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 µg/0.5 µL), LY293558 (0.01 or 0.1 µg/0.5 µL), and SCH23390 (1 µg/0.5 µL), 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.In order to survive in changing environments, animals must be able to acquire, consolidate, and retrieve pertinent information regarding a given stimulus situation. The ability to learn associations between various stimuli and events, including motor actions, is the basis of instrumental learning (Rescorla 1991;Dickinson and Balleine 1994). Appetitive instrumental learning occurs when an animal associates its behavior with a favorable outcome such as food, sex, or the avoidance of pain. For instance, in a common experimental model of instrumental learning, a hungry rat learns to press a lever to obtain a food reward.The nucleus accumbens (NAc) and its associated circuitry have been linked to the acquisition of adaptive motor responses and the control of behaviors related to natural reinforcers (Setlow 1997;Parkinson et al. 2000;Corbit et al. 2001). Because of the rich glutamatergic and dopaminergic innervation of the NAc from regions associated with motivational, cognitive, and sensory processes, many studies have focused on the role of these neurotransmitter systems with respect to instrumental and incentive learning (Berridge and Robinson 1998;Cardinal et al. 2002;Beninger and Gerdjikov 2004;Kelley 2004). For example, blockade of glutamate (N-methyl-D-aspartate, NMDA) or dopamine D1 receptors within the NAc core potently impairs instrumental learning, and coinfusion of low, individually ineffective doses of AP-5 and SCH23390 also prevents learning, suggesting that convergence of both systems on post-synaptic neurons is required In the aforementioned studies, pre-trial blockade of NMDA and D1 receptors appeared to prevent the encoding (or acquisition) of information; however, it is possible that disruption of the consolidation phase of learning or retrieval could have contribut...

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

“…Blockade of nucleus accumbens core D1 and NMDA receptors inhibited the acquisition of appetitive instrumental Pavlovian conditioning (Smith-Roe and Kelley, 2000) but had no effect on memory consolidation (Hernandez et al, 2005). Although CPP is noninstrumental Pavlovian conditioning, the finding that activation of D1 receptors had no effect on CPP consolidation may be in accord with the latter study.…”

Behavioral functions of the mesolimbic dopaminergic system: An affective neuroethological perspective

“…For example, inhibition of DA transmission within the amygdala reduces fear-potentiated startle (Greba & Kokkinidis, 2000), the retrieval of conditioned-fear associations (Nader & LeDoux, 1999), and has a general anxiolytic effect (de la Mora et al, 2005). On the other hands, rats self-administer damphetamine directly in the central nucleus of the amygdala (Chevrette et al, 2002), while DA transmission in the basolateral amygdala contribute to the establishment and reinstatement of instrumental and associative reward learning (Zarrindast et al, 2003;Andrzejewski et al, 2005;Alleweireldt et al, 2006). In sum, both positive and negative emotional behavioral dispositions appear to be stimulated by DA in the amygdala.…”

“…On the other hand, the DA transmission in the core may be involved in the expression of this emotion in the BG-thalamocortical circuits and then in the "control of goal-directed behavior by associative process" (Ito et al, 2004). Indeed, excitotoxic lesions of Nacc core disrupt Pavlovian approach behavior (Parkinson et al, 2000), conditioned reinforcement (Parkinson et al, 1999) and Pavlovian to instrumental transfer (Hall et al, 2001), while coincident activations of D1 receptors and NMDA receptors in the Nacc core are necessary for associative learning (Smith-Roe et al, 2000;Wickens et al, 2003;Hernandez et al, 2005).…”

Chronic administration of morphine is associated with a decrease in surface AMPA GluR1 receptor subunit in dopamine D1 receptor expressing neurons in the shell and non-D1 receptor expressing neurons in the core of the rat nucleus accumbens

“…Coordinated communication between glutamatergic and dopaminergic systems in the Acb is emerging as a critical signaling complex associated with reward and neural plasticity accompanying reward-related learning (Hernandez et al 2005), processes associated with opioid exposure. Thus, indirect effects of μOR stimulation on glutamatergic and dopaminergic signaling may form an alternative framework for conceptualizing the mechanisms of opioiddependent plasticity in the Acb.…”