Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning

Abstract

The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

Fig. 1.

Influence of the high dose (3 nmol) of D₁ receptor antagonist infusion into the nucleus accumbens core on acquisition of lever pressing for sucrose pellets: correct and incorrect lever responses. Animals received intra-accumbens infusion of SCH-23390 (3 nmol) or vehicle (saline) on the first 4 test days; on the remaining training days, no infusion was given except on day 10, when animals received their initial treatments (underscoreddays indicate infusion days). A, Lever presses. **p < 0.01, treatment effect;^††p < 0.01, interactions.B, Nose pokes into the food tray during learning. **p < 0.01, treatment effect;^††p < 0.01, interactions. See Materials and Methods for statistical details.

Fig. 2.

Influence of D₁ receptor antagonist SCH-23390 (0.3 nmol) or NMDA receptor antagonist AP-5 (0.5 nmol) infusion into the nucleus accumbens core on acquisition of lever pressing for sucrose pellets. See legend of Figure 1 for further details. A, Lever presses. B, Nose pokes. See Materials and Methods for statistical details.

Fig. 3.

Influence of the co-infusion of D₁receptor antagonist SCH-23390 (0.3 nmol) and NMDA receptor antagonist AP-5 (0.5 nmol) into the nucleus accumbens core on acquisition of lever pressing for sucrose pellets. See legend of Figure 1 for further details. A, Lever presses. **p < 0.01, treatment effect; ^††p < 0.01, interactions. B, Nose pokes. *p < 0.05, treatment effect; ^††p < 0.01, interactions. See Materials and Methods for statistical details.

Fig. 4.

Representative histology from a rat infused with the co-treatment (SCH-23390, 0.3 nmol; AP-5, 0.5 nmol) as shown inA and from a rat infused with saline, as shown inB.