AMPA/kainate, NMDA, and dopamine D1 receptor function in the nucleus accumbens core: a context-limited role in the encoding and consolidation of instrumental memory

Abstract

Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of learning (acquisition or consolidation) these receptors are recruited, nor is it known what role AMPA/kainate receptors have in these processes. Here we show that pre-trial intra-NAc core administration of the NMDA, AMPA/KA, and D1 receptor antagonists AP-5 (1 microg/0.5 microL), LY293558 (0.01 or 0.1 microg/0.5 microL), and SCH23390 (1 microg/0.5 microL), respectively, impaired acquisition of a lever-pressing response, whereas post-trial administration left memory consolidation unaffected. An analysis of the microstructure of behavior while rats were under the influence of these drugs revealed that glutamatergic and dopaminergic signals contribute differentially to critical aspects of the initial, randomly emitted behaviors that enable reinforcement learning. Thus, glutamate and dopamine receptors are activated in a time-limited fashion-only being required while the animals are actively engaged in the learning context.

Figure 1.

Histological analyses of representative nucleus accumbens core injections' sites. (A) Stereotaxic coordinates displayed within the sections are in millimeters from bregma. NAc core injection sites representative of LY293558, AP-5, and SCH23390 infusions are indicated by circles, triangles, and squares, respectively. Adapted with permission from Elsevier © 1998, Paxinos and Watson (1998). (B-D) Nissl stains of coronal sections indicating cannulae and injector tracts terminating in the NAc core for the LY293558, AP-5, and SCH23390 experiments, respectively.

Figure 2.

Memory consolidation is not affected by AMPA/KA receptor blockade. (A,B) Pre-trial infusions of LY293558 (0, 0.01, or 0.1 μg) dose-dependently impaired the acquisition of instrumental learning as measured by decreased (A) lever presses and (B) nose pokes. Infusions after the task was learned had no effect on memory retrieval/performance. (Inset) Lever presses made over the first three sessions. Vehicle group, n = 6; 0.01 μg group, n = 5; 0.1 μg group, n =6. (C,D) Post-trial infusions of LY293558 (0 or 0.1 μg) failed to affect (C) lever-pressing or (D) nose-poking, indicating memory for the task was consolidated normally. Vehicle group, n = 7; 0.1 μg group, n = 5. Arrows next to session 3 in B and D mark the end of noncontingent reinforcement. For all panels, data are shown as the mean number of lever presses or nose pokes ± SEM. Brackets and arrows beneath the x-axis indicate the frequency of injections. (^**) Main effect of treatment on lever-pressing, P < 0.01 (see Results for nose-poke statistics).

Figure 3.

AMPA/KA receptor blockade disrupts specific patterns of behavior during operant training. (A-D) An analysis of the microstructure of behavior of rats given pre-trial infusions of LY293558 (0, 0.01, or 0.1 μg) (see Fig. 2A,B). The 0.1-μg dose of LY293558 prevented (A) the learning-related decrease in the probability to make consecutive nose pokes, Pr(NP|NP), and (B) the increase in the probability to lever-press after retrieving a reward, Pr(LP|NP), as demonstrated by controls and the 0.01-μg group, until the task was well-learned. No reliable changes were observed in (C) the probability to retrieve a reward upon delivery, Pr(NP|Reinf), or (D) the latency to retrieve rewards. Post-learning infusions had no effect. Error bars indicate the SEM. Brackets and arrows beneath the x-axis indicate the frequency of pre-trial injections.

Figure 4.

NMDA receptor activity is not necessary for memory consolidation. (A,B) Pre-trial infusions of AP-5 (0 or 1 μg) impaired the acquisition of instrumental learning as measured by decreased (A) lever presses and (B) nose pokes. Infusions after the task was consolidated show no effect on memory retrieval or performance. (Inset) Lever presses made over the first three sessions. Vehicle group, n =7; 1 μg group, n =8. (C,D) Post-trial infusions of AP-5 (0 or 1 μg) failed to affect (C) lever-pressing or (D) nose-poking, indicating memory for the task was consolidated normally. Vehicle group, n = 7; 1 μg group, n = 8. Arrows next to session 3 in B and D mark the end of noncontingent reinforcement. For all panels, data are shown as the mean number of lever presses or nose pokes ± SEM. Brackets and arrows beneath the x-axis indicate the frequency of injections. (^**) Main effect of treatment on lever-pressing in the pre-trial condition, P < 0.01 (see Results for nose-poke statistics).

Figure 5.

NMDA receptor blockade differentially disrupts specific patterns of behavior during operant training. (A-D) An analysis of the microstructure of behavior of rats given pre-trial infusions of AP-5 (0 or 1 μg) (see Fig. 4A,B). (A) Unlike LY293558, AP-5 decreased the tendency to make consecutive nose pokes, Pr(NP|NP), while free rewards were given (see Materials and Methods), then increased the Pr(NP|NP) relative to controls until the task was well-learned. (B) AP-5 reduced the normal increase in the probability to lever-press after retrieving a reward and, in contrast to LY293558, AP-5 also (C) reduced the probability to retrieve rewards while (D) increasing the latency in which to retrieve them until the task was well-learned. Post-learning infusions had no effect. Error bars indicate the SEM. Brackets and arrows beneath the x-axis indicate the frequency of pre-trial injections.

Figure 6.

D1 receptor blockade does not affect memory consolidation. Pre-trial infusions of SCH23390 (0 or 1 μg) impaired the acquisition of instrumental learning as measured by decreased (A) lever presses and (B) nose pokes. Only infusions of SCH29330 after the task was consolidated significantly decreased lever-pressing, whereas a nonsignificant decrease in nose-poking was observed. (Inset) Lever presses made over the first three sessions. Vehicle group, n = 9; 1 μg group, n =8. Post-trial infusions of SCH23390 (0 or 1 μg) failed to affect (C) lever-pressing or (D) nose-poking, indicating that memory for the task was consolidated normally. Vehicle group, n = 8; 1 μg group, n = 7. Arrows next to session 3 in B and D mark the end of noncontingent reinforcement. For all panels, data are shown as the mean number of lever presses or nose pokes ± SEM. Brackets and arrows beneath the x-axis indicate the frequency of injections. (^*) Main effect of treatment over sessions 1-10 on lever-pressing, P ≤ 0.05. (†) Main effect of treatment over sessions 10-11 on lever-pressing, P ≤ 0.05 during the pre-trial condition (see Results for nose-poke statistics).

Figure 7.

Antagonism of D1 receptors produces disruptions in the microstructure of behavior similar to those caused by LY293558. (A-D) An analysis of the microstructure of behavior of rats given pre-trial infusions of SCH23390 (0 or 1 μg) (see Fig. 6A,B). Until the task was well learned, the 1-μg dose of SCH23390, like LY293558, prevented (A) the learning-related decrease in the probability to make consecutive nose pokes, Pr(NP|NP), and (B) the increase in the probability to lever-press after retrieving a reward, Pr(LP|NP), as demonstrated by controls. No reliable changes were observed in (C) the probability to retrieve a reward upon delivery, Pr(NP|Reinf), or (D) the latency to retrieve rewards. Post-learning infusions had no apparent effect. Error bars indicate the SEM. Brackets and arrows beneath the x-axis indicate the frequency of pre-trial injections.