Effects of intra-accumbal administration of dopamine and ionotropic glutamate receptor drugs on delay discounting performance in rats.

Acknowledgement: Michael T. Bardo,
The data presented in the current manuscript were collected as part of Justin R. Yates’ doctoral dissertation. The research was funded by NIH Grants P50 DA05312 and T32 DA007304.

Understanding the neurobiological basis of impulsive choice is important for designing effective treatment options for those with disorders characterized by increased impulsivity, such as attention-deficit/hyperactivity disorder (ADHD) and substance use disorders. Dopamine (DA) has received considerable attention because drugs that are efficacious in treating ADHD exert their effects by increasing DA, as well as norepinephrine, levels (see Bidwell, McClernon, & Kollins, 2011 for a review). Preclinical models have shown that systemic administration of DA D1 receptor antagonists increase impulsive choice (Broos, Diergaarde, Schoffelmeer, Pattij, & De Vries, 2012; Koffarnus, Newman, Grundt, Rice, & Woods, 2011; van Gaalen, van Koten, Schoffelmeer, & Vanderschuren, 2006; but see Wade, de Wit, & Richards, 2000), although results following antagonism of D2 receptors have been mixed. A couple of studies reported increases in impulsive choice following antagonism of D2 receptors (Denk et al., 2005; Wade et al., 2000), but others found no alterations in discounting (Evenden & Ryan, 1996; Koffarnus et al., 2011; van Gaalen et al., 2006).

In addition to DA, recent evidence has implicated glutamate (Glu) dysfunction in impulse-control disorders, including ADHD (Jensen et al., 2009; Miller, Pomerleau, Huettl, Gerhardt, & Glaser, 2014; Perlov et al., 2007) and substance use disorders (Ben-Shahar et al., 2012; Griffin, Haun, Hazelbaker, Ramachandra, & Becker, 2014). Directly related to impulsive choice, blocking N-methyl-D-aspartate (NMDA) receptors with the uncompetitive antagonists memantine and ketamine increases delay discounting (Cottone et al., 2013; Floresco, Tse, & Ghods-Sharifi, 2008; but see Yates, Gunkel, Rogers, Hughes, & Prior, 2017), whereas the uncompetitive antagonist MK-801 decreases discounting (Higgins et al., 2016; Yates, Batten, Bardo, & Beckmann, 2015; but see Yates, Gunkel et al., 2017). Similar to MK-801, antagonists at NR2B-containing NMDA receptors decrease impulsive choice (Higgins et al., 2016; but see Yates, Gunkel et al., 2017).

Although there is evidence to support a role for DA and Glu in impulsive choice using systemic injections, few studies have examined the neuroanatomical regions that control the effects of DA on impulsive decision making. To date, research has shown that direct infusions of D1 receptor antagonists (Pardey, Kumar, Goodchild, & Cornish, 2013; Loos et al., 2010) and D2 receptor antagonists (Pardey et al., 2013; Yates et al., 2014) into medial prefrontal cortex (mPFC) increase impulsive choice. Although blocking D2 receptors in orbitofrontal cortex (OFC) does not typically alter impulsive choice (Pardey et al., 2013; Yates et al., 2014), Zeeb, Floresco, and Winstanley, 2010 found that a D2 receptor antagonist increased impulsive choice, but only when the delay to the delivery of the large reinforcer was signaled, suggesting that environmental cues can moderate the effects of DA receptor ligands on impulsivity. To our knowledge, the effects of direct infusions of Glu receptor drugs on impulsive choice have not been examined.

One important neural mediator of impulsive choice, specifically delay discounting, is the nucleus accumbens core (NAcc). Lesions to NAcc increase preference for a small, immediate reinforcer relative to a larger, delayed reinforcer (Bezzina et al., 2007; Cardinal, Pennicott, Sugathapala, Robbins, & Everitt, 2001; da Costa Araújo et al., 2009; Galtress & Kirkpatrick, 2010; Pothuizen, Jongen-Rêlo, Feldon, & Yee, 2005; Valencia-Torres et al., 2012; but see Winstanley, Theobald, Dalley, & Robbins, 2005), although inactivation with GABA receptor agonists has been reported to either increase (Feja, Hayn, & Koch, 2014) or decrease (Moschak & Mitchell, 2014) impulsive choice. There is some evidence that NAcc DA plays an important role in impulsive choice, as overexpression of the DA transporter (DAT) leads to increased impulsivity (Adriani et al., 2009). Additionally, Winstanley et al. (2005) argue that DA and serotonin (5-HT) interactions within NAcc contribute to impulsive choice, as the increased impulsivity following 8-OH-DPAT (5-HT1A agonist) administration is not observed in DA-depleted rats. Despite the evidence for a role of NAcc in discounting, the specific contribution of DA or Glu receptors within this region is largely unknown.

The goal of the present study was to determine the contribution of NAcc DA and Glu receptors to delay discounting. Because sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude independently influence discounting of a reinforcer (Ho, Mobini, Chiang, Bradshaw, & Szabadi, 1999), we applied quantitative analyses (e.g., exponential discounting function) to determine if DA receptors and Glu receptors within NAcc differentially alter these parameters. Quantitative analyses have been used previously to determine the effects of excitotoxic lesions (Bezzina et al., 2007, 2008, 2009; da Costa Araújo et al., 2009; Kheramin et al., 2002; Valencia-Torres et al., 2012) and pharmacological manipulations (Yates et al., 2015; Yates, Gunkel et al., 2017, Yates, Rogers et al., 2017) on delay discounting. By applying quantitative analyses in the current study, we sought to determine the precise mechanisms by which NAcc DA or Glu receptors mediate discounting.

A total of 24 male, individually housed Sprague–Dawley rats (Harlan Industries; Indianapolis, IN) were used in the experiments. Rats weighed approximately 250–275g (approximately postnatal Day 60) upon arrival to the laboratory. Rats were acclimated to a colony room held at a constant temperature and were handled for 5 days upon arrival. Light and dark phases were on a 12-hr light–dark cycle, and each experiment occurred during the light phase. Rats were food restricted (approximately 80% of free feed body weight) 3 days before the beginning of behavioral training, and rats remained on food restriction during the remainder of the study, unless otherwise noted. Rats were cared for in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011), and procedures were approved by the Institutional Animal Care and Use Committee at the University of Kentucky.

The following were purchased from Sigma Aldrich (St. Louis, MO): (±)-SKF-38393 hydrochloride, (±)-SCH-23390 hydrochloride, (-)-quinpirole hydrochloride, S-(-)-eticlopride hydrochloride, (+)-MK-801 hydrogen maleate, D(-)-2-amino-5-phosphonopentanoic acid (AP-5), and 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt hydrate (CNQX). Ifenprodil hemitartrate was purchased from Tocris Bioscience (Ellisville, MO). Each drug was prepared in sterile 0.9% NaCl (saline), except for ifenprodil, which was prepared in sterile water. Concentrations were calculated based on salt weight.

Operant conditioning chambers (28 × 21 × 21 cm; ENV-008; MED Associates, St. Albans, VT) located inside sound-attenuating chambers (ENV-018M; MED Associates) were used. The front and back walls of the experimental chambers were made of aluminum, while the side walls were made of Plexiglas. There was a recessed food tray (5 × 4.2 cm) located 2 cm above the floor in the bottom-center of the front wall. An infrared photobeam was used to record head entries into the food tray. A 28-V white cue light was located 6 cm above each response lever. A white house light was mounted in the center of the back wall of the chamber. All responses and scheduled consequences were recorded and controlled by a computer interface. A computer controlled the experimental session using Med-IV software.

Rats were given 2 days of magazine training, in which sucrose-based 45 mg pellets (F0021 dustless precision pellet, Bio-Serve, Frenchtown, NJ) were noncontingently delivered into the food tray. These sessions were used to habituate rats to the operant chamber. Following magazine training, rats were given lever press training. Each session began with illumination of the house light. A head entry into the food hopper resulted in presentation of one lever. Levers were presented semirandomly, with no more than two consecutive presentations of the same lever. A response on either lever resulted in delivery of one sucrose pellet. Pellets were also delivered noncontingently on a random time 100-s schedule of reinforcement. Following a response on either lever, the house light was extinguished, and the lever was retracted for 5 s. After 5 s, the house light was illuminated. Each session lasted 30 min or following completion of 40 trials, whichever occurred first.

After three sessions, rats received reward magnitude discrimination training, which consisted of 40 trials each day. Each trial lasted 40 s and began with illumination of the house light. A head entry into the food hopper extended one of the levers (semirandomly presented, with no more than two consecutive presentations of the same lever). A response on one lever resulted in immediate delivery of one pellet, whereas a response on the other lever resulted in immediate delivery of four pellets (the lever associated with the large reward magnitude was counterbalanced across rats). Following a response, the house light was extinguished, and the lever was retracted for the remainder of the trial. If a response was not made within 10 s, the trial was scored as an omission, and the house light was extinguished for the remainder of the trial. After 7 days of reward magnitude discrimination training, rats were trained in delay discounting sessions.

Delay discounting sessions consisted of five blocks of nine trials, and each trial lasted 60 s. The first four trials in a block were forced-choice trials, in which only one lever was semirandomly presented (no more than two consecutive presentations of the same lever). The last five trials were free-choice trials, in which both levers were extended. As in reward magnitude discrimination training, a response on one lever always resulted in immediate delivery of one food pellet. A response on the other lever resulted in delivery of four pellets; however, the delay to the delivery of the large magnitude reward increased across blocks of trials (0, 5, 10, 20, 50 s). Following a response on either lever, the house light was extinguished, and the lever was retracted for the remainder of the trial. If a response was not made within 10 s, the trial was scored as an omission, and the house light was extinguished for the remainder of the trial.

After 32 sessions of delay discounting, rats were treated with the nonopioid analgesic carprofen (5 mg/kg, s.c.) 1 day prior to and on the day of surgery. Rats were anesthetized with a mixture of ketamine, xylazine, and acepromazine (75, 7.5, and 0.75 mg/kg, i.p., respectively) and were secured into a stereotaxic frame. Cannulas were implanted bilaterally into NAcc (+1.6 AP, ±1.5 ML, −5.5 DV) at the 10° angle off the midline (Paxinos & Watson, 1998). Following surgery, rats were treated with carprofen for 2 days.

Rats recovered for 3–5 days and were food restricted before receiving 12 additional training sessions in the delay-discounting task. This additional training was important to ensure that surgery did not alter discounting. For intracranial infusions, rats were gently restrained by the experimenter, and a stainless steel injection cannula (33 gauge; Small Parts, Inc, Miramar, FL) was inserted 2 mm below the tip of the guide cannulas. Each cannula was connected to a 10 μl syringe (Hamilton, Reno, NV) via PE10 tubing (Small Parts, Inc, Miramar, FL). The Hamilton syringes were mounted on an infusion pump (KDS Scientific, Holliston, MA). Half of the rats (n = 12) received direct infusions of SKF 38393 (D1-like agonist; 0.03, 0.1 μg; Loos et al., 2010; Yates et al., 2014), SCH 23390 (D1-like antagonist; 0.3, 1.0 μg; Loos et al., 2010; Yates et al., 2014; Zeeb et al., 2010), quinpirole (D2-like agonist; 0.3, 1.0 μg; Yates et al., 2014), and eticlopride (D2-like antagonist; 0.3, 1.0 μg; Yates et al., 2014; Zeeb et al., 2010); saline was used as the vehicle for each drug. The other half of the rats (n = 12) received direct infusions of MK-801 (uncompetitive NMDA antagonist; 0.3, 1.0 μg; Bakshi & Geyer, 1998; Zhang, Bast, & Feldon, 2000), AP-5 (competitive NMDA antagonist; 0.3, 1.0 μg; Baldwin, Holahan, Sadeghian, & Kelley, 2000; Dar, 2002; Sombers, Beyene, Carelli, & Wightman, 2009), ifenprodil (antagonist at NR2B-containing NMDA receptors; 0.3, 1.0 μg; Parkes & Balleine, 2013; Laurent & Westbrook, 2008), and CNQX (AMPA antagonist; 0.2 and 0.5 μg; Hitchcott & Phillips, 1997; Mesches, Bianchin, & McGaugh, 1996); saline was used as the vehicle for MK-801, AP-5, and CNQX, whereas sterile water was used as the vehicle for ifenprodil. In total, rats received either nine (DA experiment) or 10 (Glu experiment) infusions (see Tables 1 and 2). Each drug was infused over 2 min at a rate of 0.25 μl/min. Injectors were left in place for 1 min following the infusion. Rats were placed into the operant chamber immediately following the infusion. Treatments were randomly administered for each rat, and rats were given 2 days of washout (no drug microinfusion) following each infusion; on these washout days, rats were tested in delay discounting.

Following the last day of infusions, rats were euthanized, and brains were removed and flash-frozen in chromasolv (Sigma, St. Louis, MO) on dry ice and stored at −80 °C until sectioning was completed. Brain sections (40 μm) were sliced to determine the location of guide cannulas. Probe placements were evaluated according to the atlas of Paxinos and Watson (1998). Only data from rats with correct probe placements in NAcc were used in all statistical analyses.

For baseline data (averaged across final four sessions before surgery and averaged across final four sessions before first infusion), two analyses were used to determine if discounting differed across rats assigned to receive DA or Glu infusions, as well as to determine if surgery had an effect on discounting. First, a mixed factor ANOVA was used, with experiment (DA vs. Glu) as a between-subjects factor and surgery (Pre vs. Post) and delay as within-subjects factors. To probe a significant interaction, separate independent-samples t tests (with Bonferroni correction) were used. Because ANOVAs do not specify how sensitivity to reinforcer magnitude and/or sensitivity to delayed reinforcement have been altered, the exponential discounting function was fit to each subject’s data via nonlinear mixed effects modeling (NLME; Pinheiro, Bates, DebRoy, Sarkar, & R Core Team, 2017). The exponential equation was defined as V = Ae−bD, where V is the subjective value of the reinforcer, A is sensitivity to reinforcer magnitude (the intercept of the function), b represents sensitivity to delayed reinforcement (the slope of the function), and D is the delay to the larger magnitude reinforcer. The NLME model defined A and b as free parameters, surgery as a nominal, within-subjects factor, and delay as a continuous, within-subjects factor. A main effect was probed using contrasts in R.

To determine if intracranial infusions significantly altered omissions, separate Friedman tests were conducted for each drug, and Wilcoxon’s signed-ranked tests (with Bonferroni correction) were used to probe significant main effects, when appropriate. To determine if intracranial infusions of each drug altered discounting, two analyses were used. First, two-way repeated measures ANOVAs were used, with delay and drug concentration as within-subjects factors. Dunnet’s post hoc tests were used to probe a main effect of drug concentration. If there was a significant interaction, separate paired-samples t tests (with Bonferroni correction) were used. Second, separate NLME analyses for each drug were conducted, which defined A and b as free parameters, delay as a continuous, within-subjects factor, drug concentration as a nominal, within-subjects factor, and subject as a random factor. Main effects and interactions were probed using contrasts in R.

To determine if A and b parameter estimates changed across each baseline period (averaged across the two sessions between infusions, as well as across the two sessions before the first infusion and the two sessions following the final infusion), linear trend analyses were conducted for each parameter.

Statistical significance was defined as p < .05 in all cases, with the exception of the Wilcoxon’s signed-ranked tests and independent/paired-samples t tests, in which a Bonferroni correction was applied to control for Type I error. For all ANOVA analyses, degrees of freedom were corrected using Greenhouse-Geisser corrections when sphericity was violated. Additionally, partial eta squared (ηp2) was provided as a measure of effect size, with values of 0.01, 0.06, and 0.14 indicating small, medium, and large effect sizes, respectively (Cohen, 1988).

Figure 1 shows probe placements for rats given DA-selective ligands (Figure 1a) and Glu-selective ligands (Figure 1b). Four rats in the Glu experiment and six rats in the DA experiment had probe placements outside of NAcc, and were thus excluded from further analyses.

For baseline data, results of the ANOVA revealed a significant main effect of delay, F(2.088, 25.053) = 36.612, p < .001, ηp2 = .753. There were no other significant main effects or interactions, Fs ≤ 1.107, ps ≥ .364, ηp2s ≤ .084. Results of the NLME analysis showed that sensitivity to reinforcer magnitude and sensitivity to delayed reinforcement did not differ across rats assigned to receive DA or Glu infusions, and the analyses showed that surgery did not alter either parameter, Fs ≤ 3.611, ps ≥ .060 (data not shown).

Administration of AP-5 increased omissions, χ2(2) = 8.000, p = .018, although post hoc tests did not reveal a significant difference between vehicle and any concentration of AP-5. It is important to note that each rat had no omissions following vehicle treatment and that one rat had more than one omission following AP-5 administration only. None of the other intracranial infusions significantly altered the number of omissions, χ2s ≤ 5.158, ps ≥ .076 (see Table 3).

Figure 2 shows the raw proportion of responses for the large delayed reinforcer following direct infusions of SKF 38393 (Figure 2a), SCH 23390 (Figure 2b), quinpirole (Figure 2c), and eticlopride (Figure 2d). As expected, the main effect of delay was significant for each analysis, Fs ≥ 14.524, ps < .001, ηp2s ≥ .744. None of the DA-selective ligands significantly altered responding for the large magnitude reinforcer, Fs ≤ 1.970, ps ≥ .190, ηp2s ≤ .283.

Figure 3 shows the A and b parameter estimates derived from the exponential model for the DA-selective drugs, and Table 1 shows the percentage change in each parameter relative to vehicle. Although stimulating DA D1 receptors with SKF 38393 did not alter sensitivity to reinforcer magnitude, F(2, 79) = 0.136, p = .873 (Figure 3a), or sensitivity to delayed reinforcement, F(2, 79) = .248, p = .781 (Figure 3a), blocking these receptors with SCH 23390 (0.3 μg) significantly decreased sensitivity to reinforcer magnitude, F(2, 79) = 3.431, p = .037 (Figure 3b), without altering sensitivity to delayed reinforcement, F(2, 79) = 1.586, p = .211 (Figure 3b). Administration of DA D2 receptor ligands did not alter either parameter: quinpirole, F(2, 79) = 0.428, p = .653; F(2, 79) = 0.693, p = .503 (Figure 3c); eticlopride: F(2, 79) = 0.175, p = .840; F(2, 79) = 0.658, p = .521 (Figure 3d).

Figure 4 shows the raw proportion of responses for the large delayed reinforcer following direct infusions of MK-801 (Figure 4a), AP-5 (Figure 4b), ifenprodil (Figure 4c), and CNQX (Figure 4d). Similar to the results obtained with the DA-selective ligands, the main effect of delay was significant for each Glu drug tested, Fs ≥ 18.506, ps < .001, ηp2s ≥ .726, but none of the Glu-selective ligands altered responses for the large magnitude reinforcer, Fs ≤ 3.325, ps ≥ .066, ηp2s ≤ .322.

Figure 5 shows the A and b parameter estimates derived from the exponential model for the Glu-selective drugs, and Table 2 shows the percentage change in each parameter relative to vehicle. MK-801 did not alter sensitivity to reinforcer magnitude, F(2, 107) = 0.970, p = .383 (Figure 5a), or sensitivity to delayed reinforcement, F(2, 107) = 2.121, p = .125 (Figure 5a). Similarly, AP-5 did not alter either parameter, F(2, 107) = 0.881, p = .417 and F(2, 107) = 0.931, p = .398, respectively (Figure 5b). When examining the effects of ifenprodil on sensitivity to delayed reinforcement, there was a main effect of dose, F(2, 107) = 3.160, p = .046 (Figure 5c), whereas no differences in sensitivity to reinforcer magnitude emerged, F(2, 107) = 0.252, p = .778 (Figure 5c). Although a main effect of ifenprodil was observed for sensitivity to delayed reinforcement, differences between vehicle and ifenprodil (1.0 μg) only trended toward significance (p = .057). The main effect was due primarily to differences between the two ifenprodil concentrations (p = .035). A closer examination of the ifenprodil results revealed that one rat had a b parameter estimate that was approximately 143% larger relative to the average b parameter estimate, resulting in large variation in b parameter estimates following vehicle infusion. A supplementary analysis was conducted after excluding this rat, and results showed a significant effect of ifenprodil on sensitivity to delayed reinforcement, F(2, 93) = 3.337, p = .040); ifenprodil (1.0 μg) significantly decreased b parameter estimates relative to vehicle (p = .039). CNQX did not alter sensitivity to reinforcer magnitude, F(2, 107) = 0.521, p = .595, or impulsive choice, F(2, 107) = .506, p = .604 (Figure 5d).

Figure 6 shows A (Figure 6a) and b (Figure 6b) parameter estimates across each baseline session for rats treated with DA drugs and for rats treated with Glu drugs. A parameter estimates did not change across the experiment for either group of rats, DA: F(1, 58) = .467, p = .497; Glu: F(1, 86) = 3.018, p = .086. Similarly, b parameter estimates did not change across the session, DA: F(1, 58) = .401, p = .529; Glu: F(1, 86) = .002, p = .965.

The goal of the current study was to determine how accumbal DA receptors and ionotropic glutamate receptors, primarily the NMDA receptor subtype, mediate two distinct features of delay discounting: (a) sensitivity to reinforcer magnitude (A parameter); and (b) sensitivity to delayed reinforcement (b parameter). Results showed that SCH-23390 (0.3 μg) decreased sensitivity to a large magnitude reinforcer, whereas ifenprodil (1.0 μg) decreased sensitivity to delayed reinforcement. These results show that DA and Glu receptors within NAcc differentially mediate two dissociable aspects of discounting performance.

DA D1 and D2 receptors are widely expressed in NAcc (Dubois, Savasta, Curet, & Scatton, 1986; Savasta, Dubois, & Scatton, 1986). In the current study, SCH 23390 (0.3 μg) decreased the A parameter without altering the b parameter, thus suggesting a specific role of DA D1 receptors in sensitivity to reinforcer magnitude. This result is consistent with previous work showing that SCH 23390 decreases food reward (Beninger et al., 1987; Sharf, Lee, & Ranaldi, 2005). Previous research has indicated that systemic administration (Broos et al., 2012; Koffarnus et al., 2011; van Gaalen et al., 2006; but see Wade et al., 2000), as well as intramPFC infusions (Loos et al., 2010; but see Yates et al., 2014), of D1 receptor antagonists increases impulsive choice. However, since these previous studies did not determine the effects of D1 receptor blockade on sensitivity to reinforcer magnitude/delayed reinforcement, those results did not address the possibility that D1 receptors are more important for mediating sensitivity to reinforcer amount, as opposed to impulsive choice per se. This is an important distinction because there is some support for the argument that DA signaling in NAcc can be altered by different magnitudes of reinforcement. Specifically, Gan, Walton, and Phillips (2010) observed an increase in dopamine release when they increased the size of the reinforcer. The current results are consistent with this finding, as blocking D1 signaling shifted preference away from the large magnitude reinforcer, even when its delivery was immediate.

An unexpected finding from this study is that the lower concentration of SCH 23390 (0.3 μg) decreased sensitivity to reinforcer magnitude, whereas the higher concentration (1.0 μg) did not. One possible explanation for this finding is that SCH 23390 may have lost its selectivity for D1 antagonism at the higher concentration. For example, in addition to blocking D1 receptors, SCH 23390 inhibits the 5-HT transporter (SERT; Zarrindast, Honardar, Sanea, & Owji, 2011) and acts as an agonist at the 5-HT2C receptor (Ramos, Goñi-Allo, & Aguirre, 2005). Since 5-HT2C receptors are located in the NAcc (Adlersberg et al., 2000) and 5-HT signaling is known to play a role in delay discounting (Miyazaki, Miyazaki, & Doya, 2012; see Homberg, 2012 for a review), the interactive effect of SCH 23390 on both DA and 5-HT systems may explain the apparent biphasic concentration-effect curve observed here.

Regarding the lack of effect of D2 antagonism on discounting in the current study, one important consideration is that D2 receptor antagonists can be mediated by cues that signal the delay to reinforcement. Specifically, Zeeb et al. (2010) reported that a D2 receptor antagonist increased impulsive choice, but only when the delay to delivery of the large magnitude reinforcer was signaled by a stimulus light. One could argue that the null effects observed with eticlopride in the current study may have occurred because we did not signal the delay to delivery of the large reinforcer. However, this seems unlikely, as other research has shown that intracranial infusions of a D2 receptor antagonist into mPFC increases impulsive choice, even though the delay to reinforcement was not directly signaled (Yates et al., 2014). Overall, the current results, in conjunction with past research, suggest that dopaminergic activity in distinct brain regions differentially mediate discounting performance, as D2 receptors in frontal cortical areas may be more important for controlling sensitivity to delayed reinforcement, whereas D1 receptors in NAcc may be more important for controlling sensitivity to reinforcer magnitude.

Whereas blocking D1 receptors decreased sensitivity to reinforcer magnitude, ifenprodil (1.0 μg), which blocks NR2B-containing NMDA receptors, decreased sensitivity to delayed reinforcement. Caution needs to be taken because differences between the highest dose (1.0 μg) of ifenprodil and vehicle only approached statistical significance when all rats were included in the analyses. However, one rat had a b parameter estimate that was 143% higher than the average value following vehicle treatment; additionally, this rat responded for the large reinforcer 60% of the time, even when its delivery was immediate. When this rat was excluded from data analyses, results showed that ifenprodil (1.0 μg) significantly decreased sensitivity to delayed reinforcement. This result is consistent with a previous report showing that Ro 63–1908, a highly selective antagonist for NR2B-containing NMDA receptors, decreases impulsive choice (Higgins et al., 2016). Although the NR2B subunit is not widely expressed in NAcc (Wenzel et al., 1995), administration of neither the uncompetitive NMDA receptor antagonist MK-801 or the competitive antagonist AP-5 altered discounting performance; thus, the current results provide some evidence that the NR2B subunit of the NMDA receptor in NAcc plays a critical role in impulsive choice.

The finding that ifenprodil decreased sensitivity to delayed reinforcement is somewhat at odds with previous work from our laboratory showing that systemic administration of ifenprodil decreases sensitivity to reinforcer magnitude without altering impulsive choice (Yates, Gunkel et al., 2017). However, because ifenprodil binds to other receptors, particularly α1 adrenergic receptors (Chenard et al., 1991), the decreased sensitivity to reinforcer magnitude observed by Yates, Gunkel et al. (2017) could be due to ifenprodil’s actions on adrenergic receptors outside of NAcc. Future work is needed to determine if adrenergic receptors within NAcc differentially mediate sensitivity to reinforcer magnitude/delayed reinforcement, as well as to test the effects of NAcc infusions of highly selective NR2B antagonists, such as Ro 63–1908 or CP-101,606, on discounting.

Although systemic administration of MK-801 has been shown to decrease impulsive choice (Higgins et al., 2016; Yates et al., 2015; but see Yates, Gunkel et al., 2017), NAcc infusions did not significantly alter discounting in our study. This suggests that MK 801-induced alterations in delay discounting are mediated by NMDA receptors outside of NAcc. In addition, since MK-801 increases DA levels in prefrontal cortex (Tsukada et al., 2005), and DA receptor agonists decrease impulsive choice (e.g., Koffarnus et al., 2011), the results obtained by Higgins et al. (2016) and Yates et al. (2015) could be due to the increase in DA in this region as opposed to blocking Glu transmission.

Similar to previous studies (Yates, Gunkel et al., 2017; Yates, Rogers et al., 2017), we showed that the type of analysis used (ANOVA vs. NLME) alters interpretation of the current results. Overall, ANOVA results failed to detect significant differences in discounting following intracranial infusions. However, fitting the exponential discounting function to each subject’s data via NLME allowed us to detect a decrease in sensitivity to reinforcer magnitude following SCH 23390 administration and a decrease in sensitivity to delayed reinforcement (i.e., decreased impulsive choice) following ifenprodil administration. By using the exponential discounting function, we were able to dissociate how receptors within NAcc mediate task performance. In most studies assessing how pharmacological manipulations alter discounting performance, the raw proportion of responses for the large magnitude reinforcer are typically analyzed with ANOVAs (Baarendse & Vanderschuren, 2012; Cardinal, Robbins, & Everitt, 2000; Floresco et al., 2008; Koffarnus et al., 2011; Sukhotina et al., 2008; van Gaalen et al., 2006; Winstanley et al., 2005). Significant effects or interactions are interpreted to reflect either increases or decreases in impulsive choice. However, these interpretations are not always accurate. For example, Yates, Gunkel et al. (2017) recently analyzed the effects of several glutamatergic drugs on delay discounting using ANOVAs and NLME. When ANOVAs were used, the results indicated that ketamine, memantine, and ifenprodil increased impulsive choice; however, NLME analyses indicated that sensitivity to reinforcer magnitude decreased, but not impulsive choice. Future studies should consider how intracranial infusions alter different parameters that may influence an animal’s performance in decision-making procedures.

One procedural limitation to the current study is related to the number of repeated intracranial infusions into the NAcc. Each rat received either nine (DA experiment) or 10 (Glu experiment) infusions. To control for any possible order effects, we counterbalanced the order in which infusions were administered. Because of the small sample sizes (DA experiment: n = 6; Glu experiment: n = 8), we could not conduct statistical analyses to determine if drug infusion order altered the effects of each ligand on discounting, although visual inspection of Tables 1 and 2 did not reveal systematic changes in each parameter estimate as a function of infusion order. Instead, we determined if rats became more sensitive to delayed reinforcement and/or reinforcer magnitude by comparing b and A parameter estimates across each baseline (i.e., the two sessions before each infusion, as well as the two sessions following the final infusion). This analysis showed that neither sensitivity to delayed reinforcement or sensitivity to reinforcer magnitude changed across the experiment. Thus, the alterations in behavior observed following SCH 23390 or ifenprodil administration are not likely to be the result of damage to NAcc.

Another limitation is the use of a discounting procedure in which delays were only increased across the session. Previous research has shown that the order in which delays are presented can modulate drug effects in discounting procedures (Maguire, Henson, & France, 2014; Tanno, Maguire, Henson, & France, 2014; Yates, Rogers et al., 2017). Related to the current results, one could argue that the effects of ifenprodil on discounting may reflect perseverative responding on the lever associated with the large magnitude reinforcer instead of a decrease in impulsive choice. Because we did not include a separate group of rats that were tested on a discounting procedure in which the delays decreased across the session, we cannot rule out this possibility. In a probability discounting procedure, Yates et al. (2016) found that systemic administration of ifenprodil decreased risk-taking behavior when the probabilities of obtaining the large reinforcer increased across the session, but had no effect on behavior when the probabilities decreased across blocks of trials.

Despite these limitations, the results of this study show an apparent dissociation in the role of NAcc DA and Glu receptors on delay discounting. Whereas DA D1 receptors appear to mediate sensitivity to reinforcer magnitude, blocking NR2B-containing NMDA receptors decreases sensitivity to delayed reinforcement (i.e., impulsive choice). Overall, these results provide additional evidence for the utility in applying quantitative analyses to discounting data.

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Submitted: May 17, 2017 Revised: July 6, 2017 Accepted: July 17, 2017