Response-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core

Abstract

The nucleus accumbens, a site within the ventral striatum, is best known for its prominent role in mediating the reinforcing effects of drugs of abuse such as cocaine, alcohol, and nicotine. Indeed, it is generally believed that this structure subserves motivated behaviors, such as feeding, drinking, sexual behavior, and exploratory locomotion, which are elicited by natural rewards or incentive stimuli. A basic rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. It is likely, therefore, that the nucleus accumbens may serve as a substrate for reinforcement learning. However, there is surprisingly little information concerning the neural mechanisms by which appetitive responses are learned. In the present study, we report that treatment of the nucleus accumbens core with the selective competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol/0.5 microl bilaterally) impairs response-reinforcement learning in the acquisition of a simple lever-press task to obtain food. Once the rats learned the task, AP-5 had no effect, demonstrating the requirement of NMDA receptor-dependent plasticity in the early stages of learning. Infusion of AP-5 into the accumbens shell produced a much smaller impairment of learning. Additional experiments showed that AP-5 core-treated rats had normal feeding and locomotor responses and were capable of acquiring stimulus-reward associations. We hypothesize that stimulation of NMDA receptors within the accumbens core is a key process through which motor responses become established in response to reinforcing stimuli. Further, this mechanism, may also play a critical role in the motivational and addictive properties of drugs of abuse.

Figure 1

Influence of NMDA antagonist infusion into nucleus accumbens core on acquisition of lever-pressing for sucrose pellets. Animals received intra-accumbens infusion of AP-5 (5 nmol) or vehicle (saline) on the first four test days; on the remaining training days, no infusion was given except on day 10, when all animals (including those previously infused with vehicle) were infused with AP-5. (A) Lever presses. In addition to treatment effect ∗∗, there were significant day × treatment ††, [F(8,112) = 4.7, P < 0.001], lever × treatment [F(1,14) = 17.6, P < 0.001], and day x lever x treatment [F(8,-112) = 3.9, P < 0.001] interactions, when all 9 days were analyzed. See text for further differences between groups. Also note that a separate ANOVA of days 3 and 4 (when animals were still receiving treatment) revealed a significant treatment effect {[F(1,14) = 7.1, P < 0.01], day × treatment interaction [F(1,14) = 13.4, P < 0.01], lever × treatment interaction [F(1,14) = 16.7, P < 0.001], and day × lever × treatment interaction [F(1,14) = 18.9, P < 0.001]}. These interactions indicate that on these days, control animals were beginning to learn to lever-press and to discriminate between correct and incorrect levers, whereas the AP-5 treated rats were not. Inc, incorrect responses. (B) Nose-pokes into food tray during learning. ∗∗, Significant effect of treatment; ††, day × treatment interaction, P < 0.01.

Figure 2

Influence of NMDA antagonist infusion into nucleus accumbens shell on acquisition of lever-pressing for sucrose pellets. See legend of Fig. 1 for further details. (A) Lever presses. ††, P < 0.01, day × lever × treatment interaction. ∗∗, P < 0.01, day × lever interaction for days 4 and 5. Inc, incorrect responses. (B) Nose-pokes into food tray.

Figure 3

Acquisition of responding for CR in animals treated previously with AP-5 or vehicle in the nucleus accumbens core during discriminated approach (classical conditioning) training, as shown in Table 2. (Note that animals did not have intra-accumbens treatment during the tests for which data is shown above.) Animals were exposed to CR and NCR (no CR) levers on days 1–3, and on day 5, with no drug treatment. On day 4, all rats were given the dopamine-releasing drug pipradrol (5 mg/kg i.p.). (A) Comparison of responding between days 3 and 5 revealed significant effect of day (∗∗, P < 0.01) and a significant day × lever interaction (†, P < 0.05), indicating that treatment with pipradrol on day 4 potentiated acquisition of responding. On days 1–3 animals also showed significant preference for CR lever, regardless of pretreatment (see text). C, correct (CR) lever; I/Inc, incorrect (NCR) lever. (B) Treatment with pipradrol markedly and selectively enhanced responding for the CR lever, although magnitude of enhancement varied considerably between rats.