Single Cocaine Exposure Triggers
Long-Lasting Surge Of Brain Activity

A single exposure to cocaine triggers a week-long surge of activity in a brain region central to the development of addiction, according to new research on mice published this week in Nature. The changes may prime the brain for addiction, the researchers say.

The first drug exposure appears to throw open a window of vulnerability that may make the brain acutely responsive to subsequent exposures for a week to ten days, accelerating the molecular process of memory formation that underlies addiction, according to the scientists.

The single exposure doubles the responsiveness of dopamine neurons, known to play a key role in the experience of a drug high and subsequent drug craving.

The research led by a team at UCSF's Ernest Gallo Clinic and Research Center provides the first direct evidence that a single cocaine exposure -- comparable in humans to a recreational dose -- causes dramatic changes in the brain like those underlying learning and memory, the scientists report.

"The study shows that the capacity for strengthening connections between nerve cells - the basis for learning and memory - can be usurped by drugs of abuse," said Antonello Bonci, MD, senior author of the paper. Bonci is University of California, San Francisco assistant professor of neurology and a principal investigator at the Gallo Center.

"The single exposure appears to hijack the brain's normal molecular mechanisms of memory formation for around a week," he said.

Other research has shown that learning and memory are crucial elements in the development of addiction, and involve activation of the same type of brain cells -- the dopamine neurons -- in this same brain region, known as the ventral tegmental area, or VTA.

In a widely used laboratory model of the molecular changes that accompany learning, chemical connections are strengthened between neurons that release the neurotransmitter glutamate and their target neurons. While this popular model is based on studies in the hippocampus region of the brain, the new study used electrophysiological tests of brain tissue from cocaine-treated mice to demonstrate the same dynamics - known as long-term potentiation or LTP -- in the dopamine-rich VTA brain region.

"Lots of people have studied LTP in brain slices, but demonstrating that this key process actually occurs following any kind of learning has been difficult," said Mark Ungless, PhD, a post-doctoral scientist at UCSF and lead author on the paper.

When it reaches dopamine neurons, glutamate activates "excitatory" NMDA receptors, which in turn change the properties of a second type of excitatory receptor, called AMPA. The result is a long-lasting increased activity of AMPA receptors in response to glutamate. The AMPA activity is converted into electrical impulses which pass very rapidly along the neuron, triggering release of dopamine. This is long-term potentiation, the physiological hallmark of learning that the team measured.

The changes in brain neuron activity induced by the single cocaine exposureare stunning, said Ungless.

"When you learn something, you might expect to see a change in very few synaptic connections - the junctions between communicating neurons. What's so amazing is that nearly all dopamine neurons are affected by this single cocaine exposure. This kind of response is extremely rare, and would have a profound effect throughout the brain, particularly other areas involved in addiction."

Since the dopamine "reward system" permeates most brain regions, the researchers expect that the robust neural changes found in the study affect a wide range of behaviors related to drug abuse, in particular, the neural process underlying increased sensitivity to repeated drug exposure: the essence of addiction.

The powerful neural changes found in the study may underlie drug relapse, the researchers say, in which just a single exposure to a drug after prolonged abstinence can induce renewed drug-seeking behavior. In addition, they believe that the strong surge of activity they measured most likely takes place as a result of exposure to most other drugs of abuse as well, since research with mice and rats has shown that nicotine, morphine, amphetamine and alcohol all affect glutamate receptors, the key molecules involved in the cocaine study.

Ungless and Bonci hope that this research can inform new approaches to treatment of drug addiction. "The question," Bonci said, "is how to develop drugs that interfere with these cocaine-induced changes but not with normal memory formation. This is something we plan to explore."

* * *

Co-authors on the paper with Ungless and Bonci are Jennifer L. Whistler, PhD, principal investigator at UCSF's Gallo Clinic and Research Center; and Robert C. Malenka, MD, PhD, professor of psychiatry at Stanford University School of Medicine.

This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B. & J.L.W) and by grants from the NIH (R.C.M.).

The Ernest Gallo Clinic & Research Center (EGCRC) at the University of California, San Francisco (UCSF) was established in 1980 to study basic neuroscience and the effects of alcohol and drugs of abuse on the brain. It is the only center studying alcoholism in the United States that is based in a department of neurology. In the 20 years since its inception, the EGCRC has grown to a staff of over 150 and occupies nearly 77,000 square feet of newly constructed space in Emeryville, CA. The EGCRC has major neuroscience laboratories in cell biology, molecular biology, biochemistry, pharmacology, neurophysiology, behavioral pharmacology and physiology, and invertebrate, mouse and human genetics.

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