Methylphenidate, but not citalopram, decreases impulsive choice in rats performing a temporal discounting task

Abstract

Introduction: Drugs targeting monoamine systems remain the most common treatment for disorders with impulse control impairments. There is a body of literature suggesting that drugs affecting serotonin reuptake and dopamine reuptake can modulate distinct aspects of impulsivity - though such tests are often performed using distinct behavioral tasks prohibiting easy comparisons.

Methods: Here, we directly compare pharmacologic agents that affect dopamine (methylphenidate) vs serotonin (citalopram) manipulations on choice impulsivity in a temporal discounting task where rats could choose between a small, immediate reward or a large reward delayed at either 2 or 10s. In control conditions, rats preferred the large reward at a small (2s) delay and discounted the large reward at a long (10s) delay.

Results: Methylphenidate, a dopamine transport inhibitor that blocks reuptake of dopamine, dose-dependently increased large reward preference in the long delay (10s) block. Citalopram, a selective serotonin reuptake inhibitor, had no effect on temporal discounting behavior. Impulsive behavior on the temporal discounting task was at least partially mediated by the nucleus accumbens shell. Bilateral lesions to the nucleus accumbens shell reduced choice impulsivity during the long delay (10s) block. Following lesions, methylphenidate did not impact impulsivity.

Discussion: Our results suggest that striatal dopaminergic systems modulate choice impulsivity via actions within the nucleus accumbens shell, whereas serotonin systems may regulate different aspects of behavioral inhibition/impulsivity.

Keywords: citalopram; impulsivity; methylphenidate; nucleus accumbens; temporal discounting.

Figure 1

(A) The task structure for our version of the temporal discounting task is shown. Briefly, subjects must choose between a small reward (10µL) delivered immediately (500ms after response) and a large reward (30µL) delivered after a delay. In block 1 (first 65 trials) the large reward delay is 2s following response. In block 2 (>65 trials) the large reward delay is 10s). The schematics show the outline for a single trial with events including houselights, noseport (NP) LEDs, noseport responses and water delivery. (B) In block 1 when the large reward delay is short (2s), rats make 81% large reward responses. In block 2, when the large reward delay is long (10s), rats only make 13% large reward responses.

Figure 2

(A) Experiment 1 timeline and design. 12 male Long-Evans rats start Experiment 1 after 12 weeks of behavioral training and habituation. First, we tested intraperitoneal (IP) injections of methylphenidate at 5 doses (0.5, 1.0, 2.0, 5.0, 10.0 mg/kg). As a control, saline injections were given the session prior to a drug session. After a one-week wash-out period the study design was repeated using citalopram injections. Each subject completed two repeated measures at each drug and dose. (B) Methylphenidate dose-dependently increased the proportion of large reward choices but only in the long delay (10s) block (p<.001). There was no difference in large reward choices between saline and methylphenidate in the short delay (2s) block (p=.191). Post-hoc analyses reveal that, compared to the saline control, 5.0 mg/kg (p=.017) and 10.0 mg/kg (p=.004) of methylphenidate significantly increased the proportion of large reward choices in block 2. (C) Citalopram had no effects on proportion of large reward choice at any dose (p=.908) and there was no interaction between dose and block (p=.751). (D) Preference for large reward on block 1 (light) and block 2 (dark) did not change in control days from early sessions (methylphenidate) and late sessions (citalopram). Graphs show Mean and SEM. * p<.05, ** p<.01.

Figure 3

(A) Experiment 2 timeline and design. In the same cohort of rats, we repeated a modified drug study based on results from Experiment 1. First, rats received an excitotoxic NMDA lesion centered over bilateral NAcSh. Rats recovered for one week following surgery and then began the modified drug study. IP injections of methylphenidate were given at two doses (1.0 and 10.0 mg/kg). As a control, saline injections were given the session prior to a drug session. Each subject completed two repeated measures at each drug and dose. (B) Schematic showing the lesion sites at coronal sections from bregma AP +2.70 to +0.70. Dark green represents the largest lesion and light green represents the smallest lesion at each section as seen from the thionin stained tissue. (C) The NAc lesion increased the proportion of large reward choices in the long delay (10s) block (p<.001) and did not change choice behavior in the short delay (2s) block (p=.203). These results only include saline control days from pre- and post-lesion sessions. (D) The NAc lesion increases preference for large reward in the long delay (10s) block to a similar level as the 10mg/kg methylphenidate dose from Experiment 1. (E) Only the pre-lesion data (color) show a dose-dependent effect of methylphenidate (p=.005) in block 2. Post-lesion data (grey scale) show no difference between the saline, low and high methylphenidate doses. (F) Compared to pre-lesion data (color), the proportion of large reward choices during block 2 was greater following the lesion (grey scale) during 1mg/kg methylphenidate sessions (p=.030) but was no different in 10 mg/kg methylphenidate sessions (p=.554). Graphs show Mean and SEM. * p<.05, ** p<.01, *** p<.001.