Psychopharmacology DOI 10.1007/s00213-015-4176-7

ORIGINAL INVESTIGATION

Effects of lisdexamfetamine and s-citalopram, alone and in combination, on effort-related choice behavior in the rat Samantha E. Yohn 1 & Laura Lopez-Cruz 2 & Peter H. Hutson 3 & Merce Correa 2 & John D. Salamone 1

Received: 28 September 2015 / Accepted: 25 November 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Rationale Effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue, are an important aspect of depression and other disorders. Motivational symptoms are resistant to some treatments, including serotonin transport (SERT) inhibitors. Objectives Tests of effort-based choice using operant behavior tasks (e.g., concurrent lever pressing/ chow feeding tasks) can be used as animal models of motivational symptoms. Tests of effort-related choice allow animals to choose between high-effort actions that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued rewards (i.e., less preferred or lower magnitude). Rats treated with the vesicular monoamine transport inhibitor tetrabenazine, or the cytokine interleukin-1β (IL-1β), which are associated with depressive symptoms in humans, can alter effort-related choice, reducing selection of the high effort alternative (lever pressing) while increasing intake of freely available chow. Methods The present studies focused upon the ability of lisdexamfetamine (LDX) to increase exertion of effort in rats responding on effort-based choice tasks under several different conditions. Results LDX attenuated the shift from fixed ratio 5 lever pressing to chow intake induced by tetrabenazine and IL-1β. In contrast, the SERT inhibitor s-citalopram failed to reverse * John D. Salamone [email protected]

1

Department of Psychology, University of Connecticut, Storrs, CT 06261-1020, USA

2

Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, Castelló 12071, Spain

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Shire, 1400 Chesterbrook Blvd., Wayne, PA 19087, USA

the effects of tetrabenazine. When given in combination with tetrabenazine+s-citalopram, LDX significantly increased lever pressing output compared to tetrabenaine+citalopram alone. LDX also increased work output in rats responding on a progressive ratio/chow feeding choice task. Conclusions LDX can increase work output in rats responding on effort-based choice tasks, which may have implications for understanding the neurochemistry of motivational symptoms in humans. Keywords Dopamine . Motivation . SSRI . Fatigue . Behavioral activation . Decision making

Introduction Vyvanse (lisdexamfetamine dimesylate, LDX) is a novel prodrug of d-amphetamine that has become widely used as a treatment for attention deficit hyperactivity disorder (ADHD; Najib 2009; Weisler et al. 2009) and has recently been approved in the USA for the treatment of moderate to severe binge eating disorder in adults (FDA News Release 2015). The chemical structure of LDX includes the naturally occurring amino acid, L-lysine, which is covalently bound to damphetamine via an amide linkage (Rowley et al. 2012). Compared to d-amphetamine, LDX has been shown to produce smaller but longer lasting elevations of extracellular catecholamines, including dopamine (DA) in the nucleus accumbens (Rowley et al. 2012). In addition to being used to treat ADHD, stimulants such as amphetamines and methylphenidate are employed off label for the treatment of several psychiatric conditions. One such usage is the treatment of motivational/psychomotor symptoms such as reduced behavioral activation, anergia, apathy, and fatigue. Motivational symptoms are among the most common of all psychiatric

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symptoms (Demyttenaere et al. 2005) and can be seen in people with a variety of disorders, including major depression, Parkinson’s disease, schizophrenia, chronic fatigue syndrome, and fatigue resulting from immune system challenge (Salamone et al. 2015). Fatigue and apathy are common in patients with Parkinson’s disease, and several reports indicate that methylphenidate can attenuate these symptoms (Friedman et al. 2007; Devos et al. 2013). Osmotic-release oral methylphenidate produced rapid improvement of apathy and fatigue symptoms in people with major depression (Rizvi et al. 2014). Stotz et al. (1999) reported that amphetamine and methylphenidate increased self-reported energy and psychomotor activity in depressed patients within hours after administration. These findings are consistent with the literature indicating that the catecholamine uptake inhibitor bupropion (Wellbutrin) can improve motivational symptoms (Papakostas et al. 2006; Pae et al. 2007; Cooper et al. 2014). In contrast, several studies have indicated that drugs that block serotonin transport (SERT) are relatively poor at treating motivational dysfunctions related to behavioral activation and exertion of effort, and may in fact exacerbate these symptoms in some people (Katz et al. 2004; Nutt et al. 2007; Padala et al. 2012; Stenman and Lilja 2013; Fava et al. 2014; Rothschild et al. 2014). In view of the clinical significance of motivational symptoms involving reduced behavioral activation and exertion of effort, it is important to develop animal models of these symptoms. Recent research has demonstrated that animal studies of effort-based choice behavior can be used to develop models of effort-related motivational symptoms in psychopathology (Nunes et al. 2013a, b, 2014; Randall et al. 2014, 2015; Yohn et al. 2015a, b, c). Effort-related choice behavior is studied using tasks that offer choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options (Salamone et al. 2003, 2007, 2012). Behavioral procedures used with rodents include operant behavior tasks that offer a choice between lever pressing for a preferred food vs. approaching and consuming a less preferred food that is readily available (Salamone et al. 1991, 2002; Cagniard et al. 2006; Randall et al. 2012, 2014). a T-maze barrier choice task that uses a vertical barrier as the effort-related challenge (Salamone et al. 1994; Cousins et al. 1996; Mott et al. 2009; Pardo et al. 2012; Yohn et al. 2015a). and discounting procedures involving physical effort (Floresco et al. 2008; Bardgett et al. 2009; Hosking et al. 2015). Recent studies have shown that the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine (TBZ), which induces depressive symptoms in people (Frank 2009, 2010; Guay 2010). can alter effort-related choice, biasing animals towards the low effort option when tested on the concurrent fixed ratio 5 (FR5)/chow feeding choice task (Nunes et al. 2013b; Yohn et al. 2015c). the concurrent progressive ratio (PROG)/chow feeding choice task (Randall et al. 2014). and the T-maze barrier choice task

(Yohn et al. 2015a, b). Moreover, these effects of TBZ were reversed by co-administration of bupropion (Nunes et al. 2013b; Randall et al. 2014; Yohn et al. 2015b, c). Bupropion administered alone also increased exertion of effort in rats tested on the PROG/chow feeding choice task (Randall et al. 2015). Additional studies have shown that the proinflammatory cytokine interleukin-1β (IL-1β), like TBZ, can alter effort-related choice (Nunes et al. 2014). Because the effects of low doses of TBZ and IL-1β were not accompanied by changes in appetite, food preference, or discrimination of reward magnitude (Nunes et al. 2013b, 2014; Randall et al. 2014; Yohn et al. 2015a; Pardo et al. 2015). and did not resemble the effects of reinforcer devaluation or appetite suppressant drugs (Randall et al. 2012, 2014). it has been suggested that the effects of these treatments appear to be related to actions on behavioral activation and effort-related processes rather than primary food motivation. The present studies assessed the effects of LDX on effortrelated choice behavior in rats tested across a number of conditions. Several experiments used the FR5/chow feeding choice task. The ability of LDX to reverse the effects of TBZ was assessed in the first experiment. In subsequent experiments, the ability the SERT inhibitor s-citalopram (CIT) to reverse the effects of TBZ also was studied, and because of recent work indicating that SERT inhibition does not reverse the effects of TBZ (Yohn et al. 2015c). the ability of LDX to increase lever pressing in animals treated with TBZ and CIT was assessed. LDX also was tested for its ability to reverse the effects of IL-1β, and to increase lever pressing output in rats tested on the concurrent PROG/chow feeding choice task. It was hypothesized that LDX, either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) CIT, would reverse TBZ-induced shifts in behavior. In addition, it was hypothesized that LDX would reverse the effort-related effects of IL-1β in rats tested on the FR5/chow feeding choice task and, when administered alone, would shift effort-related choice behavior and increase selection of PROG lever pressing while decreasing chow consumption.

Materials and methods Animals Adult male, Sprague Dawley rats (N = 44; Harlan SpragueDawley, Indianapolis, IN, USA) were housed in a colony maintained at 23 °C with 12 h light/dark cycles (lights on at 0700 hours). All animals weighed 275–300 g at the beginning of the study and were food restricted, initially to 85 % of their body weight, but allowed modest growth throughout the duration of the experiment. Rats were fed weighed amounts of supplemental chow to maintain the food restriction and were allowed modest growth over the course of the experiment; ad

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libitum water was available in their home cages. Animal protocols were approved by the University of Connecticut Institutional Animal Care and Use Committee.

rats consumed all the operant pellets that were delivered during each session. Pharmacological agents and dose selection

Behavioral procedures 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 at least 1 week before being introduced to the concurrent FR5/chow-feeding 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, four to five large pieces) were concurrently available in the chamber during the 30min 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. PROG/chow feeding choice task Behavioral sessions were conducted in operant chambers (28 × 23 × 23 cm3; Med Associates, Putney, VT) with 30min sessions 5 days/week. Rats were initially trained to lever press on a continuous reinforcement schedule (highcarbohydrate 45-mg pellets, Bio-serv, Frenchtown, NJ) and then shifted to the PROG schedule (Randall et al. 2012). For PROG sessions, the ratio started at FR1 and was increased by 1 additional response every time 15 reinforcements were obtained (FR1×15, FR2×15, etc.). A Btime-out^ feature deactivated the response lever if 2 min elapsed without a completed ratio. After 9 to 10 weeks of PROG training, chow was introduced. Weighed amounts of laboratory chow (Laboratory Diet, 5P00 Prolab RMH 3000, Purina Mills, St. Louis, MO; typically 15–20 g) were concurrently available on the floor of the chamber during the PROG sessions. Chow intake was determined by weighing the remaining food (including spillage). Rats were trained on the PROG/chow feeding choice procedure for 4 to 5 weeks, after which drug testing began. On baseline and drug treatment days,

TBZ (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 11b hexahydrobenzo[a]quinolizin-2-one), the VMAT-2 inhibitor, was purchased from Tocris Bioscience (Bristol, UK). TBZ was dissolved in a vehicle solution of 0.9 % saline (80 %) and DMSO (20 %). 1 N HCl/mL volume was then added to adjust the pH and get the drug completely into solution. The final pH of the TBZ solution was 3.5–4.0, and the dose of 0.75 mg/kg and the 90-min lead time were selected based upon previous studies (Nunes et al. 2013a; Randall et al. 2014; Yohn et al. 2015a, b, c). The 20 % DMSO/saline vehicle solution was administered as the vehicle control. The dose of TBZ used (0.75 mg/kg) was based upon previous research (Nunes et al. 2013b; R a n d a l l e t a l . 2 0 1 4 ; Yo h n e t a l . 2 0 1 5 a , b , c ) . Lisdexamfetamine dimesylate (LDX) was supplied by Shire Pharma (Lexington, MA, USA). LDX is a mesylate salt with a MW of 455.59, the free base has a MW of 263.38; hence, there is a correction factor of 1.73. (455.59/263.38). For the present experiments, LDX was corrected back to amphetamine (MW 135.21) using a correction factor of 3.37 (455.59/135.21). We used this conversion factor to express doses of LDX in terms of damphetamine base, so that it is possible to compare with previous studies in which d-amphetamine dose was also expressed as base. The SERT inhibitor, escitalopram oxal a t e ( C I T; S - ( + ) - c i t a l o p r a m o x a l a t e , S - ( + ) 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3dihydro-5-isobenzofurancarbonitrile oxalate), was purchased from Sigma Aldrich (Milwaukee, WI, USA). The doses of CIT were selected based on previous research and extensive pilot studies. Recombinant rat IL-1β was obtained from R&D systems (Minneapolis, MN, USA). The doses of IL-1β were based on previously published data (Merali et al. 2003; Nunes et al. 2014). LDX, CIT, and IL-1β were all dissolved in a vehicle solution of 0.9 % warmed saline. Experimental procedures Rats were trained as described above. All experiments used a within-groups design in which each rat received all IP 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). Immediately after the 30-min session, rats were removed from the chambers, total lever presses were recorded, and chow consumed was

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calculated. Baseline (non-drug) training sessions were conducted 4 days per week.

Experiment 5: ability of LDX to attenuate IL-1β-induced shifts in choice behavior in rats performing on the FR5/chow choice task

Experiment 1: ability of LDX to reverse TBZ-induced shifts in behavior in rats performing on the FR5/chow choice task

Trained rats (n = 16) received IP injections of vehicle or the following combined treatments of IL-1β- or IL-1β-vehicle 90 min before testing plus LDX or its respective vehicle 60 min prior to testing: IL-1β-vehicle + LDX vehicle; 4.0 μg/kg IL-1β- + LDX vehicle; 4.0 μg/kg IL-1β- + 0.09375 mg/kg LDX; 4.0 μg/kg IL-1β- + 0.1875 mg/kg LDX; 4.0 μg/kg IL-1β- + 0.375 mg/kg LDX; 4.0 μg/kg IL1β- + 0.75 mg/kg LDX.

Trained rats (n = 10) received IP injections of vehicle or the following combined treatments of TBZ (0.75 mg/kg IP) or TBZ vehicle 90 min before testing plus LDX or its respective vehicle 60 min prior to testing: TBZ vehicle + LDX vehicle; 0.75 mg/kg TBZ + LDX vehicle; 0.75 mg/kg TBZ + 0.09375 mg/kg LDX; 0.75 mg/kg TBZ + 0.1875 mg/kg LDX; 0.75 mg/kg TBZ + 0.375 mg/kg LDX; 0.75 mg/kg TBZ + 0.75 mg/kg LDX.

Experiment 2: ability of the SSRI, CIT, to attenuate TBZ-induced shifts in behavior in rats performing on the FR5/chow choice task Trained rats (n = 6) received the following IP treatments; TBZ administered 90 min prior to testing and CIT administered 60 min prior to testing: TBZ vehicle + CIT vehicle; 0.75 mg/kg TBZ + CIT vehicle; 0.75 mg/kg TBZ + 1.875 mg/kg CIT; 0.75 mg/kg TBZ + 3.75 mg/kg CIT; 0.75 mg/kg TBZ + 7.0 mg/kg CIT; 0.75 mg/kg TBZ + 15.0 mg/kg CIT.

Experiment 3: ability of LDX to increase effort in TBZ-CIT-treated rats performing on the FR5/chow choice task Trained animals (n = 16, using the rats tested in experiments 1 and 2 above) received IP injections of vehicle or the following drug treatments prior to testing (injection times prior to testing are listed): TBZ (90 min), CIT (60 min), and LDX (60 min). All rats received three injections of the following eight treatments: TBZ vehicle + CIT vehicle+ LDX vehicle; 0.75 mg/kg TBZ + CIT vehicle + LDX vehicle; TBZ vehicle + 3.75 mg/kg CIT + LDX vehicle; TBZ vehicle + CIT vehicle + 0.75 mg/kg LDX; 0.75 mg/kg TBZ + 15.0 mg/kg CIT + LDX vehicle; 0.75 mg/kg TBZ + 15.0 mg/kg CIT + 0.1875 mg/kg LDX; 0.75 mg/kg TBZ + 15.0 mg/kg CIT + 0.375 mg/kg LDX; 0.75 mg/kg TBZ + 15.0 mg/kg CIT + 0.75 mg/kg LDX.

Experiment 4: ability of LDX to increase lever pressing output in rats performing in the PROG/chow choice task Trained rats (n = 12) received IP injections of either vehicle or varying doses of LDX (0.1875, 0.375, 0.75, and 1.5 mg/kg IP; 60 min before testing).

Statistical analyses 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 21.0 for Windows) was used to perform all analyses. When there was a significant ANOVA, non-orthogonal planned comparisons using the overall error term were employed 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). For the PROG/chow feeding choice experiment, analyses also were performed on highest ratio achieved and active lever time (i.e., time spent with the lever active before the time out was activated).

Results Experiment 1: ability of LDX to reverse TBZ-induced shifts in behavior in rats performing on the FR5/chow choice task LDX attenuated the effects of TBZ on the concurrent FR5/ chow feeding task. The overall treatment effect for lever pressing was statistically significant [F(5,45 = 14.6, p < 0.001; Fig. 1a], and planned comparisons revealed that TBZ significantly decreased lever pressing compared to the vehiclevehicle treatment (p<0.01). LDX produced a reversal of the suppression of lever pressing induced by TBZ, with 0.1875, 0.375, and 0.75 mg/kg being statistically different from TBZvehicle (planned comparisons 0.1875 and 0.375 mg/kg, p < 0.05; 0.75 mg/kg LDX, p < 0.01). The overall treatment effect for chow consumption was also statistically significant [F(5,45) = 19.8, p<0.001; Fig. 1b]. Planned comparisons showed that TBZ significantly increased chow consumption compared to vehicle animals (p < 0.01). Chow consumption was statistically reduced at 0.1875, 0.375, and 0.75 mg/kg LDX plus TBZ compared to TBZ alone (planned comparisons 0.1875 and 0.375 mg/kg, p < 0.05; 0.75 mg/kg LDX, p < 0.01).

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Fig. 1 The effects of LDX on tetrabenazine-induced changes in performance on the concurrent FR5 lever pressing/chow feeding procedure. Rats (n = 10) received IP injections of vehicle plus vehicle (Veh/Veh), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh), and tetrabenazine plus 0.09375, 0.1875, 0.375, and 0.75 mg/kg doses of LDX (L). a Mean (±SEM) number of lever presses (FR5 schedule) during the 30-min session are shown. b Mean (±SEM) chow consumption (in grams) during the 30-min session. Tetrabenazine plus vehicle significantly differed from vehicle/vehicle, #p < 0.05; significantly different from tetrabenazine plus vehicle, **p < 0.05

TBZ plus LDX significantly increased lever pressing and decreased chow consumption relative to TBZ vehicle-treated animals; these effects were fully reversed by coadministration of the highest dose of LDX. Experiment 2: ability of the SSRI, CIT, to attenuate TBZ-induced shifts in behavior in rats performing on the FR5/chow choice task CIT did not reverse the effects of TBZ in rats tested on the FR5/chow feeding choice test, and in fact tended to exacerbate them (Fig. 2a, b). There was an overall significant effect of drug treatment on lever pressing [F(5,25 = 66.7, p < 0.001; Fig. 2a]. Planned comparisons showed

Fig. 2 The effects of s-citalopram on tetrabenazine-induced changes in performance on the concurrent FR5 lever pressing/chow feeding procedure. Rats (n = 6) received IP injections of vehicle plus vehicle (Veh/Veh), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh), and tetrabenazine plus 1.875, 3.75, 7.5, and 15.0 mg/kg doses of scitalopram (C). a Mean (±SEM) number of lever presses (FR5 schedule) during the 30-min session are shown. b Mean (±SEM) chow consumption (in grams) during the 30-min session. Tetrabenazine plus vehicle significantly differed from vehicle/vehicle, #p < 0.05; significantly different from tetrabenazine plus vehicle, **p < 0.05

that TBZ significantly decreased lever pressing compared to vehicle-control treatment (p < 0.01), but administration of CIT plus TBZ did not significantly affect lever pressing compared to vehicle plus TBZ. If anything, CIT tended to produce an additional suppression of lever pressing in TBZ-treated rats, with 5/6 rats showing reduced levels of lever pressing after injection of 15.0 mg/kg CIT plus TBZ compared to the vehicle plus TBZ condition. The overall treatment effect for chow consumption was also statistically significant [F(5,25) = 9.9, p < 0.001; Fig. 2b]. TBZ-treated animals showed significantly increased chow consumption compared to vehicle-control animals (planned comparisons, p < 0.01). Chow consumption was

Psychopharmacology

presses relative to vehicle control (planned comparison, p < 0.01). Planned comparisons also revealed that administration of 3.75 mg/kg CIT significantly decreased lever pressing compared to vehicle-treated rats (planned comparisons, p < 0.01). Co-administration of 0.375 and 0.75 mg/kg LDX with CIT and TBZ significantly increased lever pressing compared to the CIT plus TBZ condition (p < 0.01). However, 0.75 mg/kg LDX had no significant effect on responding when administered alone. The overall treatment effect for chow consumption was also statistically significant [F(7, 105) = 40.5, p < 0.001]. Chow intake was significantly increased by TBZ relative to vehicle (p < 0.01). Administration of 3.75 mg/kg CIT had no effect on the consumption of the concurrently available lab chow. Planned comparisons showed that chow intake was significantly reduced in CIT plus TBZ-treated rats by co-administration of 0.375 and 0.75 mg/kg LDX (p < 0.01). Administration of 0.75 mg/kg LDX alone did not affect chow consumption. Thus, the combination of TBZ and CIT produced a very robust suppression of lever pressing and an increase in chow intake; these effects were partially reversed by co-administration of LDX at the two highest dose. Experiment 4: ability of LDX to increase lever pressing output in rats performing on the PROG/chow choice task

Fig. 3 The effects of s-citalopram, tetrabenazine, and LDX, either alone or in combination, on FR5 lever pressing/chow feeding performance. Rats (n = 16) received three IP injections on drug test days, and there were eight total treatments (Veh/Veh/Veh, 0.75 mg/kg tetrabenazine (Tbz)/Veh/Veh, Veh/3.75 mg/kg IP s-citalopram (Cit)/Veh, Veh/Veh/ 0.75 mg/kg LDX, Tbz/Cit/Veh, and Tbz plus three different doses of (0.1875, 0.375 and 0.75 mg/kg LDX IP). a Mean (±SEM) number of lever presses (FR5 schedule) during the 30-min session. b Mean (±SEM) chow consumption (in grams) during the 30-min session. Brackets indicate significant planned comparisons (significant difference **p < 0.05)

significantly reduced by 15.0 mg/kg CIT plus TBZ compared to TBZ alone (p < 0.01). Experiment 3: ability of LDX to increase effort exertion in TBZ-CIT-treated rats performing on the FR5/chow choice task Administration of LDX substantially attenuated the effects of CIT in TBZ-treated rats (Fig. 3a, b). There was an overall significant effect of drug treatment on lever presses [F(7, 105) = 57.7, p < 0.001]. TBZ significantly lowered lever

The effects of LDX on PROG/chow feeding choice performance are shown in Fig. 4a–d. Repeated measures ANOVA revealed that there was a significant drug effects for all four variables: total lever presses [F(4,44) = 4.9, p < 0.005], highest ratio achieved [F(4,44) = 4.543, p < 0.005], active lever time [F(4,44) = 12.9, p < 0.001], and chow consumption [(F(4, 44) = 6.7, p < 0.001]. Planned comparisons demonstrated that 0.75 and 1.5 mg/kg LDX significantly increased total number of lever presses, highest ratio achieved, and active lever time relative to vehicle (p < 0.01). In addition, administration of these doses significantly reduced consumption of the concurrently available lab chow (planned comparisons, p < 0.01) compared to vehicle. Experiment 5: ability of LDX to attenuate IL-1β-induced shifts in choice behavior in rats performing on the FR5/chow choice task Repeated measures ANOVA demonstrated that there was an overall significant effect of drug treatment on lever presses [F(5,75) = 11.6, p < 0.001; Fig. 5a]. Planned comparisons showed that 4.0 μg/kg IL-1β decreased lever pressing compared to vehicle-control treated animals (p < 0.01). In addition, co-administration of three doses of LDX (0.09, 0.375, and 0.75 mg/kg) with IL-1β significantly increased lever pressing compared to IL-1β plus vehicle (planned comparisons, p < 0.05). There was also an overall significant effect of drug

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treatment on chow consumption [F(5,75) = 8.1, p < 0.001; Fig. 5b]. Administration of 4.0 μg/kg IL-1β increased consumption of the concurrently available lab chow compared to vehicle-treated animals (planned comparisons, p < 0.01). Similar to the effects seen on lever pressing, co-administration of 0.09, 0.375, and 0.75 mg/kg LDX significantly decreased chow consumption relative to IL-1β-treated animals (planned comparisons, p < 0.01). Thus, administration of LDX to IL1β-treated animals produced a partial reversal of the effects of this cytokine on lever pressing and chow consumption.

Discussion The present experiments were undertaken to characterize the effects of LDX on tests of effort-related choice behavior in rats. LDX is a pro-drug of d-amphetamine that enhances striatal DA efflux (Rowley et al. 2012) and is currently used for the treatment of ADHD (Najib 2009; Weisler et al. 2009). LDX is of particular interest because of evidence indicating that inhibition of DA reuptake by bupropion or stimulants may be relatively effective for treating psychomotor slowing, fatigue, and anergia observed in psychiatric patients (Stotz et al. 1999; Stahl 2002; Demyttenaere et al. 2005; Papakostas et al. 2006). More specifically, these studies were conducted to determine if LDX (a) could attenuate the shift in behavior associated with injections of TBZ or IL-1β on the concurrent FR5/chow choice task, (b) enhance lever pressing

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Fig. 4 The effects of LDX in rats (n = 13) performing on the concurrent PROG/chow feeding procedure. Rats received IP injections of vehicle (Veh), 0.1875, 0.375, 0.75, and 1.5 mg/kg doses of LDX. a Mean (+SEM) number of lever presses (PROG schedule) during the 30min session are shown. b Mean (+ SEM) highest ratio achieved. c Mean (+SEM) active lever time (i.e., time spent responding before timeout, in seconds). d Mean (+ SEM) chow consumption (in grams) during the 30-min session. Significantly different from tetrabenazine plus vehicle, **p < 0.05

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output in rats treated with the SERT inhibitor CIT plus TBZ, and (c) increase the tendency to work for food as measured by the PROG/chow choice procedure. The VMAT-2 inhibitor TBZ was used as a tool to alter effort-related choice behavior because this compound has been reported to induce depressive-like symptoms in humans (Chen et al. 2012; Frank 2009) and exert behavioral effects in classic rodent models of depression (Tadano et al. 2000; Wang et al. 2010). TBZ has been shown to alter effort-related choice behavior across multiple tasks; decreasing selection of the high effort option for highly valued reinforcers and increasing selection of the lower valued option that can be obtained through minimal work (Nunes et al. 2013b; Randall et al. 2014; Yohn et al. 2015a, b, c). These TBZ-induced shifts in behavior can be attenuated through co-administration of the adenosine A2A antagonist MSX-3, the catecholamine uptake inhibitor bupropion (BUP; Nunes et al. 2013b; Randall et al. 2014; Yohn et al. 2015a, c). and the DA transport (DAT) inhibitor GBR-12909 (Yohn et al. 2015c). In experiment 1, it was shown that LDX was able to reverse TBZ-induced shifts in behavior in rats performing on the concurrent FR5/ chow choice task. Administration of LDX to TBZ-treated rats largely restored the normal baseline pattern of responding, increasing lever pressing and decreasing chow intake in TBZ-treated rats. Thus, LDX produced a profile of behavioral effects comparable to those previously reported for bupropion (Nunes et al. 2013b) and GBR12909 (Yohn et al. 2015c). LDX is known to increase DA transmission (Rowley et al.

Psychopharmacology

Fig. 5 The effects of LDX on FR5 lever pressing/chow feeding performance induced by IL-1β. Rats (n = 16) received IP injections of vehicle plus vehicle (Veh + Veh), 4.0 μg/kg IL-1β plus vehicle (IL-1β + Veh), and 4.0 μg/kg IL-1β plus 0.09375, 0.1875, 0.375, and 0.75 mg/kg doses of LDX (L). a Mean (+SEM) number of lever presses (FR5 schedule) during the 30-min session. b Mean (+SEM) chow consumption (in grams) during the 30-min session. Tetrabenazine plus vehicle significantly differed from vehicle/vehicle, #p < 0.05; significantly different from tetrabenazine plus vehicle, **p < 0.05

2012). and based upon the well characterized role of DA in effort-related choice based upon physical effort costs (Salamone et al. 1994, 2002, 2007, 2012; Floresco et al. 2008; Mai et al. 2012; Salamone and Correa 2012; Hosking et al. 2015; Floresco 2015). it is reasonable to suggest that the behavioral effects of LDX observed in experiment 1 above are probably due to direct actions of LDX on DA neurotransmission. Recent studies indicate that inhibition of norepinephrine transport with desipramine does not reverse the effects of TBZ (Yohn et al. 2015c). Furthermore, the effects of TBZ on effortrelated choice were not reversed by the SERT inhibitors fluoxetine (Yohn et al. 2015c) or CIT (experiments 2–3; see discussion below). Nevertheless, future research should investigate the effort-related effects of additional monoamine

uptake inhibitors and should characterize the neural effects LDX in TBZ-treated animals by examining DA-related signal transduction activity using immunocytochemistry for phosphorylated DARRP-32, as well as extracellular DA, norepinephrine and 5-HT as measured by microdialysis (Nunes et al. 2013b; Randall et al. 2015). In contrast to the effects of LDX, the SERT inhibitor CIT failed to reverse the effects of TBZ (experiment 2) and in fact tended to lower lever pressing in TBZ-treated rats. These findings are consistent with recent research showing that the SERT inhibitor fluoxetine fails to reverse the effort-related effects of TBZ, and in fact can produce a further reduction in lever pressing in TBZ-treated rats (Yohn et al. 2015c). Moreover, several clinical reports have indicated that SERT inhibitors are relatively ineffective for treating motivational dysfunctions, and in fact can induce or exacerbate these symptoms (Nutt et al. 2007; Padala et al. 2012; Fava et al. 2014; Rothschild et al. 2014). Experiment 3 studied the effects of combined administration of LDX with TBZ plus CIT. Combined treatment with LDX/CIT/TBZ was associated with higher levels of lever pressing compared to TBZ alone and TBZ plus CIT. Thus, administration of 0.375 and 0.75 mg/kg LDX produced a partial reversal of the combined effects of TBZ and CIT on lever pressing. However, this effect was not as robust as the effect of LDX in the first experiment (i.e., in the presence of TBZ alone). Taken together, the results of these experiments indicate that inhibition of 5-HT uptake with CIT suppresses lever pressing and does not reverse the effects of TBZ, but in fact tends to make TBZ-treated rats respond at even lower levels. Moreover, although LDX increased responding in rats treated with TBZ and CIT, it appears that CIT also blunts the ability of LDX to reverse the effects of TBZ. The ability of LDX to increase lever pressing in animals treated with CIT is consistent with clinical data indicating that drugs that block DA transport may be beneficial as adjunct therapy to SSRI-induced fatigue (Green 1997). Furthermore, stimulant drugs that act to increase DA transmission produced significant short-term improvement of depressive symptoms, including fatigue (Candy et al. 2008). and methylphenidate was reported to improve apathy and fatigue symptoms in depressed patients (Ravindran et al. 2008). Experiment 4 studied the ability of acute IP injections of LDX to increase effort-related responding in rats tested on the concurrent PROG/chow feeding choice task. For this study, LDX was administered without TBZ. The PROG/chow feeding task is well suited for studying the ability of drugs to increase selection of high effort alternatives because the within-session increases in the work requirement (i.e., the progressive increase in the ratio requirement) make this a difficult task for animals to

Psychopharmacology

perform. Previous work has shown that administration of the adenosine A 2A antagonist MSX-3 (Randall et al. 2012) and the catecholamine uptake inhibitor bupropion (Randall et al. 2015) can shift effort-related choice, increasing PROG lever pressing while decreasing chow intake. A similar pattern of effects was shown by the DA uptake inhibitor MRZ-9547 (Sommer et al. 2014). In experiment 4, this pattern of effects was shown by LDX; this compound significantly increased all three markers of PROG lever pressing (number of lever presses, highest ratio achieved, total time responding) and decreased intake of the concurrently available chow (Fig. 4). The dose-response curve for lever pressing was linear in the dose range tested, with the maximum increase seen at 1.5 mg/kg LDX. Thus, LDX shifted effort-related choice behavior and increased selection of a high effort activity (PROG lever pressing) when administered alone. Pro-inflammatory cytokines have been implicated in depression, and administration of cytokines to humans has been shown to produce motivational effects such as fatigue and anergia (Miller 2009; Dantzer et al. 2012; Felger and Lotrich 2013). As in previous studies (Nunes et al. 2014). administration of 4.0 μg/kg IL-1β shifted effort-related choice behavior, decreasing lever pressing while producing a concomitant increase in consumption of the concurrently available lab chow. Results from experiment 5 showed that co-administration of LDX with IL-1β led to a partial reversal of the effects of the cytokine; rats treated with LDX plus IL-1β showed increased lever pressing and decreased chow intake relative to that seen with IL-1β alone. However, there was only a maximum of about a 50 % restoration of lever pressing at the two highest doses of LDX (0.375 and 0.75 mg/kg), which contrasts substantially with the nearly complete reversal seen in experiment 1 when LDX was co-administered with TBZ. This pattern of effects could have occurred because TBZ exerts its response-suppressing effects via depletion of DA (Nunes et al. 2013a). and LDX is able to easily reverse this effect because it inhibits DA uptake and increases DA release. In contrast, the precise mechanism through which IL-1β produces its effort-related effects is unknown, and it is likely that this action includes both DAergic as well as non-DAergic actions (Dantzer 2009; Dantzer et al. 2012; Felger and Miller 2012; Felger et al. 2015). Thus, LDX administered to IL-1βtreated animals was able to partially restore the baseline pattern of behavior. In summary, LDX appears to be similar to the catecholamine reuptake inhibitor bupropion in terms of its ability to attenuate the effort-related effects of TBZ. LDX produced a nearly complete reversal of the effects of TBZ in experiment 1, and also produced a partial restoration of the normal pattern of behavior when it was co-administered with TBZ plus CIT

(experiment 3) and IL-1 β (experiment 5). Furthermore, LDX induced a dose-related increase in selection of the high effort option (i.e., lever pressing on the PROG schedule) and a decrease in the selection of the low effort option (lab chow intake). Clearly, LDX appears to be more effective than SSRIs such as fluoxetine and CIT for increasing effort-related motivational performance in this model. This observation is consistent with human clinical reports indicating that SERT inhibitors are relatively poor at treating motivational symptoms such as fatigue and apathy, and may even produce fatigue as a side effect (Fava et al. 2014). Motivational dysfunctions are seen across many neurological and psychiatric disorders (Caligiuri et al. 2003; Demyttenaere et al. 2005; Salamone et al. 2007; Treadway and Zald 2011; Fava et al. 2014; Chong et al. 2015). and there may be common brain mechanisms involved across these disorders. One common feature may be the involvement of DA transmission in effort-related processes, which is seen in both preclinical and human research (Salamone et al. 2007, 2015; Wardle et al. 2011; Treadway et al. 2012; Chong et al. 2015). DA systems exert a bi-directional control over behavioral activation, energy expenditure, and work output. Decreases in DA transmission impair behavioral activation and effort-related aspects of motivated behavior (Salamone et al. 1991, 2003, 2007, 2012; Artaloytia et al. 2006; Kegeles et al. 2010). whereas increases in DA neurotransmission increase energy expenditure and work output in motivated behavior (Cagniard et al. 2006; Bardgett et al. 2009; Wardle et al. 2011; Beeler et al. 2012, 2015). Although there is no recognized gold-standard treatment for motivational dysfunctions, there is growing literature emphasizing the use of agents that facilitate DA neurotransmission (Becker et al. 2004; Candy et al. 2008; Kerr et al. 2012; Ravindran et al. 2008; Rosenberg et al. 2013; Sevy et al. 2005). The present results with LDX are consistent with clinical and preclinical data demonstrating that drugs such as methylphenidate, bupropion, and modafinil, which act to increase DA transmission, may be useful treat motivational dysfunctions (Becker et al. 2004; Bardgett et al. 2009; Lasser et al. 2013; Young 2013; Nunes et al. 2013a; Randall et al. 2014, 2015; Sommer et al. 2014; Tanno et al. 2014; Yohn et al. 2015a, b, c). Although inhibition of DAT also can lead to abuse liability, it is possible that slow release formulations could lessen this risk. Acknowledgments We wish to thank Emily Errante for her assistance. Compliance with ethical standards Funding and disclosure This research was supported by grants from NIH/NIMH, the University of Connecticut Research Foundation, and the Psychology Department Undergraduate Research Grant program. HC received an NSF Bridge to the Doctorate grant. JS has received grants from, and done consulting work for, Pfizer, Roche, Shire, and Prexa. PHH is an employee of Shire and holds stock and/or stock options in Shire. The authors have nothing to disclose in terms of competing interests.

Psychopharmacology

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