Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing

The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D-2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D-2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D-2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D-2 overexpression is reversed in the adult. Here we report that overexpression of striatal D-2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D-2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D-2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D-2 signaling in the adult regulates motivational process. Moreover, overexpression of D-2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.