John Wang, of the University of Missouri, Kansas City School of Medicine, and his colleagues published their findings in the December 7, 2006, issue of the journal Neuron, published by Cell Press.
Neurons trigger nerve impulses in their neighbors by launching bursts of chemicals called neurotransmitters at them. The neurotransmitters activate protein receptors on the receiving neurons, which induce the nerve impulses in the receiving cell. These receptors also adjust themselves in complex ways to alter the sensitivity of the receiving neuron to stimulation.
Researchers had long known that cocaine affects both dopamine and glutamate receptors on neurons, but the molecular details of those effects were unknown. In their experiments, Wang and colleagues first determined that cocaine reduces the activation of glutamate-responsive neurons by affecting a specific component, or subunit, of the receptor, called NR2B.
Further experiments revealed that when rats were given cocaine, a specific subunit of dopamine receptors, called D2R, tended to attach to the NR2B subunit and was responsible for preventing the normal activation of the glutamate receptor. Such activation normally involves addition to NR2B of a molecular group called a phosphate by an enzyme called a kinase, and the cocaine-induced D2R attachment blocked this event.
Wang and his colleagues found that this interaction between D2R and NR2B occurred specifically in the striatum of the brain—the region known to be responsible for cocaine's stimulating effects.
The researchers also analyzed whether this interaction between D2R and NR2B affected the rats' behavioral response to cocaine—specifically the hyperactivity and intensive sniffing and biting the drug elicits in the animals. They found that drugs that either activated the D2R subunit or inactivated the NR2B subunit tended to enhance such behavioral responses to cocaine.
"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," concluded the researchers.