Effects of N-methyl-d-aspartate receptor (NMDAr) uncompetitive antagonists in a delay discounting paradigm using a concurrent-chains procedure.

Impulsive choice is often assessed in rodents using a delay discounting (DD) paradigm in which the delay to a large reinforcer (LR) increases across the session. This procedure allows one to test the effects of pharmacological manipulations within a single session. Because discounting is influenced by sensitivity to reinforcer magnitude (SRM) and sensitivity to delayed reinforcement (SDR), applying quantitative analyses (e.g., fitting hyperbolic function) is important for determining the precise behavioral mechanisms being altered following drug administration. One caveat to this approach is that observing increases in SMR/SDR can be difficult (e.g., most rats choose the LR when its delivery is immediate, whereas some rats may show exclusive preference for the small reinforcer [SR] when a delay on the LR is imposed). We utilized a variant of a concurrent-chains procedure in which rats (n = 8) could not show exclusive preference for either reinforcer, thus allowing one to observe increases/decreases in responding at each delay. The NMDAr antagonists MK-801 (0, 0.003, 0.01, 0.03 mg/kg), ketamine (0, 1.0, 5.0, 10.0 mg/kg), and memantine (0, 2.5, 5.0, 7.5 mg/kg) were administered following baseline training because this receptor has recently been implicated in DD. MK-801 (0.03 mg/kg) decreased SRM and SDR. Memantine (7.5 mg/kg) decreased SRM only. These results show that this variant of the concurrent-chains procedure can be used to study the effects of pharmacological manipulations on distinct aspects of DD.

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.

Metabotropic glutamate receptor 1 (mGluR1) blockade has been shown to decrease impulsive choice, as measured in delay discounting. However, several variables are known to influence an animal's discounting, including sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude. The goal of this experiment was to determine the effects of mGluR1, as well as mGluR5, antagonism on these parameters. Forty Sprague Dawley rats were trained in delay discounting, in which consistently choosing a small, immediate reward reflects impulsive choice. For half of the rats, the delay to the large reinforcer increased across blocks of trials, whereas the delay decreased across the session for half of the rats. Following training, half of the rats received injections of the mGluR1 antagonist JNJ 16259685 (JNJ; 0, 0.1, 0.3, or 1.0mg/kg; i.p), and half received injections of the mGluR5 antagonist MPEP (0, 1.0, 3.0, or 10.0mg/kg; i.p.). Administration of JNJ increased sensitivity to delayed reinforcement (i.e., promoted impulsive choice), regardless of which schedule was used. However, the order in which delays were presented modulated the effects of JNJ on sensitivity to reinforcer magnitude. Specifically, JNJ decreased sensitivity to reinforcer magnitude in rats trained on the descending schedule only. MPEP did not alter sensitivity to reinforcer magnitude or sensitivity to delayed reinforcement. These results show that mGluR1 is an important mediator of impulsive choice, and they provide further evidence that delay order presentation is an important variable that influences drug effects in delay discounting.

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

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.