First, Zhang and colleagues examine multiple polymorphisms in the D2 receptor gene and find that none of the "standard" ones that have been linked to clinical characteristics actually affected D2 receptor density in prefrontal cortex or striatum. However, they find that two other, previously unstudied polymorphisms altered the relative expression of short versus long isoforms of the D2 receptor, likely reflecting presynaptic and postsynaptic D2 receptors, respectively. These findings could provide a basis for understanding several perplexing effects in the literature, such as opposing effects of D2 receptor drugs on cognition in individuals with low and high working memory ability, who are shown here to have differential pre- versus postsynaptic D2 receptor function.

Further, the presynaptic receptor is thought to regulate phasic dopamine signaling via its autoreceptor functions (in addition to controlling glutamate release in corticostriatal terminals via the heteroreceptors alluded to in the article). Thus, based on current evidence, it is expected that these polymorphisms should affect not only working memory, but also positive and negative reinforcement learning processes thought to depend on phasic dopamine signaling, and which are clearly implicated in the development of addictive habits.

Finally, these polymorphisms are in linkage disequilibrium with some of the other standard D2 SNPs that have been associated with alcohol abuse, schizophrenia, and sensitivity to reinforcement, and therefore may provide a more direct mechanistic explanation for these prior associations.

View all comments by Michael J. Frank