http://www.sciam.com/article.cfm?chanID=sa003&articleID=5A1BB998-E7F2-99DF-3BE3969781E4EBD9
Molecular Mechanism of Cocaine High Revealed
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. --David Biello
http://news.sawf.org/Health/29471.aspx
How cocaine gives its hyperactive high
Washington, Dec 7: That cocaine, a stimulating alkaloid crushed out of the leaves of the coca plant—increases euphoria and energy as well as triggers off a mind-killing addiction in humans, is well known.
But researchers have now for the first time shed light on how it causes its effect on the brain, by tracing the hyperactive high of cocaine to interactions between two types of receiving stations in neurons for nerve signals from their neighbors.
John Wang, of the University of Missouri, Kansas City School of Medicine, and his colleagues who conducted studies in rats found that when the animals received cocaine, a component of a receptor for the neurotransmitter dopamine tends to grab onto a component of a receptor for glutamate.
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.
The researchers found that in the striatum of the brain the dopamine receptors known as D2 interfered with the normal function of some glutamate receptors--known as NR2B--by blocking their activation.
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.
The study is published in the December 7 issue of the journal Neuron. (ANI)
http://www.eurekalert.org/pub_releases/2006-12/cp-chc120106.php
Cocaine high caused by interference in neuronal receiving stations
Researchers have found evidence for a fundamental molecular mechanism underlying the hyperactive high of cocaine. In studies with rats, they have traced the effect to interactions between two types of receiving stations in neurons for nerve signals from their neighbors. The researchers' studies in rats found that when the animals received cocaine, a component of a receptor for the neurotransmitter dopamine tends to grab onto a component of a receptor for glutamate. The result, they found, was interference with normal activation of this glutamate receptor.
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.
The researchers include Xianyu Liu, Limin Mao, Guochi Zhang, Nikhil K. Parelkar, Eugene E. Fibuch, Michelle Haines, and John Q. Wang of University of Missouri, Kansas City School of Medicine in Kansas City, MO; Xiangping Chu, Minghua Li, and Zhigang Xiong of Robert S. Dow Neurobiology Laboratories, Legacy Research in Portland, OR; Min Wang and Fang Liu of University of Toronto in Toronto, Canada; Hongxiang Lan and Kim A. Neve Oregon Health and Science University and Veterans Affairs Medical Center in Portland, OR.
This work was supported by the NIH grants DA010355 (J.Q.W.) and MH061469 (J.Q.W.). We thank Dr. Xiaoqiang Yu, Dr. Nilofer Qureshi, and Brian Vukusic for technical support and comments, and Dr. Yves Auberson for providing NVP-AAM077.
Liu et al.: "Modulation of D2R-NR2B Interactions in Response to Cocaine." Publishing in Neuron 52, 897–909, December 7, 2006. DOI 10.1016/j.neuron.2006.10.011 www.neuron.org
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