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 (A P-5; 5 nmol͞0.5 l bilaterally) impairs responsereinforcement learning in the acquisition of a simple leverpress 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 stimulusreward 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.The basal ganglia constitute a group of structures in the mammalian forebrain that have traditionally been considered as motor control regions. Indeed, one of the most prominent signs of basal ganglia disorders is motor disturbance or impairment (1). However, in more recent years empirical work has implicated the striatum (a major component of the basal ganglia) in cognition, reinforcement mechanisms, and sensorimotor integration (2, 3). Although the outflow of the striatum indeed reaches major extrapyramidal motor centers such as globus pallidus, substantia nigra, and subthalamic nucleus, the input to this structure, arising from the neocortex, limbic system, and midbrain, suggests that it plays a complex integrative role in adaptive motor actions (4, 5).One region of the striatum that has received considerable attention in this regard is the nucleus accumbens. The nucleus accumbens is best known for its role in mediating the reinforcing and rewarding properties of drugs of abuse (6). Drugs such as cocaine, heroin, alcohol, and even nicotine are hypothesized to produce their rewarding effects via activation of accumbens dopamine (7), and it has been recently postulated that chronic neuroadaptations in this system may underlie the addiction process (8...

NMDA, But Not Dopamine D2, Receptors in the Rat Nucleus Accumbens Are Involved in Guidance of Instrumental Behavior by Stimuli Predicting Reward Magnitude

“…Correspondingly, intra-NAc infusion of APV impaired response-reinforcement learning only in the early stages of acquisition but not in well trained animals (Kelley et al, 1997). Furthermore, motor impairments after intra-NAc infusion of APV were not observed.…”

Out of Context: NMDA Receptor Antagonism in the Avian 'Prefrontal Cortex' Impairs Context Processing in a Conditional Discrimination Task.

“…Although there are a few exceptions (Lee, Choi, Brown, & Kim, 2001;Roesler, Kuyven, Kruel, Quevedo, & Ferreira, 1998), unimpaired recall has been demonstrated for various conditioning scenarios (Baron & Moerschbaecher, 1996;Bohn et al, 2003;Churchill et al, 2001;Di Ciano, Cardinal, Cowell, Little, & Everitt, 2001;Kelley et al, 1997;Smith-Roe et al, 1999;Xu, Bazner, Qi, Johnson, & Freidhoff, 2003). However, in most of these studies, the requirement was to recall unambiguous stimulus-response associations, with one stimulus being the Sϩ and the other being the SϪ.…”

Glutamatergic mechanisms in addiction

“…70 Injection of the NMDA receptor antagonist AP-5 into the NAS core impaired the acquisition (but not the performance) of this task, while leaving feeding and locomotor responses and the formation of stimulus-reward associations intact. Co-infusion of low doses of the D1 receptor antagonist SCH23390 and AP-5 strongly potentiated the impairment in the acquisition of intrumental learning that each drug produced when administered alone, suggesting that a glutamate-dopamine interaction (co-activation of NMDA and D1 receptors) is a key mechanism in the acquisition of appetitive instrumental learning.…”