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

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 (Smith-Roe and Kelley 2000). The coincident detection of glutamate and dopamine signals has been shown to be required for long-term potentiation (Wickens et al. 1996; Arbuthnott et al. 2000; Floresco et al. 2001; Kerr and Wickens 2001) by regulating the transcription and translation of plasticity-related immediate-early genes through various second messenger systems (Sharp et al. 1995; Sutton and Beninger 1999; Berke and Hyman 2000; Horvitz 2002; Reynolds and Wickens 2002; Steward and Worley 2002; Kelley 2004). Indeed, post-training inhibition of cAMP-dependent protein kinase (PKA) (Baldwin et al. 2002a) or inhibition of de novo protein synthesis within the NAc core (Hernandez et al. 2002) prevents the consolidation, or long-term stabilization, of memory for response-outcome contingencies. 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 contributed to the observed impairments. Thus, it remains unclear as to whether glutamate and dopamine are required only to initiate plasticity or whether these neurotransmitters also modulate consolidation. As such, post-trial infusions are often used to temporally dissociate encoding from consolidation (Breen and McGaugh 1961). Therefore, the present study compared the effects of pre- and post-trial infusions of antagonists specific for NMDA or D1 receptors in the NAc core of male Sprague-Dawley rats in the same task. In addition, we investigated the effects of an antagonist specific for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) receptors, since their role in instrumental learning has not yet been described. Lastly, we used a time-stamp behavioral analysis program that records the temporal relationship of task-related events and behaviors during training in order to gain insight into which behaviors are critical for instrumental learning.