Molecular Mechanism of Cocaine High Revealed

Cocaine's boost derives from reward-prompting receptors actively blocking their signaling counterpart, according to new research.

Cocaine--a stimulating alkaloid crushed out of the leaves of the coca plant--has been reported to increase euphoria and energy as well as to trigger a mind-killing addiction in humans. The appeal is not limited to our species; rats and other animals given access to the drug will pursue it with a vigor normally reserved for procreation. This vigorous drive for the drug derives from its ability to stimulate the brain's reward pathways, altering the chemical dance of neurotransmitters that tells us what is good to do--again and again and again. Neuroscientist John Wang of the University of Missouri-Kansas City and his colleagues have now traced that effect to one of the brain's most basic molecular mechanisms.

Previous research has shown that cocaine triggers the reward pathway by activating the mesolimbic dopamine system--a series of neurons that originate near the base of the brain and project signals to its front. Their first stop en route is a section known as the striatum, where the signals are first received. These signals inhibit the release of the neurotransmitter glutamate and increase the amount of the neurotransmitter dopamine by blocking the latter's normal reabsorption into the synapses that released it.

Taking a closer look at this process, Wang and his colleagues examined the brains of rats after they had been injected with the drug. They found that in the striatum the dopamine receptors known as D2 interfered with the normal function of some glutamate receptors--known as NR2B--by blocking their activation.

In living rats, researchers found that animals dosed with other drugs that mimicked these neuroreceptor effects engaged in similar activities: intensive sniffing, biting and motion in their cages. In fact, when dosed with cocaine, the rats both traveled more broadly and more frenetically in cages that had been outfitted with a crisscrossing grid of lasers that enabled software to track the subjects' movements, according to Wang.

The effect seems to be confined to the striatum, though the receptors involved are also present in other regions of the brain known to be involved in cocaine's effect, such as the amygdala. But this game of musical chairs between glutamate and dopamine receptors seems key to the drug's impact, the researchers write in the paper presenting their finding in the December 7 Neuron. If the NR2B glutamate receptors in the neurons of the striatum are not blocked, the rats don't get that extra energy bump.

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