Dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and...

The dopamine D2 receptor (D2) is implicated in drug addiction, learning and memory. Two isoforms of the D2 receptor, termed D2L (long form) and D2S (short form), have been identified. We previously generated mice lacking D2L (D2L-/-), but expressing functional D2S. In this study, we investigated the role of D2L in the positive and negative reinforcing properties of abused drugs and electrical stimuli, using D2L-/- mice as a model system. Mice were trained in three associative learning tasks: conditioned place preference to morphine and cocaine, conditioned place aversion to naloxone-precipitated morphine withdrawal, and active avoidance. D2L-/- mice, like wild type mice, developed a place preference to cocaine. In contrast to wild type mice, D2L-/- mice did not develop a place preference to morphine, nor did they attain a place aversion to morphine withdrawal. D2L-/- mice also failed to acquire avoidance behavior in response to electrical stimuli. There were no significant differences between D2L-/- and wild type mice in mu-opioid receptor density, morphine-induced locomotor stimulation and morphine withdrawal symptoms. These results suggest that D2L may have a greater impact than D2S on the rewarding aspects of morphine, and the aversive properties of morphine withdrawal and electrical stimulus. These findings also suggest that the presence of D2L is critical in the acquisition (learning) and/or retention (memory) of context-stimulus associations in certain situations. On the other hand, D2L is not essential for the rewarding aspects of cocaine and for the development of morphine dependence. Thus, these studies reveal distinct functional roles of D2L and/or D2S in drug addiction and avoidance learning, which may lead to a better understanding of the neurobiological basis underlying these behaviors.