Dopamine D2 autoreceptors in the mouse midbrain play a critical role in the feedback regulation of dopamine transmission, and influence both food-seeking behavior and an animal's sensitivity to the rewarding properties of cocaine. These findings, published online this week in Nature Neuroscience, provide an opportunity to better understand the role of D2 autoreceptors in feedback regulation and their role in reward sensitivity.

Dopamine (DA) neurotransmitters help control many complex brain functions ranging from planning of motor activities to predicting goal- and reward-oriented behavior, such as food intake. DA pathways in the brain are also implicated in compulsive behavior such as drug abuse. Though most D2 receptors are present postsynaptically at non-dopaminergic neurons, there are also D2 autoreceptors present on DA-releasing neurons, and these autoreceptors produce feedback inhibition of DA transmission. Previous work has suggested that reduced autoreceptor availability could be linked to impulsivity, such as seen in drug abuse, and vulnerability to relapse. However, previous pharmacological and genetic approaches have been unable to conclusively address the selective importance of the feedback regulation of D2 receptors.

Marcelo Rubinstein and colleagues found that mutant mice that lack D2 autoreceptors on DA neurons in the midbrain lack the normal inhibition of dopamine release, which would be regulated through the feedback system. These mice exhibit increased preference for cocaine and food rewards. The authors also found that these mice were supersensitive to the psychomotor effects of cocaine.