Role of D4 receptors of the prefrontal cortex in executive functioning

The Attentional Set Shifting Task (ASST) is a rodent analog of the Wisconsin Card Sorting Task (WCST), which measures executive functioning. The ASST tests for reversal of stimulus-response learning and the formation and maintenance of attentional sets. D4 receptor antagonism has been shown to improve performance of visual discrimination in drug naïve rats. The study presented here questioned if a D4-specific antagonist, L-745,870, could have a similar effect on animals even after being treated with repeated doses of cocaine, amphetamine or the D2/D3 receptor agonist quinpirole. Cocaine treated rats showed impairments in both reversals and attentional shifts, while amphetamine impaired only reversal stages and quinpirole only impaired attentional shifts. All groups, however, when pretreated with the D4 antagonist L-745,870 improved on previously impaired stages. D4 antagonism also increased the latency to respond in some cases. D4 receptors are involved in NMDA receptor functioning and striatal-cortical loops that executive functioning depend on. Also, D4 receptors play a role in cue salience and by blocking these receptors, animals display less attachment to previously rewarded cues. Results of the study can help elucidate this role and have implications for targeting D4 receptors as cognitive enhancers.