A is for Addiction Research
Good science, like any other form of endeavor, thrives on fresh ideas and youthful enthusiasm. That is particularly true of addiction science, which, in deconstructing how drugs commandeer the brain's learning pathway, requires novel experiments, a willingness to take risks and sheer doggedness to advance. It is no surprise then that as the reputation of UCSF's Wheeler Center for the Neurobiology of Addiction grows, it is attracting student-scientists interested in making their research mark. And, as the four graduate students profiled here attest, this group may one day be making headlines as well.
Steve Shabel — It was during a brief stint in Ulrike Heberlein's laboratory that Steve Shabel first encountered a drunken fruit fly - and the larger question of how science might be used to explain addiction. "I was always interested in how the brain learns," says the 24-year-old Shabel. So when it came time to choose a rotation in UCSF's Program in Biological Sciences (PIBS), Shabel was quick to select the Ernest Gallo Clinic and Research Center - a research organization that is both partner to and supporter of the Wheeler Center's scientific odyssey.
The object of Shabel's attention was — and remains — the neurotransmitter known as dopamine, an important signaling molecule in addiction. Now working in Patricia Janak's laboratory, Shabel will soon join Antonello Bonci's team as he continues to track the role of dopamine in the brains of rats conditioned to associate the sound of certain tones with addictive behavior. "Once I have been able to measure and follow the changes in neurons, I'll take away the tones and see if dopamine by itself can induce the same response in the target neurons." In a companion experiment, Shabel plans to shut down the dopamine pathway, sound the tones and measure what does — and does not — happen in target neurons. Assuming the results confirm dopamine's importance, they will also suggest his next research questions: how does dopamine work and does it work alone? It is an agenda that should keep Shabel on the addiction trail as his career matures. "I have been given a lot of freedom here and I plan to use it well."
Elyssa Margolis, a 24-year-old PhD student in the laboratory of Wheeler Center director Howard Fields, brings an engineering perspective to the search for therapeutic drugs that might ameliorate addiction. A student in the Joint UCSF/UC Berkeley Graduate Bioengineering Program, Margolis is particularly interested in understanding the mechanisms underlying the behavior and emotions associated with addiction. For that reason, she has zeroed in on a class of natural painkilling drugs known as kappa opioids, which are known to have countervailing effects on the brain's reward system.
"Rats that have been given kappa opioids will avoid the room where they receive them," explains Margolis. While it is an interesting observation, it is far from a drug therapy that would take away an addict's uncontrollable preference for drugs of abuse, she insists. "We have to learn much more about how different opioids interfere with the dopamine signal, particularly into the region of the brain known as the Ventral Tegmental Area (VTA)."
For Margolis, matching global effects with major control points is akin to creating an engineering system. "I am more interested in inputs and outputs than the specific dynamic at the cell membrane," she explains. It boils down to whether a cell is going to fire or not. Studying kappa opioids has revealed that they inhibit dopamine by dialing in on dopamine-containing neurons in the VTA and keeping the lines busy so that no other signal gets through.
Margolis has also developed new respect for a class of so-called tertiary cells that resemble the dopamine cells, but that have a different "active ingredient." The role of these tertiary cells in forming the circuit has been largely ignored and therefore offers a tempting target for continued research. "It could be that we can't understand addiction until we understand what these cells do."
Irene Yun also made a research course correction after attending the Wheeler Center's inaugural seminar. "I was looking for a way to combine my background in psychology with my interest in neuroscience and came away from the seminar realizing that there were lots of cool possibilities."
Yun, a 26-year-old student in Howard Fields' laboratory, has long been interested in how the environment guides behavior. Drug addiction, particularly the cues associated with relapse — from sights to songs — provided an enticing series of questions. How can these environmental cues trigger relapse? And why had animal models of relapse not yielded more insight into human behavior?
In time, Yun realized that researchers studying cued behavior had been using a limited model. "Most animal studies of relapse rely on cues that are presented during reward delivery when the rat is feeling the drug effect," Yun explains. But humans are different. "The key is not delivery but access — like getting a paycheck, seeing a dealer, walking through a particular neighborhood."
As a result, Yun has created an animal "access model." In this controlled world, animals that press a lever while a buzzer is sounding get a drug; hitting the lever while the buzzer is off does not trigger a reward. Once the animal learns that the cue signals drug availability, hearing it will send conditioned rats scurrying to the bar in search of a reward. Following what happens at the cellular level — by recording from electrodes implanted in the brains of rats and recording and analyzing the neural circuits involved — should help unlock the mechanisms behind cued behavior. And that would be cool indeed.
Paul German had been dreaming of vision physiology when addiction science suddenly conjured up new possibilities. "I was a first-year graduate student when the Wheeler Center held its founding symposium in 1998. It was fantastic." What crystallized that day was a research question that in the three years since, the 28-year-old German has worked hard to answer: "What explains the 'drive states' of the human brain?"
To answer that question required that German adapt a model of motivated behavior, which he could then correlate with the activity of nerve cells in the region of the brain known as the nucleus accumbens. The model he chose was a simple box, divided into two rooms, each with its own colors and smells. The rats are allowed to explore the box, and they do so without any clear preference for one room over another. That changes once the rats have been locked into one room, injected with morphine and then given free rein to roam once the drug has worn off.
"They prefer the injection room," German notes, a clear case of conditioned preference — the animal equivalent of a crack house. "But what information do the nerve cells transmit?" German asks. "Is it the quality of the room or a state of craving?" He hopes to find out with ever more refined experiments and careful measurements of electrical activity among targeted neurons. "Some day we may be able to devise behavioral therapies that re-train the brain."
by Jeff Miller
Top photo: Clockwise: Steve Shabel, Elyssa Margolis, Irene Yun and Paul German. Photos by Robert Foothorap.