Researchers led by 2017 BBRF Young Investigator Kevin T. Beier, Ph.D., have discovered a way to predict individual behavioral responses to cocaine in mice never exposed to the drug, and have also found that carnosic acid, which is found in extract from the herb rosemary, can reduce volitional cocaine use in mice by reducing activity in a key brain circuit that controls cocaine-induced behavioral changes.

Dr. Beier, of the University of California, Irvine, is among researchers who in recent years have studied the system that regulates release of the neurotransmitter dopamine from a region called the ventral tegmental area (VTA). Dopamine release from cells in this area has been implicated in all phases of substance misuse (not only cocaine), from the initial rewarding effect to withdrawal and ultimately to compulsive drug-seeking.

But as Dr. Beier and colleagues note in their new paper, appearing in the journal Neuron, “it is precisely because the dopamine system is central to so many functions that it has proved to be a poor target to combat substance abuse.” Given dopamine’s ubiquity in the brain, rather than try to regulate the dopamine system as a whole as a way of modifying drug addiction, researchers including Dr. Beier and colleagues have turned to the idea of modulating signaling in particular dopamine subcircuits.

In prior research, Dr. Beier’s team demonstrated the role of a key subcircuit centered on dopamine-releasing cells in the VTA that contributed to some of the later stages of substance misuse including withdrawal and reinstatement of use after forced cessation. In the team’s new experiments just reported, they sought to map circuits that control the earliest stages of substance use disorder (SUD)—those that mediate drug reward as well as the urge to take the drug.

While most SUD research has focused on several brain regions involved in reward and aversion processing including the VTA, nucleus accumbens, and medial prefrontal cortex, Dr. Beier’s team has focused on a less-explored region called the globus pallidus externus (GPe), which appears to play an important role in mediating behavioral changes that occur following use of an addictive drug like cocaine.

The question in the new study was which areas of the brain controlled individual differences in behavioral response to cocaine. While cocaine is an addictive drug, not everyone who uses cocaine develops an SUD; Dr. Beier’s team was interested in whether individual differences in behavioral responses to cocaine could be predicted prior to repeated use of cocaine. Through a series of experiments in living mice, the team was able, first, to implicate the GPe “as the central mediator” in cocaine reward as well as in sensitization to the drug (responding more strongly to each subsequent drug exposure). Beyond this, they were able to show that by dampening the activity of parvalbumin (PV)-containing cells in the GPe, they could reduce volitional cocaine intake in mice. This likely occurred through modulating activity in a subset of dopamine cells in the VTA that critically regulate cocaine reward. PV is a protein whose presence is used to distinguish a particular subset of neurons in the brain.

Importantly, the researchers identified a specific mechanism that appeared to be essential in getting this response: they “dampened” GPe cell activity by activating proteins called KCNQ3 and KCNQ5. These are proteins that help regulate the flow of charged molecules (ions) of potassium into and out of nerve cells. The flow of ions like potassium is one of the essential ways that nerve cells regulate their activity—whether and how often they fire.

Interestingly, the experiments demonstrated that in cocaine-naïve mice, levels of firing activity of PV-containing GPe cells correlated directly with how rewarding a mouse found a subsequent cocaine dose to be. Cocaine-naïve animals with high levels of activity in such cells were more susceptible to long-lasting behavioral effects of cocaine than those with low levels of activity.

This result provided a rationale to test whether artificially lowering the activity level in PV-containing GPe cells would lower the behavioral response to cocaine, including the desire of animals to self-administer it when offered. This proved to be the case. The effect was the same in mice of both sexes and was thought by the team to occur via the blocking or lowering of reward from taking the drug.

There were two important takeaways. One is that measuring the baseline activity of PV-containing cells in the GPe is a potential biomarker for cocaine sensitivity—perhaps in people, as in mice. This is important, says Dr. Beier, because “only a subset of people is vulnerable to developing substance-use disorder, but we cannot yet identify who they are. If globus pallidus cell activity can effectively predict behavioral responses to cocaine, it could serve as a biomarker for the most vulnerable, which could be an important method for reducing dependence and ultimately, substance misuse.”

The second major takeaway was that the method used to lower the activity of PV-containing GPe cells—administration of carnosic acid obtained from rosemary extract—is a potential novel treatment for cocaine-use disorder and perhaps for other substance use disorders. As Dr. Beier notes, “there are no effective therapeutics for dependence on psychostimulants like cocaine. Our study deepens our understanding of basic brain mechanisms that increase vulnerability and provides a foundation for development of new interventions.”

The team noted: “Carnosic acid has [previously] been reported to exhibit wide-ranging health benefits, demonstrating anti- inflammatory, antiviral, anti-obesity, anti-carcinogenic, and anti-depressive properties, and generally shows promise as a neuroprotective agent, including against Alzheimer’s and Parkinson disease. However, to our knowledge, this is the first report of its potential as an anti-addictive agent. As such, we should note that much remains unknown about carnosic acid’s effects on the brain, both acutely and long term.”

Translation of results in rodents to humans is a major undertaking. The next steps in the research include thoroughly assessing any negative side effects of carnosic acid, and determining optimal dosages and timing of treatments. This would precede any tests of efficacy in people. The team is also interested in testing carnosic acid’s effectiveness in reducing the desire for other drugs.

Jason Aoto, Ph.D., 2016 BBRF Young Investigator, was also a member of the team.