Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: Behav Neurosci. 2017 Oct;131(5):392–405. doi: 10.1037/bne0000214

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

Justin R Yates 1, Michael T Bardo 1
PMCID: PMC5679283  NIHMSID: NIHMS896691  PMID: 28956947

Abstract

Nucleus accumbens core (NAcc) has been implicated in impulsive choice, as measured in delay discounting. The role of dopamine (DA) in impulsive choice has received considerable attention, whereas glutamate (Glu) has recently been shown to be an important mediator of discounting. However, research has not examined how DA or Glu receptors in NAcc mediate different aspects of delay discounting performance, i.e., (1) sensitivity to reinforcer magnitude and (2) sensitivity to delayed reinforcement. Adult male Sprague Dawley rats were first trained in a delay discounting task, in which the delay to a large magnitude food reinforcer increased across blocks of trials. Following behavioral training, rats received bilateral implantation of guide cannulae into NAcc. Half of the rats (n = 12) received infusions of the DA-selective ligands SKF 38393 (D1-like agonist: 0.03 or 0.1 μg), SCH 23390 (D1-like antagonist: 0.3 or 1.0 μg), quinpirole (D2-like agonist: 0.3 or 1.0 μg), and eticlopride (D2-like antagonist: 0.3 or 1.0 μg). The other half received infusions of the ionotropic Glu ligands MK-801 (NMDA uncompetitive antagonist: 0.3 or 1.0 μg), AP-5 (NMDA competitive antagonist: 0.3 or 1.0 μg), ifenprodil (noncompetitive antagonist at NR2B-containing NMDA receptors: 0.3 or 1.0 μg), and CNQX (AMPA competitive antagonist: 0.2 or 0.5 μg). Results showed that SCH 23390 (0.3 μg) decreased sensitivity to reinforcer magnitude without altering impulsive choice, whereas ifenprodil (1.0 μg) decreased sensitivity to delayed reinforcement (i.e., impulsive choice). The current results show that DA and NMDA receptors in NAcc mediate distinct aspects of discounting performance.

Keywords: Impulsive choice, Sensitivity to delayed reinforcement, Sensitivity to reinforcer magnitude, Nucleus accumbens, Dopamine, Glutamate

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; Koffanus 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, Huetti, 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, 2017a), whereas the uncompetitive antagonist MK-801 decreases discounting (Higgins et al., 2016; Yates, Batten, Bardo, & Beckmann, 2015; but see Yates et al., 2017a). Similar to MK-801, antagonists at NR2B-containing NMDA receptors decrease impulsive choice (Higgins et al., 2016; but see Yates et al., 2017a).

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; Pothuzien, Jongen-Relo, 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, 2017a, 2017b) 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.

Method

Subjects

A total of 24 male, individually-housed Sprague Dawley rats (Harlan Industries; Indianapolis, IN) were used in the experiments. Rats weighed approximately 250–275 g (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 12:12 h 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.

Drugs

(±)-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) were purchased from Sigma Aldrich (St. Louis, MO). 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.

Behavioral Apparatus

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 x 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.

Procedure

Rats were given 2 days of magazine training, in which sucrose-based 45 mg pellets (F0021 dustless precision pellet, Bio-Serve, Frenchtown, NJ) were non-contingently 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 semi-randomly, 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 non-contingently 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 (semi-randomly 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 semi-randomly 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.

Surgery

After 32 sessions of delay discounting, rats were treated with the non-opioid 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. Cannulae 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.

Intracranial Infusions

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 cannulae. 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, & Wrightman, 2009), ifenprodil (antagonist at NR2B-containing NMDA receptors; 0.3, 1.0 μg; Parkes & Balleine, 2013; Laurent & Westbook, 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.

Table 1.

Microinfusion Schedule for Each Subject in the DA Experiment and Percentage Change for Each Discounting Parameter Estimate

Percentage Change in A Parameter Estimates
Infusion Order 426 427 430 431 440 444
1 SCH 1.0 (12.005) Quin 0.3 (−2.393) Etic 0.3 (−0.572) Quin 1.0 (−14.962) SCH 1.0 (−18.243) Etic 0.3 (0.1)
2 SCH 0.3 (26.897) Quin 1.0 (15.622) Saline Quin 0.3 (−23.456) SCH 0.3 (−9.556) Etic 1.0 (3.600)
3 Saline Etic 1.0 (17.029) Etic 1.0 (−2.193) SCH 0.3 (−43.503) SKF 0.03 (−14.590) Quin 0.3 (0.100)
4 Quin 1.0 (−8.399) Etic 0.3 (−3.194) Quin 0.3 (4.957) Saline SKF 0.1 (−9.044) Saline
5 Quin 0.3 (19.708) Saline Quin 1.0 (−4.194) SCH 1.0 (−20.612) Saline Quin 1.0 (−16.850)
6 Etic 1.0 (13.032) SKF 0.03 (−1.819) SCH 1.0 (−1.239) SKF 0.03 (6.403) Etic 1.0 (−19.138) SCH 1.0 (−18.240)
7 Etic 0.3 (8.639) SKF 0.1 (13.457) SCH 0.3 (−4.671) SKF 0.1 (3.296) Etic 0.3 (−16.246) SCH 0.3 (−40.000)
8 SKF 0.1 (4.040) SCH 1.0 (13.565) SKF 0.1 (11.723) Etic 1.0 (3.296) Quin 0.3 (−12.969) SKF 0.1 (−19.790)
9 SKF 0.03 (28.951) SCH 0.3 (−11.443) SKF 0.03 (3.432) Etic 0.3 (−24.651) Quin 1.0 (−21.254) SKF 0.03 (3.6)
Percentage Change in b Parameter Estimates
Infusion Order 426 427 430 431 440 444
1 SCH 1.0 (−80.106) Quin 0.3 (−84.004) Etic 0.3 (139.276) Quin 1.0 (−44.956) SCH 1.0 (85.009) Etic 0.3 (−44.076)
2 SCH 0.3 (−23.287) Quin 1.0 (−56.663) Saline Quin 0.3 (−32.125) SCH 0.3 (31.567) Etic 1.0 (−71.155)
3 Saline Etic 1.0 (−63.592) Etic 1.0 (231.030) SCH 0.3 (389.422) SKF 0.03 (−41.823) Quin 0.3 (−44.076)
4 Quin 1.0 (−68.600) Etic 0.3 (−47.843) Quin 0.3 (14.156) Saline SKF 0.1 (53.629) Saline
5 Quin 0.3 (22.906) Saline Quin 1.0 (398.093) SCH 1.0 (7.052) Saline Quin 1.0 (−71.921)
6 Etic 1.0 (−39.221) SKF 0.03 (−26.674) SCH 1.0 (312.536) SKF 0.03 (−46.024) Etic 1.0 (−41.772) SCH 1.0 (−67.522)
7 Etic 0.3 (−33.949) SKF 0.1 (26.291) SCH 0.3 (1330.172) SKF 0.1 (−27.316) Etic 0.3 (19.676) SCH 0.3 (−16.731)
8 SKF 0.1 (−24.663) SCH 1.0 (−21.679) SKF 0.1 (39.895) Etic 1.0 (7.238) Quin 0.3 (24.923) SKF 0.1 (−50.442)
9 SKF 0.03 (61.424) SCH 0.3 (−83.105) SKF 0.03 (34.199) Etic 0.3 (180.676) Quin 1.0 (−32.385) SKF 0.03 (−71.155)
Open in a new tab

Table 2.

Microinfusion Schedule for Each Subject in the Glu Experiment and Percentage Change for Each Discounting Parameter Estimate

Percentage Change in A Parameter Estimates
Infusion Order 432 436 438 439 441 443 445 447
1 AP5 1.0 (9.363) CNQX 0.2 (15.542) Ifen 1.0 (16.038) AP5 0.3 (0.180) MK 1.0 (21.804) CNQX 0.5 (3.497) Water AP5 0.3 (2.813)
2 AP5 0.3 (−2.124) CNQX 0.5 (18.546) Saline AP5 1.0 (−13.603) MK 0.3 (36.386) CNQX 0.2 (−0.100) Ifen 1.0 (−1.801) AP5 1.0 (−0.873)
3 Saline Ifen 0.3 (7.101) Water MK 0.3 (−0.180) CNQX 0.5 (30.678) Ifen 0.3 (59.286) Ifen 0.3 (−20.076) MK 0.3 (0)
4 Ifen 1.0 (−1.739) Ifen 1.0 (−48.649) Ifen 0.3 (6.657) Saline CNQX 0.2 (21.866) Water AP5 0.3 (−1.491) MK 1.0 (0.873)
5 Ifen 0.3 (−1.478) Water AP 0.3 (5.099) MK 1.0 (−7.547) Ifen 1.0 (2.233) Ifen 1.0 (61.198) Saline CNQX 0.5 (−6.101)
6 Water AP5 1.0 (17.891) AP5 1.0 (7.290) CNQX 0.2 (−5.840) Saline AP5 1.0 (2.098) AP5 1.0 (−11.698) CNQX 0.2 (3.298)
7 CNQX 0.5 (9.266) AP5 0.3 (−4.476) MK 0.3 (28.158) CNQX 0.5 (−17.601) Ifen 0.3 (3.220) AP5 0.3 (1.099) MK 1.0 (5.232) Ifen 1.0 (−13.461)
8 CNQX 0.2 (5.888) MK 1.0 (22.476) MK 1.0 (0.496) Water Water MK 0.3 (0) MK 0.3 (5.331) Saline
9 MK 1.0 (8.301) MK 0.3 (22.476) CNQX 0.5 (23.198) Ifen 0.3 (−3.223) AP5 1.0 (32.911) Saline CNQX 0.2 (0.987) Ifen 0.3 (6.053)
10 MK 0.3 (2.896) Saline CNQX 0.2 (23.198) Ifen 1.0 (−0.716) AP5 0.3 (32.911) MK 1.0 (−19.870) CNQX 0.5 (2.270) Water
Percentage Change in b Parameter Estimates
Infusion Order 432 436 438 439 441 443 445 447
1 AP5 1.0 (−55.979) CNQX 0.2 (−27.367) Ifen 1.0 (−72.641) AP5 0.3 (−27.622) MK 1.0 (−81.049) CNQX 0.5 (−48.421) Water AP5 0.3 (9.867)
2 AP5 0.3 (−48.746) CNQX 0.5 (−25.923) Saline AP5 1.0 (−5.761) MK 0.3 (−58.984) CNQX 0.2 (78.814) Ifen 1.0 (35.765) AP5 1.0 (−24.582)
3 Saline Ifen 0.3 (−42.764) Water MK 0.3 (−17.696) CNQX 0.5 (−50.921) Ifen 0.3 (334.489) Ifen 0.3 (−28.690) MK 0.3 (97.057)
4 Ifen 1.0 (−16.890) Ifen 1.0 (−81.188) Ifen 0.3 (104.539) Saline CNQX 0.2 (−59.849) Water AP5 0.3 (62.384) MK 1.0 (−67.646)
5 Ifen 0.3 (14.915) Water AP 0.3 (475.576) MK 1.0 (−60.768) Ifen 1.0 (0.861) Ifen 1.0 (39.133) Saline CNQX 0.5 (−5.540)
6 Water AP5 1.0 (0.175) AP5 1.0 (98.548) CNQX 0.2 (−56.691) Saline AP5 1.0 (−41.925) AP5 1.0 (−6.932) CNQX 0.2 (−46.088)
7 CNQX 0.5 (−64.702) AP5 0.3 (−29.059) MK 0.3 (137.916) CNQX 0.5 (−62.895) Ifen 0.3 (22.452) AP5 0.3 (−33.045) MK 1.0 (−9.935) Ifen 1.0 (−69.875)
8 CNQX 0.2 (−57.129) MK 1.0 (29.759) MK 1.0 (46.114) Water Water MK 0.3 (0) MK 0.3 (9.242) Saline
9 MK 1.0 (−48.614) MK 0.3 (29.759) CNQX 0.5 (74.125) Ifen 0.3 (−27.199) AP5 1.0 (127.009) Saline CNQX 0.2 (21.165) Ifen 0.3 (26.753)
10 MK 0.3 (−43.703) Saline CNQX 0.2 (152.946) Ifen 1.0 (−6.757) AP5 0.3 (300.391) MK 1.0 (−11.383) CNQX 0.5 (59.982) Water
Open in a new tab

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 cannulae. Probe placements were evaluated according to the atlas of Paxinos and Watson (2016). Only data from rats with correct probe placements in NAcc were used in all statistical analyses.

Statistical Analysis

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 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 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).

Results

Figure 1 shows probe placements for rats given DA-selective ligands (Fig. 1a) and Glu-selective ligands (Fig. 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.

Figure 1.

Figure 1

Figure 1

Open in a new tab

Schematics of coronal sections showing probe placements for rats infused with DA-selective ligands (a) and for rats infused with Glu-selective ligands (b). From The Rat Brain in Stereotaxic Coordinates, Deluxe (4th ed.), pp. 8–12 by G. Paxinos & C. Watson, 1998, Orlando, FL: Academic Press. Copyright 1998 by Elsevier Academic Press. Adapted (or reprinted) with permission. Black circles indicate probe placements within NAcc, whereas crosses indicate probe place placements outside of NAcc. Note that rats with probe placements outside of NAcc were excluded from data analysis. Numbers beside each plate correspond to mm anterior to bregma. c) Photomicrograph showing bilateral guide cannulae placement in NAcc.

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, all F’s ≤ 1.107, all p’s ≥ .364, all ηp2’s ≤ .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, all F’s ≤ 3.611, all p’s ≥ .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, all χ2’s ≤ 5.158, all p’s ≥ .076 (Table 3).

Table 3.

Mean (± SEM) Omissions Following Infusions of DA and Glu Receptor Ligands

DA-Selective Ligands Glu-Selective Ligands
Drug Concentration M SEM Drug Concentration M SEM
Saline 0.0 μg 1.833 0.601 Saline/H20 0.0 μg 0.000/0.125 0.000/0.125
SKF 38393 0.03 μg 0.833 0.307 MK-801 0.3 μg 0.250 0.375
SKF 38393 0.1 μg 0.333 0.333 MK-801 1.0 μg 0.250 0.375
SCH 23390 0.3 μg 1.667 0.615 AP-5 0.3 μg 0.375 0.183
SCH 23390 1.0 μg 3.000 1.693 AP-5 1.0 μg 0.750 0.250
Quinpirole 0.3 μg 0.667 0.211 Ifenprodil 0.3 μg 0.000 0.000
Quinpirole 1.0 μg 1.000 0.447 Ifenprodil 1.0 μg 0.375 0.263
Eticlopride 0.3 μg 1.667 0.333 CNQX 0.3 μg 0.375 0.263
Eticlopride 1.0 μg 1.000 0.365 CNQX 1.0 μg 0.375 0.375
Open in a new tab

Note. For the Glu-selective ligands, saline was the vehicle for MK-801, AP-5, and CNQX, and sterile water was the vehicle for ifenprodil.

Figure 2 shows the raw proportion of responses for the large delayed reinforcer following direct infusions of SKF 38393 (Fig. 2a), SCH 23390 (Fig. 2b), quinpirole (Fig. 2c), and eticlopride (Fig. 2d). As expected, the main effect of delay was significant for each analysis, all F’s ≥ 14.524, all p’s < .001, all ηp2’s ≥ .744. None of the DA-selective ligands significantly altered responding for the large magnitude reinforcer, all F’s ≤ 1.970, all p’s ≥ .190, all ηp2’s ≤ .283.

Figure 2.

Figure 2

Open in a new tab

Mean (± SEM) proportion of choices for the large delayed reinforcer following administration of SKF 38393 (a), SCH 23390 (b), quinpirole (c), and eticlopride (d). n = 6 each drug.

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 (Fig. 3a), or sensitivity to delayed reinforcement, F(2, 79) = .248, p = .781 (Fig. 3a), blocking these receptors with SCH 23390 (0.3 μg) significantly decreased sensitivity to reinforcer magnitude, F(2, 79) = 3.431, p = .037 (Fig. 3b), without altering sensitivity to delayed reinforcement, F(2, 79) = 1.586, p = .211 (Fig. 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 (Fig. 3c); eticlopride: F(2, 79) = 0.175, p = .840; F(2, 79) = 0.658, p = .521 (Fig. 3d).

Figure 3.

Figure 3

Open in a new tab

Mean (± SEM) A parameter estimates (sensitivity to reinforcer magnitude; closed symbols) and b parameter estimates (sensitivity to delayed reinforcement; open symbols) following administration of SKF 38393 (a), SCH 23390 (b), quinpirole (c), and eticlopride (d). n = 6 each drug. *p < .05, relative to vehicle.

Figure 4 shows the raw proportion of responses for the large delayed reinforcer following direct infusions of MK-801 (Fig. 4a), AP-5 (Fig. 4b), ifenprodil (Fig. 4c), and CNQX (Fig. 4d). Similar to the results obtained with the DA-selective ligands, the main effect of delay was significant for each Glu drug tested, all F’s ≥ 18.506, all p’s < .001, all ηp2’s ≥ .726, but none of the Glu-selective ligands altered responses for the large magnitude reinforcer, all F’s ≤ 3.325, all p’s ≥ .066, all ηp2’s ≤ .322.

Figure 4.

Figure 4

Open in a new tab

Mean (± SEM) proportion of choices for the large delayed reinforcer following administration of MK-801 (a), AP-5 (b), ifenprodil (c), and CNQX (d). n = 8 each drug.

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 (Fig. 5a), or sensitivity to delayed reinforcement, F(2, 107) = 2.121, p = .125 (Fig. 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 (Fig. 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 (Fig. 5c), whereas no differences in sensitivity to reinforcer magnitude emerged, F(2, 107) = 0.252, p = .778 (Fig. 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 (Fig. 5d).

Figure 5.

Figure 5

Open in a new tab

Mean (± SEM) A parameter estimates (sensitivity to reinforcer magnitude; closed symbols) and b parameter estimates (sensitivity to delayed reinforcement; open symbols) following administration of MK-801 (a), AP-5 (b), ifenprodil (c), and CNQX (d). n = 8 each drug.

Figure 6 shows A (Fig. 6a) and b (Fig. 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.

Figure 6.

Figure 6

Open in a new tab

Mean (± SEM) A parameter estimates (sensitivity to reinforcer magnitude; a) and mean (± SEM) b parameter estimates (sensitivity to delayed reinforcement; b) across baseline sessions during the infusion phase of the experiment.

Discussion

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: (1) sensitivity to reinforcer magnitude (A parameter); and (2) 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 intra-mPFC 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, & Owii, 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 et al., 2017a). However, because ifenprodil binds to other receptors, particularly α1 adrenergic receptors (Chenard et al., 1991), the decreased sensitivity to reinforcer magnitude observed by Yates et al. (2017a) 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 et al., 2017a), 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 et al., 2017a, 2017b), 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 et al. (2017a) 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 intra-cranial infusions into the NAcc. Each rat received either 9 (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 et al., 2017b). 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.

Footnotes

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.

References

  1. Adlersberg M, Arango V, Hsiung S, Mann JJ, Underwood MD, Liu K, … Tamir H. In vitro autoradiography of serotonin 5-HT(2A/2C) receptor-activated G protein: Guanosine-5′(gamma-[(35)S]thio)triphosphate binding in rat brain. Journal of Neuroscience Research. 2000;61:674–685. doi: 10.1002/1097-4547(20000915)61:6<674::AID-JNR11>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  2. Baarendse PJJ, Vanderschuren LJMJ. Dissociable effects of monoamine reuptake inhibitors on distinct forms of impulsive behavior in rats. Psychopharmacology. 2012;219:313–326. doi: 10.1007/s00213-011-2576-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bakshi VP, Geyer MA. Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. The Journal of Neuroscience. 1998;18:8394–8401. doi: 10.1523/JNEUROSCI.18-20-08394.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baldwin AE, Holahan MR, Sadeghian K, Kelley AE. N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning. Behavioral Neuroscience. 2000;114:84–98. doi: 10.1037//0735-7044.114.1.84. [DOI] [PubMed] [Google Scholar]
  5. Beninger RJ, Cheng M, Hahn BL, Hoffman DC, Mazurski EJ, Morency MA, … Stewart RJ. Effects of extinction, pimozide, SCH 23390, and metoclopramide on food-rewarded operant responding of rats. Psychopharmacology. 1987;92:343–349. doi: 10.1007/BF00210842. [DOI] [PubMed] [Google Scholar]
  6. Ben-Shahar OM, Szumlinksi KK, Lominac KD, Cohen A, Gordon E, Ploense KL, … Woodward N. Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex. Addiction Biology. 2012;17:746–757. doi: 10.1111/j.1369-1600.2011.00428.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bezzina G, Body S, Cheung THC, Hampson CL, Bradshaw CM, Szabadi E, … Deakin JFW. Effect of disconnecting the orbital prefrontal cortex from the nucleus accumbens core on inter-temporal choice behaviour: a quantitative analysis. Behavioural Brain Research. 2008;191:272–279. doi: 10.1016/j.bbr.2008.03.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bezzina G, Body S, Cheung THC, Body S, Deakin JFW, Anderson IM, … Szabadi E. Quantitative analysis of the effect of lesions of the subthalamic nucleus on inter-temporal choice: further evidence for enhancement of the incentive value of food reinforcers. Behavioural Pharmacology. 2009;20:437–446. doi: 10.1097/FBP.0b013e3283305e4d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bezzina G, Cheung TH, Asgari K, Hampson CL, Body S, Bradshaw CM, … Anderson IM. Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: A quantitative analysis. Psychopharmacology. 2007;195:71–84. doi: 10.1007/s00213-007-0882-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bidwell LC, McClernon FJ, Kollins SH. Cognitive enhancers for the treatment of ADHD. Pharmacology, Biochemistry and Behavior. 2011;99:262–274. doi: 10.1016/j.pbb.2011.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Broos N, Diergaarde L, Schoffelmeer ANM, Pattij T, De Vries TJ. Trait impulsive choice predicts resistance to extinction and propensity to relapse to cocaine seeking: A bidirectional relationship. Neuropsychopharmacology. 2012a;37:1377–1386. doi: 10.1038/npp.2011.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt BJ. Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science. 2001;292:2499–2501. doi: 10.1126/science.1060818. [DOI] [PubMed] [Google Scholar]
  13. Cardinal RN, Robbins TW, Everitt BJ. The effects of d-amphetamine, chlordiazepoxide, α-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats. Psychopharmacology. 2000;152:362–375. doi: 10.1007/s002130000536. [DOI] [PubMed] [Google Scholar]
  14. Chenard BL, Shalaby IA, Koe BK, Rounau RT, Butler TW, Prochiniak MA, … Fox CB. Separation of α1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds. Journal of Medicinal Chemistry. 1991;34:3085–3090. doi: 10.1021/jm00114a018. [DOI] [PubMed] [Google Scholar]
  15. Cohen J. Statistical power analysis for the behavioral sciences. 2. Hillsdale, NJ: Erlbaum; 1988. [Google Scholar]
  16. Cottone P, Lemolo A, Narayan AR, Kwak J, Momaney D, Sabino V. The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats. Psychopharmacology. 2013;226:127–138. doi: 10.1007/s00213-012-2898-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. da Costa Araújo S, Body S, Hampson CL, Langley RW, Deakin JF, Anderson IM, … Szabadi E. Effects of lesions of the nucleus accumbens core on inter-temproal choice: Further observations with an adjusting-delay procedure. Behavioural Brain Research. 2009;202:272–277. doi: 10.1016/j.bbr.2009.04.003. [DOI] [PubMed] [Google Scholar]
  18. Denk F, Walton ME, Jennings KA, Sharp T, Rushworth MFS, Bannerman DM. Differential involvement of serotonin and dopamine systems in cost-benefit decisions about delay or effort. Psychopharmacology. 2005;179:587–596. doi: 10.1007/s00213-004-2059-4. [DOI] [PubMed] [Google Scholar]
  19. Dubois A, Savasta M, Curet O, Scatton B. Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience. 1986;19:125–137. doi: 10.1016/0306-4522(86)90010-2. [DOI] [PubMed] [Google Scholar]
  20. Evenden JL, Ryan CN. The pharmacology of impulsive behaviour in rats: The effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology. 1996;128:161–170. doi: 10.1007/s002130050121. [DOI] [PubMed] [Google Scholar]
  21. Feja M, Hayn L, Koch M. Nucleus accumbens core and shell inactivation differentially affects impulsive behaviours in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2014;54:31–42. doi: 10.1016/j.pnpbp.2014.04.012. [DOI] [PubMed] [Google Scholar]
  22. Floresco SB, Tse MTL, Ghods-Sharifi G. Dopaminergic and glutamatergic regulation of effort- and delay-based decision making. Neuropsychopharmacology. 2008;33:1966–1979. doi: 10.1038/sj.npp.1301565. [DOI] [PubMed] [Google Scholar]
  23. Galtress T, Kirkpatrick K. The role of the nucleus accumbens core in impulsive choice, timing, and reward processing. Behavioral Neuroscience. 2010;124:26–43. doi: 10.1037/a0018464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gan JO, Walton ME, Phillips PEM. Dissociable cost and benefit encoding of future rewards by mesolimbic dopamine. Nature Neuroscience. 2010;13:25–27. doi: 10.1038/nn.2460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Griffin WC, 3rd, Haun HL, Hazelbaker CL, Ramachandra VS, Becker HC. Increased extracellular glutamate in the nucleus accumbens promotes excessive ethanol drinking in ethanol dependent mice. Neuropsychopharmacology. 2014;39:707–717. doi: 10.1038/npp.2013.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Higgins GA, Silenieks LB, MacMillan C, Sevo J, Zeeb FD, Thevarkunnel S. Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment. Behavioural Brain Research. 2016;311:1–14. doi: 10.1016/j.bbr.2016.05.025. [DOI] [PubMed] [Google Scholar]
  27. Hitchcott PK, Phillips GD. Amygdala and hippocampus control dissociable aspects of drug-associated conditioned rewards. Psychopharmacology. 1997;131:187–195. doi: 10.1007/s002130050283. [DOI] [PubMed] [Google Scholar]
  28. Ho MY, Mobini S, Chiang TJ, Bradshaw CM, Szabadi E. Theory and method in the quantitative analysis of “impulsive choice” behaviour: Implications for psychopharmacology. Psychopharmacology. 1999;146:362–372. doi: 10.1007/pl00005482. [DOI] [PubMed] [Google Scholar]
  29. Homberg JR. Serotonin and decision making processes. Neuroscience & Biobehavioral Reviews. 2012;36:218–236. doi: 10.1016/j.neubiorev.2011.06.001. [DOI] [PubMed] [Google Scholar]
  30. Kheramin S, Body S, Mobini S, Ho MY, Velázquez-Martinez DN, Bradshaw CM, … Anderson IM. Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis. Psychopharmacology. 2002;165:9–17. doi: 10.1007/s00213-002-1228-6. [DOI] [PubMed] [Google Scholar]
  31. Koffarnus MN, Newman AH, Grundt P, Rice KC, Woods JH. Effects of selective dopaminergic compounds on a delay-discounting task. Behavioural Pharmacology. 2011;22:300–311. doi: 10.1097/FBP.0b013e3283473bcb. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jensen V, Rinholm JE, Johansen TJ, Medin T, Storm-Mathisen J, Sagvolden T, … Bergersen LH. N-methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience. 2009;158:353–364. doi: 10.1016/j.neuroscience.2008.05.016. [DOI] [PubMed] [Google Scholar]
  33. Laurent V, Westbook F. Distinct contributions of the basolateral amygdala and the medial prefrontal cortex to learning and relearning extinction of context conditioned fear. Learning & Memory. 2008;15:657–666. doi: 10.1101/lm.1080108. [DOI] [PubMed] [Google Scholar]
  34. Loos M, Pattij T, Janssen MC, Counotte DS, Schoffelmeer AN, Smit AB, … van Gaalen MM. Dopamine receptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats. Cerebral Cortex. 2010;20:1064–1070. doi: 10.1093/cercor/bhp167. [DOI] [PubMed] [Google Scholar]
  35. Maguire DR, Henson C, France CP. Effects of amphetamine on delay discounting in rats depend on the manner in which delay is varied. Neuropharmacology. 2014;87:173–179. doi: 10.1016/j.neuropharm.2014.04.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mesches MH, Bianchin M, McGaugh JL. The effects of intra-amygdala infusion of the AMPA receptor anatagonist CNQX on retention performance following aversive training. Neurobiology of Learning and Memory. 1996;66:324–340. doi: 10.1006/nlme.1996.0073. [DOI] [PubMed] [Google Scholar]
  37. Miller EM, Pomerleau F, Huetti P, Gerhardt GA, Glaser PE. Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology. 2014;231:3019–3029. doi: 10.1007/s00213-014-3479-4. [DOI] [PubMed] [Google Scholar]
  38. Miyazaki KW, Miyazaki K, Doya K. Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. The Journal of Neuroscience. 2012;32:10451–10457. doi: 10.1523/JNEUROSCI.0915-12.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Moschak TM, Mitchell SH. Partial inactivation of nucleus accumbens core decreases delay discounting in rats without affecting sensitivity to delay or magnitude. Behavioural Brain Research. 2014;268:159–168. doi: 10.1016/j.bbr.2014.03.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. National Research Council. Guide for the care and use of laboratory animals. Washington, DC: National Academies Press; 2011. [Google Scholar]
  41. Pardey MC, Kumar NN, Goodchild AK, Cornish JL. Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex. Journal of Psychopharmacology. 2013;27:203–212. doi: 10.1177/0269881112465497. [DOI] [PubMed] [Google Scholar]
  42. Parkes SL, Balleine BW. Incentive memory: Evidence the basolateral amydala encodes and the insular cortex retrieves outcome values to guide choice between goal-directed actions. The Journal of Neuroscience. 2013;33:8753–8763. doi: 10.1523/JNEUROSCI.5071-12.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 7. San Diego, CA: Academic Press; 2016. [DOI] [PubMed] [Google Scholar]
  44. Perlov E, Phillipsen A, Hesslinger B, Buechert M, Ahrendts J, Feige B, … Tebartz van Elst L. Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder – A magnet resonance spectroscopy study. Journal of Psychiatry Research. 2007;41:934–941. doi: 10.1016/j.jpsychires.2006.12.007. [DOI] [PubMed] [Google Scholar]
  45. Pinheiro J, Bates D, DebRoy S, Sarkar D R Core Team. nlme: Linear and nonlinear mixed effects models. R package version 3.1–131. 2017 https://CRAN.R-project.org/package=nlme.
  46. Pothuzien HH, Jongen-Relo AL, Feldon J, Yee BK. Double dissociation of the effects of selective nucleus accumbens core and shell lesions on impulsive-choice behaviour and salience learning in rats. European Journal of Neuroscience. 2005;22:2605–2616. doi: 10.1111/j.1460-9568.2005.04388.x. [DOI] [PubMed] [Google Scholar]
  47. Ramos M, Goñi-Allo B, Aguirre N. Administration of SCH 23390 into the medial prefrontal cortex blocks the expression of MDMA-induced behavioral sensitization in rats: An effect mediated by 5-HT2C receptor stimulation and not by D1 receptor blockade. Neuropsychopharmacology. 2005;30:2180–2191. doi: 10.1038/sj.npp.1300735. [DOI] [PubMed] [Google Scholar]
  48. Savasta M, Dubois A, Scatton B. Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390. Brain Research. 1986;375:291–301. doi: 10.1016/0006-8993(86)90749-3. [DOI] [PubMed] [Google Scholar]
  49. Sharf R, Lee DY, Ranaldi R. Microinjections of SCH 23390 in the ventral tegmental area reduce operant responding under a progressive ratio schedule of food reinforcement in rats. Brain Research. 2005;1033:179–185. doi: 10.1016/j.brainres.2004.11.041. [DOI] [PubMed] [Google Scholar]
  50. Sombers LA, Beyene M, Carelli RM, Wrightman RM. Synaptic overflow of dopamine in the nucleus accumbens from neuronal activity in the ventral tegmental area. The Journal of Neuroscience. 2009;29:1735–1742. doi: 10.1523/JNEUROSCI.5562-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sukhotina IA, Dravolina OA, Novitskaya Y, Zvartau EE, Danysz W, Bespalov AY. Effects of mGlu1 receptor blockade on working memory, time estimation, and impulsivity in rats. Psychopharmacology. 2008;196:211–220. doi: 10.1007/s00213-007-0953-2. [DOI] [PubMed] [Google Scholar]
  52. Tanno T, Maguire DR, Henson C, France CP. Effects of amphetamine and methylphenidate on delay discounting in rats: Interactions with order of delay presentation. Psychopharmacology. 2014;231:85–95. doi: 10.1007/s00213-013-3209-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino E. Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropharmacology. 2005;30:1861–1869. doi: 10.1038/sj.npp.1300732. [DOI] [PubMed] [Google Scholar]
  54. Valencia-Torres L, Olarte-Sánchez CM, da Costa Araújo S, Body S, Bradshaw CM, Szabadi E. Nucleus accumbens and delay discounting in rats: Evidence from a new quantitative protocol for analysing inter-temporal choice. Psychopharmacology. 2012;219:271–283. doi: 10.1007/s00213-011-2459-1. [DOI] [PubMed] [Google Scholar]
  55. van Gaalen MM, van Koten R, Schoffelmeer ANM, Vanderschuren LJMJ. Critical involvement of dopaminergic neurotransmission in impulsive decision making. Biological Psychiatry. 2006b;60:66–73. doi: 10.1016/j.biopsych.2005.06.005. [DOI] [PubMed] [Google Scholar]
  56. Wade TR, de Wit H, Richards JB. Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats. Psychopharmacology. 2000;150:90–101. doi: 10.1007/s002130000402. [DOI] [PubMed] [Google Scholar]
  57. Wenzel A, Scheurer L, Künzi R, Fritschy JM, Mohler H, Benke D. Distribution of NMDA receptor subunit proteins NR2A, 2B, 2C, and 2D in rat brain. Neuroreport. 1995;7:45–48. [PubMed] [Google Scholar]
  58. Winstanley CA, Theobald DEH, Dalley JW, Robbins TW. Interactions between serotonin and dopamine in the control of impulsive choice in rats: Therapeutic implications for impulse control disorders. Neuropsychopharmacology. 2005;30:669–682. doi: 10.1038/sj.npp.1300610. [DOI] [PubMed] [Google Scholar]
  59. Yates JR, Batten SR, Bardo MT, Beckmann JS. Role of ionotropic glutamate receptors in delay and probability discounting in the rat. Psychopharmacology. 2015;232:1187–1196. doi: 10.1007/s00213-014-3747-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yates JR, Breitenstein KA, Gunkel BT, Hughes MN, Johnson AB, Rogers KK, Sharpe SM. Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation. Pharmacology, Biochemistry and Behavior. 2016;150–151:31–38. doi: 10.1016/j.pbb.2016.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yates JR, Gunkel BT, Rogers KK, Hughes MN, Prior NA. Effects of N-methyl-D-aspartate receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure. Psychopharmacology. 2017a;234:461–473. doi: 10.1007/s00213-016-4469-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Yates JR, Perry JL, Meyer AC, Gipson CD, Charnigo R, Bardo MT. Role of medial prefrontal and orbitofrontal monoamine transporters and receptors in performance in an adjusting delay procedure. Brain Research. 2014;1574:26–36. doi: 10.1016/j.brainres.2014.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yates JR, Rogers KK, Gunkel BT, Prior NA, Hughes MN, Sharpe SM, … Shults HN. Effects of Group I metabotropic glutamate receptor antagonists on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting task in rats: Contribution of delay presentation order. Behavioural Brain Research. 2017b;322:29–33. doi: 10.1016/j.bbr.2017.01.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Zarrindast MR, Honardar Z, Sanea F, Owii AA. SKF 38393 and SCH 23390 inhibit reuptake of serotonin by rat hypothalamic synaptosomes. Pharmacology. 2011;87:85–89. doi: 10.1159/000323232. [DOI] [PubMed] [Google Scholar]
  65. Zeeb FD, Floresco SB, Winstanley CA. Contributions of the orbitofrontal cortex to impulsive choice: Interactions with basal levels of impulsivity, dopamine signalling, and reward-related cues. Psychopharmaclology. 2010;211:87–98. doi: 10.1007/s00213-010-1871-2. [DOI] [PubMed] [Google Scholar]
  66. Zhang WN, Bast T, Feldon J. Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity. Neuroscience. 2000;101:589–599. doi: 10.1016/s0306-4522(00)00418-8. [DOI] [PubMed] [Google Scholar]

RESOURCES