Reward‐seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors

The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4^?/?) and their wild‐type (WT) littermates, neonatally treated with 6‐hydroxydopamine (6‐OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food‐pellet was delivered after every lever press, showed that 6‐OHDA‐treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4^?/? mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two‐choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward‐paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4^?/? mice were as efficient as their normodopaminergic Drd4^?/? siblings in selecting the reward‐paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs. Synapse 63:991–997, 2009. © 2009 Wiley‐Liss, Inc.