Dopamine D₂ receptors mediate two-odor discrimination and reversal learning in C57BL/6 mice

Background: Dopamine modulation of neuronal signaling in the frontal cortex, midbrain, and striatum is essential for processing and integrating diverse external sensory stimuli and attaching salience to environmental cues that signal causal relationships, thereby guiding goal-directed, adaptable behaviors. At the cellular level, dopamine signaling is mediated through D₁-like or D₂-like receptors. Although a role for D₁-like receptors in a variety of goal-directed behaviors has been identified, an explicit involvement of D₂ receptors has not been clearly established. To determine whether dopamine D₂ receptor-mediated signaling contributes to associative and reversal learning, we compared C57Bl/6J mice that completely lack functional dopamine D₂ receptors to wild-type mice with respect to their ability to attach appropriate salience to external stimuli (stimulus discrimination) and disengage from inappropriate behavioral strategies when reinforcement contingencies change (e.g. reversal learning). Results: Mildly food-deprived female wild-type and dopamine D₂ receptor deficient mice rapidly learned to retrieve and consume visible food reinforcers from a small plastic dish. Furthermore, both genotypes readily learned to dig through the same dish filled with sterile sand in order to locate a buried food pellet. However, the dopamine D₂ receptor deficient mice required significantly more trials than wild-type mice to discriminate between two dishes, each filled with a different scented sand, and to associate one of the two odors with the presence of a reinforcer (food). In addition, the dopamine D₂ receptor deficient mice repeatedly fail to alter their response patterns during reversal trials where the reinforcement rules were inverted. Conclusions: Inbred C57Bl/6J mice that develop in the complete absence of functional dopamine D₂ receptors are capable of olfaction but display an impaired ability to acquire odor-driven reinforcement contingencies. Furthermore, the ability of dopamine D₂ receptor deficient mice to adjust their responding to a previously reinforced stimulus when unexpected outcomes are encountered is significantly impaired. These findings suggest that signaling mediated by the dopamine D₂ receptor is important for regulating associative and reversal learning and may have implications for the treatment of human attention disorders.