Targeted Deletion of the GluR-1 AMPA Receptor in Mice Dissociates General and Outcome-Specific Influences of Appetitive Rewards on Learning Alexander W. Johnson Cardiff University David Bannerman and Nick Rawlins Oxford University Rolf Sprengel Max-Planck-Institut fu ¨r Medizinische Forschung Mark A. Good Cardiff University The authors assessed the hypothesis that deletion of the GluR-1 subtype of the alpha-amino-3-hydroxy- 5-methyl-4-isoxazole propionate (AMPA) receptor in mice disrupts the associative activation of a sensory-specific representation of an appetitive reward. In Experiment 1, mice received training on a Pavlovian–instrumental transfer task. In the test stage, conditioned stimulus (CS) presentations enhanced instrumental actions in both groups. However, this effect was specific to the action that shared the same outcome as the CS in wild-type (WT), but not GluR-1 / , mice. In Experiment 2, the mice were trained on a heterogeneous instrumental chain in which rewards were obtained for emitting 1 response (R1, that was distal to reward delivery), followed by a 2nd response (R2, that was proximal to reward delivery). A change in general motivational state (from hungry to sated) reduced the number of R2 responses in both groups. In contrast, an outcome-specific satiety treatment produced a selective decline in R1 responding only in WT mice. The results support the hypothesis that GluR-1 deletion impairs the associative activation of a representation of the sensory-specific incentive motivational properties of an appetitive reward. Keywords: AMPA, receptor, motivation, mouse, amygdala Recent evidence suggests that mice lacking the GluR-1 subunit of the -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor are impaired in learning specific aspects of stimulus– outcome associations (Mead & Stephens, 2003). Thus, GluR-1 / mice display normal approach to a cue that has previ- ously signaled reward, but are impaired in learning a novel instru- mental response to obtain presentations of a conditioned stimulus (CS; conditioned reinforcement; Mackintosh, 1974), or respond under a second-order schedule of reinforcement. These results suggest that mice with a targeted deletion of the GluR-1 AMPA receptor subunit are impaired in processing the affective or moti- vational properties of outcomes (Mead & Stephens, 2003). More recently, we proposed that the GluR-1 deletion impaired incentive learning processes (Johnson, Bannerman, Rawlins, Sprengel, & Good, 2005). More specifically, we suggested that GluR-1 / mice are unable to use a cue or an action to access a representation of the sensory-specific motivational properties of a reward (such as its texture, sweetness, etc.; e.g., Dickinson & Balleine, 1994). In contrast, learning about the general motiva- tional or arousing properties of an outcome (i.e., whether it is a positive or negative reward) is independent of GluR-1 receptors (Johnson et al., 2005). This hypothesis is able to account for the preserved capacity of a Pavlovian CS to augment instrumental behavior (Pavlovian–instrumental transfer; PIT) in GluR-1 / mice if one assumes that the PIT task reflects the general affective or arousing properties of reward on performance (Mead & Ste- phens, 2003; Dickinson & Dearing, 1978). Experiment 1 tested this proposal using an outcome-specific form of the PIT procedure. This task allows the simultaneous assessment of both a general and an outcome-specific form of Pavlovian-to-instrumental transfer (Blundell, Hall, & Killcross, 2001; Corbit & Balleine, 2005). We predicted that GluR-1 deletion would not disrupt changes in per- formance reflecting a general Pavlovian–instrumental transfer ef- fect (Mead & Stephens, 2003) but would disrupt the ability of a CS to specifically enhance an instrumental action that shared the same outcome as the CS. The analysis of the GluR-1 / deficit offered by Johnson et al. (2005) asserts that these mice are unable to use a cue or action to activate a sensory-specific representation of an outcome. An alter- native interpretation is that on tasks that involve a selection be- tween different actions GluR-1 / mice are unable to modulate Alexander W. Johnson and Mark A. Good, School of Psychology, Cardiff University, Cardiff, Wales, United Kingdom; David Bannerman and Nick Rawlins, Department of Experimental Psychology, Oxford Uni- versity, Oxford, England, United Kingdom; and Rolf Sprengel, Department of Molecular Neurobiology, Max-Planck-Institut fu ¨r Medizinische For- schung, Heidelberg, Germany. Correspondence concerning this article should be addressed to Alex- ander W. Johnson, who is now at the Department of Psychological and Brain Sciences, Johns Hopkins University, 3400 North Charles Street, Baltimore MD 21218; or to Mark A. Good, School of Psychology, Cardiff University, Park Place, Cardiff CF10 3AT, UK. E-mail: awj@jhu.edu or Good@cardiff.ac.uk Behavioral Neuroscience Copyright 2007 by the American Psychological Association 2007, Vol. 121, No. 6, 1192–1202 0735-7044/07/$12.00 DOI: 10.1037/0735-7044.121.6.1192 1192