Cocaine Inhibits Dopamine D(2) Receptor Signaling via Sigma-1-D(2) Receptor Heteromers

Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D(1)-like family of dopamine receptors and inputs of aversion coming from neurons containing the D(2)-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D(1) reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D(2) receptors function, we present evidence of σ(1) receptor molecular and functional interaction with dopamine D(2) receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D(2) receptors (the long isoform of the D(2) receptor) can complex with σ(1) receptors, a result that is specific to D(2) receptors, as D(3) and D(4) receptors did not form heteromers. We demonstrate that the σ(1)-D(2) receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ(1) -D(2) receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ(1) knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D(2) receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D(1) and D(2) receptor containing neurons in the brain.