Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation

Abstract

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making.

Keywords: Glutamate; NMDA receptor; Probability discounting; Rat; Risky decision making.

Figure 1

Hypothetical probability-discounting data for 12 rats showing how a drug can differentially alter A and b parameter estimates. (a) The drug decreases responding for the large magnitude reinforcer when the odds against obtaining that reinforcer are set to 3, 7, 15, and 31 (left column), which corresponds to no change in the A parameter estimate (center column) but an increase in the b (log-transformed) parameter estimate (indicating increased risk aversion; right column). (b) The drug decreases responding for the large magnitude reinforcer across each block of trials (left column), which corresponds to a decrease in the A parameter estimate (indicating decreased sensitivity to reinforcer magnitude; center column) but no change in risk taking (right column). The data are presented as mean (± SEM). *p < .05 relative to drug treatment.

Figure 2

Baseline performance in rats trained with an ascending (n = 8) and descending (n = 8) schedule. (a) Mean (± SEM) proportion of responses for the large, probabilistic reinforcer as a function of the odds against receiving the reinforcer. (b) Mean (± SEM) log-transformed b parameter estimates. (c) Mean (± SEM) A parameter estimates. *p < .05, relative to rats trained on the ascending schedule.

Figure 3

Mean (± SEM) proportion of responses for the large, probabilistic reinforcer following administration of MK-801 (a and b), ketamine (c and d), and ifenprodil (e and f). Figures in the left column correspond to the ascending schedule, whereas figures in the right column correspond to the descending schedule.

Figure 4

Mean (± SEM) log-transformed b parameter estimates following administration of MK-801 (a), ketamine (b), and ifenprodil (c). *p < .05, relative to vehicle.