation (r = − 0.49, df = 29, p b 0.005). In contrast, there 640 was no significant correlation between dose and latency when arm 641 choice was controlled for in the partial correlation. This pattern of 642 effects indicates that latency is not serving as a strong mediator of the 643 effect of ecopipam on arm choice. 644 In fact, it is not surprising that a DA D1 antagonist could slow re645 sponse speed (Baldo et al., 2002; Dreher and Jackson, 1989; Gong 646 et al., 1999; Knab and Lightfoot, 2010). DA has been implicated in be647 havioral activation, in part because interference with DA transmission 648 has been shown to reduce locomotor activity stimulated by novelty, 649 stimulant drugs, and motivational conditions such as scheduled presen650 tation of food pellets (Salamone, 1988, 1992, 2010a, 2010b; McCullough 651 and Salamone, 1992; Salamone et al., 2007; Robbins and Everitt, 2007). 652 Movement parameters such as vigor, speed and persistence are also 653 viewed as fundamental markers of activational aspects of motivation 654 (Salamone, 1992, 2010a, 2010b; Salamone and Correa, 2002; McGinty 655 et al., 2013). Moreover, there is considerable overlap between the neu656 ral circuits regulating aspects of movement control and motivation 657 (Salamone and Correa, 2012). For example, nucleus accumbens has 658 been suggested to serve as a “limbic-motor interface” that is involved 659 in translating motivation into action (Mogenson et al., 1980). Neverthe660 less, it would be difficult to argue that the effects of ecopipam and 661 tetrabenazine on arm choice in the T-maze barrier task are simply an ar662 tifact of slowed response speed. Rather, response choice and response 663 speed appear to be dissociable aspects of the impairment in behavioral 664 activation induced by ecopipam and tetrabenazine. 665 Taken together, the present results highlight the role of D1 receptor 666 transmission in effort-related choice behavior. Moreover, they empha667 size the need for future research on the specific neural mechanisms 668 and anatomical circuits mediating the effects of D1 agonists and antago669 nists. At present, much more is known about the circuitry mediating the 670 effort-related effects of D2 antagonists than is known about D1 antago671 nism. Conditions of reduced D2 receptor transmission that are associat672 ed with changes in effort-related choice behavior are accompanied by 673 increased expression of c-Fos and DARPP-32 phosphorylated at the 674 threonine 34 residue in enkephalin-positive neurons in nucleus accum675 bens (Farrar et al., 2010; Santerre et al., 2012; Nunes et al., 2013b). 676 Moreover, co-administration of adenosine A2A antagonists reverses 677 both the signal transduction and the effort-related behavioral effects 678 of reduced D2 transmission (Farrar et al., 2010; Santerre et al., 2012; 679 Nunes et al., 2013b). There is a preferential localization of D2 receptor/ 680 enkephalin positive neurons in accumbens core relative to the shell 681 Q16 (Lu et al., 1998), and a dense projection of enkephalin positive neurons

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