Cocaine addiction: stuck in a protein loop?

Assistant Professor AJ Robison
While we’re hoping to develop pharmacological agents to tackle addiction, I think in the long run this will be achieved with genetic medicine as it develops over the coming decades.
Professor A.J. Robison
Research reported in The Journal of Neuroscience has demonstrated the existence of a molecular process which influences the response of the brain to cocaine. It is hoped that the association between two key proteins that has been uncovered will provide a target for future addiction interventions, according to the researchers behind the study.

Understanding how the so-called ‘pleasure centre’ of the brain reacts to a substance such as cocaine and how long-term, chronic exposure affects this and other regions of the brain are necessary to a working knowledge of addiction (and how it may be prevented or reversed). The work was funded by the US National Institute on Drug Abuse (NIDA).

A.J. Robison [above], who led the study, is now an Assistant Professor in the Department of Physiology and the Neuroscience Program at Michigan State University (MSU). In an interview, he outlined for ScienceOmega.com how previous research led him and his colleagues to discover a ‘feed-forward loop’ involved in normal cocaine responses and to establish an association between the two proteins involved in that loop.

While carrying out most of the research, Professor Robison was a postdoctoral fellow in Dr Eric Nestler’s lab at the Icahn School of Medicine at Mount Sinai (formerly known as the Mount Sinai School of Medicine) in New York City. Researchers there have been studying one of the proteins involved – DeltaFosB – for 20 years.

"Production of DeltaFosB is induced by cocaine in the nucleus accumbens, the part of the brain that is responsible for reward responses," Professor Robison explained. "The nucleus accumbens is active when you feel pleasure, whether you are using cocaine, eating food that you like, or having sex."

The neuroscientist has spent most of his scientific career to date studying another protein called CaMKII. While DeltaFosB is associated with cocaine addiction, CaMKII is thought to be involved in learning and memory processes. This study has shown for the first time that there is a reciprocal relationship between the two; CaMKII production is stimulated by the presence of DeltaFosB and vice versa. Each also stabilises levels of the other, resulting in what Professor Robison terms a ‘feed-forward loop’.

To test the role of the loop in cocaine response, the team disrupted the process, both physiologically and structurally, in mouse models using genetic medicine.

"We used a viral vector – an attenuated virus that does not replicate – which delivers specific genes to the regions of the brain where they are injected," Professor Robison related. "In this case, we delivered a gene to cause the expression of a small peptide that inhibits CaMKII function, thus breaking the loop.

"When this happened, we no longer saw the ability of DeltaFosB to alter cocaine responses. The two proteins must work in concert; for DeltaFosB to correctly function and alter behaviour, CaMKII needs to be working."

It is hard to say for sure whether the feed-forward loop is engaged from the very first instance of cocaine exposure, but Professor Robison speculated that this is likely to be the case.

"Baseline levels of DeltaFosB are particularly low, and the first exposure to the drug causes very little DeltaFosB induction," he said. "One of the most important properties of DeltaFosB is that it builds up over time after chronic exposure; this is one reason for believing it is important to the response as an addiction.

"Although I would guess that the loop is initially engaged after the very first exposure, it is only after chronic exposure to the drug – leading to a build up of the DeltaFosB protein – that the loop becomes truly important as far as physiological responses go."

Evidence has also been found that the same kind of feed-forward loop was at work in the brains of people who have died while addicted to cocaine. As far as Professor Robison is concerned, this is compelling news from the point of view of potential implications for human users of cocaine.

"The aim of this type of study is to discover new avenues, from a molecular and signalling standpoint, that we can use to pharmacologically or genetically intervene in the process of addiction," he told me. "This is with the hope that, if we were to develop drugs that interfere with these pathways, we could prevent addiction from happening or even reverse addiction."

These drugs do not exist. Viral vectors like the ones used in the mouse model in this research have been used in humans in pilot studies over the last couple of decades, but they have not as yet been used successfully to treat diseases.

"The tools to interfere with the addiction process at the molecular level in a human are still in their infancy," he commented. "While we’re hoping to develop pharmacological agents to tackle addiction, I think in the long run this will be achieved with genetic medicine as it develops over the coming decades."

Further research in Professor Robison’s lab at Michigan State University is planning to concentrate on a different brain region. Although study of the nucleus accumbens is essential because it is there that cocaine causes a pleasure response, other parts of the brain are also very important for the addiction process.

"The hippocampus in particular is involved in learning, especially explicit learning," Professor Robison went on. "It is required to make associations between the environment and the drug, the people you’re with and the drug, or the paraphernalia and the drug, for example. When someone is addicted to a drug, one of the things that can cause them to relapse or experience cravings is being in the environment that they associate with drug use. This is one of the reasons it’s so hard to quit."

The lab’s efforts will focus on the ways that certain molecules are induced by drugs of abuse in the hippocampus, and particularly the role of DeltaFosB there in altering drug related behaviours.

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Thanks to ScienceOmega.com and Katy Edgington for a clear, well-written article. Looking forward to working with you again in the future.

AJ Robison - Michigan State University, United States
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