The Catalyst

Lab uncovering clues to relapse, addiction

By Dawn Brazell
Public Relations

Smokers who’ve tried to kick the habit and failed, take heart.

A recent study published in the Proceedings of the National Academy of Sciences by MUSC researchers casts light on the brain biology of nicotine relapse that can fundamentally shift how cigarette addiction is treated, said Peter Kalivas, Ph.D., professor and co-chair in the Department of Neurosciences.

Above, Dr. Peter Kalivas (left) with research associates Dr. Cassandra Gipson, lead author on the study, and Dr. Yoni Kupchik.
Dr. Peter Kalivas (left) with research associates Dr. Cassandra Gipson, lead author on the study, and Dr. Yoni Kupchik.

The two-year study evolved as researchers in his lab shifted their focus to look at addiction as a compulsive, relapsing disorder, studying what’s happening in the signaling in the brain that causes relapse, he said.

An addiction researcher, Kalivas said the field traditionally has relied on replacement therapies to treat drug dependent patients, such as giving methodone for heroin and varenicline (trademarked Chantix) for smoking cessation.

“That’s the state of the art right now in the treatment of addiction. The experiments in this report point out new avenues to treat the impaired ability to regulate a maladaptive habit, drug use in the case of smoking. If these avenues become a focus of pharmaceutical development, it’s a very different focus than we’ve had to date. We may be dealing with the pathology that is mediating this behavior regardless of whether the maladaptive behavior is associated with drugs, eating or gambling. It’s potentially a whole new way of looking at drug development for treating addiction.”

Kalivas and Cassandra Gipson, Ph.D., lead author on the study, said they were surprised by the study’s results. Researchers in Kalivas’ lab study the neuroplasticity underlying the development of addiction to drugs of abuse. They had hoped that the signaling pathologies found in the brain in previous cocaine and heroin studies might also play out for nicotine, but they didn’t expect the findings to be so close.

The idea behind the study was this: People know addictive drug use leads to negative consequences, ranging from difficulty coping with family and job issues to serious health problems, yet many still cannot control their habitual, drug-seeking behavior, he said. There’s a disconnect in the regulation of brain circuits between the decision-making frontal cortex and the nucleus accumbens, the portal by which the frontal cortex can regulate habit circuitry. Gipson said they decided to measure signaling between these areas while nicotine- addicted animals were in the process of relapsing.

“While the animal is relapsing, we can measure things like an increase in glutamate, which is a neurotransmitter,” Gipson said. “By presenting the nicotine-addicted rat with cues that it associates with nicotine delivery, we induced a release of glutamate that causes relapse and a rapid, transient change in the structure and function of accumbens neurons that is correlated with the intensity of relapse.”

Kalivas said the study shows an expansion in the receptive area in the brain during this relapse period with it becoming much more sensitive to the glutamate. The researchers went on to show that when they used a compound to block glutamate receptors, or a compound to prevent the large release of glutamate, the rats were no longer motivated to seek nicotine, even when given the sound and light cues that signaled nicotine availability.

An electrophysiology ‘rig’ is used to study brain tissue.
An electrophysiology ‘rig’ is used to study brain tissue.

“In this study, we were able to prevent this increased sensitivity of the nucleus accumbens by pretreating the animal with a drug, and it blocked the whole thing,” Kalivas said. “The animal didn’t relapse and show this big expansion in synaptic strength.”

The team now is working with Kevin Gray, M.D., an MUSC colleague in psychiatry on a pilot clinical trial to test one of these compounds, N-acetylcysteine, in cigarette smokers. Gipson said they will use N-acetylcysteine in combination with varenicline to treat smoking relapse, hoping for an additive effect that will prove to be a more effective way to stop smoking.

Gipson said she loves how rapidly their work is being translated to potentially help patients. “It’s exciting to have a finding like this. You cross your fingers, and you graph it, and you hope. Everyone knows someone who smokes. It’s a difficult habit to kick, and the relapse rates are ridiculously high. It’s a huge personal and societal health care problem that may be diminished if our ideas are correct,” she said.

Kalivas said varenicline acts to suppress nicotine cravings, whereas the compound in their study targets the more fundamental neural circuitry that his team thinks underlies the basic pathology of the addiction. “By fixing the neuropathology as well as suppressing craving, the combination of drugs might help turn the key and be a very useful combination in treating cigarette addiction and possibly other addictions, as well.”

Pushing the lab’s research beyond illegal drugs into the realm of other addictive substances, such as nicotine, serves as an economic incentive to pharmaceutical companies potentially attracted by the larger population that could be served by drug development in this area, Kalivas said.

“Pharmaceutical companies are interested in finding drugs to treat nicotine and alcohol addictions, and obesity as well, since there can be a compulsive component to why some people gain weight,” he said, citing ongoing research in his lab exploring if there are similar disorders in brain signaling in obesity-prone animals, as has been found after cocaine, heroin and nicotine use.

“It worked for nicotine to our surprise, so we’re betting that the obese-prone animals will show similar cue-induced changes in cortical regulation of habit circuitry, whereas the obese-resistant animals will not.”
At any rate, it gets Kalivas one step closer to his dream as a scientist and researcher.

“I’d love it if our research generated effective drugs for treating addiction. That would be the ultimate. If we can target the maladaptive brain physiology underlying addiction, it’s just a matter of time before pharmaceutical agents are developed that can help lessen or even reverse the effects.”

For more information, read the abstract paper “Reinstatement of nicotine seeking is mediated by glutamatergic plasticity” and the PNAS First Look Blog about "The brain biology of nicotine relapse."

June 19, 2013
 
 
 

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