Why Does Cocaine Get You High?

The molecular mechanism has been decoded

Scientists had long known that cocaine gets you into another universe: it confuses both neuronal dopamine and glutamate receptors, but the molecular mechanism was unknown.

Now, researchers at the University of Missouri, Kansas City School of Medicine have solved a part of the puzzle.

Using rats, they have mapped the interactions between the two types of receptors for signals from their neighboring neurons. Cocaine turned a component of dopamine receptor to grab onto a component of glutamate receptor, provoking a disturbance in the normal activity of the glutamate receptor.

Nerve impulses pass from one nerve cell to another by bursts of chemicals called neurotransmitters. The neurotransmitters activate receptors on the receiving neurons, which induce the nerve impulses in the receiving cell being transmitted further. The receptors also change themselves in complex ways to tune the sensitivity of the receiving neuron to impulses.

The team discovered that cocaine inhibited the activation of glutamate receptors by affecting a specific component (subunit), named NR2B. A specific subunit of dopamine receptors, called D2R, was attaching to the NR2B and prevented the normal activity of the glutamate receptor. Normal activation involves phosphorylation of the NR2B (addition of a phosphate molecule) by an enzyme called a kinase, and the cocaine-induced D2R attachment blocked this chemical event.

The D2R-NR2B interaction took place specifically in the striatum, the brain region already highly associated with the cocaine's stimulating effects. Not only this, but the scientists found that the rats changed behaviorally and got dependence, actively searching the drug. "These results provide strong evidence supporting a critical role of the D2R-NR2B interaction in mediating cocaine's effect on [kinase binding and phosphorylation] and in constructing a full-scale motor response to cocaine," wrote the research team.