Reward and autoreceptors

Both natural rewards and addictive drugs increase extracellular dopamine (DA) in the striatum. Although studies have found that DA receptors are involved in addiction, the results are conflicting. Susceptibility to drug addiction is correlated with reduced availability of striatal D₂ receptors, yet D₂ receptor knockout mice show reduced responses to drugs of abuse. These contradictory results may arise because there are two populations of D₂ receptors. Most D₂ receptors are postsynaptic, responding to DA release from striatal dopaminergic neurons. However, D₂ receptors are also expressed presynaptically on DA-releasing neurons (autoreceptors), which exert negative feedback. Previous genetic and pharmacological studies have not been able to differentiate between these two populations of D₂ receptors. On page 1033, Bello and colleagues dissect the selective role of D₂ autoreceptors and find that deleting D₂ autoreceptors increases DA synthesis and release, resulting in increased sensitivity to cocaine.

The authors created mice lacking D₂ receptors only in DA-releasing neurons (autoDrd2KO mice). Striatal dopaminergic neurons in autoDrd2KO mice did not show inhibitory currents in response to D₂ agonists. This lack of negative feedback was accompanied by increased DA synthesis and release. AutoDrd2KO mice were hyperactive, and hypersensitive to cocaine. They exhibited increased cocaine-seeking in a conditioned place preference procedure and worked harder for a food reward in an operant conditioning procedure, suggesting that the role of D₂ autoreceptors extends to natural rewards.