Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex

Abstract

Through its complex role in cognition, memory, and emotion, the mammalian prefrontal cortex is thought to contribute to the organization of adaptive behavioral actions. In the present studies we examined the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning. Hungry rats with bilateral indwelling cannulas aimed at the medial prefrontal cortex were trained to lever-press for food. Infusion of the selective D1 antagonist SCH-23390 (0.15, 0.3, 3.0 nmol) dose-dependently impaired acquisition of this behavior. Higher doses also impaired expression of this task. Co-infusion of the lowest dose of SCH 23390 with a low dose of the NMDA antagonist AP-5 (0.5 nmol), each of which had no effect on learning when infused alone, potently reduced the ability to acquire the response. Inhibition of intracellular protein kinase A with the selective PKA inhibitor Rp-cAMPS also disrupted acquisition, suggesting that PKA is an intracellular substrate for a D1-NMDA receptor interaction. In control experiments, drug infusions that impaired learning did not affect food intake or locomotion, suggesting a specific effect on learning. We hypothesize that coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.

Fig. 1.

Histological reconstructions of cannula placements in the various experiments and representative histology.A, Histological sections were examined under a light microscope, and the site of infusion was estimated. Each pair of symbols on a particular section represents one rat. For this reconstruction, representative infusion sites were plotted for four rats receiving the high dose (3 nmol) of SCH-23390 in experiment 2 (●) and four control rats from experiment 3 (▪). Infusion sites for all animals receiving the combined low doses of AP-5 (0.5 nmol) and SCH-23390 (0.15 nmol) in experiment 3 (♦) are also plotted. Theshaded regions represent the areas containing all infusion sites from all experiments. From Paxinos and Watson (1998). Adapted with permission. Representative histology from a rat treated with the high dose of SCH-23390 (B) and the combined low doses of AP-5 and SCH-23390 (C).

Fig. 2.

Influence of intra-mPFC infusions of high, medium, or low doses of the D1 receptor antagonist SCH-23390 on appetitive instrumental learning. Animals received infusions of SCH-23390 or saline on the first 5 test days and were tested without infusions on days 6–10. On day 11, animals receiving the low dose of SCH-23390 or vehicle were given a final infusion, as on days 1–5. Animals receiving the high and medium doses of SCH-23390 were tested for an additional 5 d without infusion and then received a final drug infusion on day 16. A, Lever presses for food. *p < 0.05 treatment effect; ††p < 0.01 interactions. B,Nosepokes into food tray during learning. *p < 0.05 treatment effect; ††p < 0.01 interactions. See Results for details of statistical analysis.

Fig. 3.

Influence of intra-mPFC infusions of a low dose of the NMDA receptor antagonist AP-5 on appetitive instrumental learning. Animals received infusions of AP-5 or saline on the first 5 test days, no infusions on days 6–10, and a final infusion of drug or vehicle on day 11. Intra-mPFC infusions of AP-5 had no impact on either lever presses (A) or nosepokes (B).

Fig. 4.

Influence of intra-mPFC co-infusions of low doses of AP-5 and SCH-23390 on appetitive instrumental learning. See legend of Figure 2 for general test procedure. Animals received a subsequent infusion of drug or vehicle on day 11 and again on day 16.A, Lever presses for food. *p < 0.05 treatment effect; †p < 0.05 interactions.B, Nosepokes into food tray during learning. ††p < 0.01 interactions. See Results for details of statistics.

Fig. 5.

Influence of intra-mPFC co-infusions of PKA inhibitor Rp-cAMPS on appetitive instrumental learning. See legend of Figure 2 for general test procedure. A, Lever presses for food. *p < 0.05 treatment effect; †p < 0.05 interactions. B,Nosepokes into food tray during learning. *p < 0.05 treatment effect; †p < 0.05 interactions. See Results for details of statistics. Control group is the same as that presented in Figure 4.