Rae M Photo2

Dr. Rae Matsumoto. Image credit Dr. Rae Matsumoto.

Dr. Rae Matsumoto obtained her Ph.D. in psychology at Brown University. She subsequently received post-doctoral training in biochemistry and physiology at Brown and Northwestern Universities. She then served as an Assistant Professor of Neurology at the University of California Irvine, and as Co-Director of its Parkinson’s and Movement Disorders Program. In 1996, Dr. Matsumoto moved to the University of Oklahoma Health Sciences Center in the College of Pharmacy, where her research focused on medications development for the treatment of drug abuse. In 2004, Dr. Matsumoto moved to the University of Mississippi, where she served as the founding Director of the Center for Research Excellence in Natural Products Neuroscience after leveraging the school’s first COBRE grant. She joined West Virginia University in 2008 to serve as the Associate Dean for Research and Graduate Programs, a newly created position in the School of Pharmacy. Dr. Matsumoto joined Touro University California as the Dean of the College of Pharmacy in 2014 where she continues to encourage the training of future leaders for the profession by promoting innovation, excellence, and service.

Dr. Matsumoto recent research focuses on the development of potential new drugs for the treatment of neurological and psychiatric disorders, and elucidation of cellular mechanisms by which they produce their therapeutic effects. During her talk, she introduced sigma receptors and their role as potential drug targets for an array of neurological and psychiatric conditions. She also presented on the therapeutic development of novel sigma ligands and their ability to mitigate neurodegenerative and cognitive deficits caused by methamphetamine in preclinical studies.

SAGE sat down with Dr. Matsumoto to ask a few more questions… 

Q: Have you tested the interaction between sigma receptor antagonists and the level of dopamine or serotonin transporters?

At this point in our studies we have not looked at the direct effect of sigma receptors on the dopamine or serotonin transporter. Our work mostly focused on the end result – the damage caused by methamphetamine. Methamphetamine interacts and affects multiple cellular functions beyond dopamine or serotonin transporters. We are interested in drugs of abuse and stimulants like methamphetamine and cocaine because there are no FDA approved treatments for it. The field has spent many years doing high quality research examining the interaction of methamphetamine with dopamine and other monoamine transporters, but it has not yet resulted in a treatment for humans. The lack of a dopamine focused treatment has led our lab to consider other possibilities, including sigma receptors which also interact with methamphetamine. There is the possibility that blocking the interaction of sigma receptors with methamphetamine, would result in a viable human treatment for health related consequences due to methamphetamine abuse.

Q: What is the difference between methamphetaminecaused neurodegeneration and aging-caused neurodegeneration?

It appears that many of their mechanisms overlap, including oxidative stress mechanisms, ER stress, and mitochondrial functions that become compromised. One can see these specific pattern changes repeatedly in aging, Parkinson’s, Alzheimer’s and methamphetamine related neurodegeneration. These mechanisms are only part of the cause of neurodegeneration. I think of methamphetamine as another contributing factor by which cellular function could become compromised, leading to neurodegeneration.

Q: Does the sigma receptor also play a role in age-related neurodegeneration? 

The sigma receptor could potentially serve as a therapeutic target for many age-related neurodegenerative conditions including Parkinson’s disease and Alzheimer’s disease. There have been a number of recent preclinical studies that have shown that intervention is possible in models of progressive neurodegeneration. It is likely that the sigma receptor is not going to be the only target, but it is one of the potential targets.

Q: Do sigma receptor antagonists can also help with the addiction to methamphetamine? 

Addiction is an interesting topic from a scientific point of view because it is not a static condition or disease. If one had not become an addict, then one would have a normal brain that would still respond to a drug like methamphetamine. People who are addicts feel a compulsion to take the drug. Both human and animal studies have shown that when individuals are repetitively exposed to drugs of abuse, persistent changes occur in nervous system function. These changes alter the way in which the brain processes information, when compared to a normal brain’s response to a specific drug. This altered process is one of the reasons for addict specific phenotypes compared to the recreational drug user, who are not serious addicts.

The neurobiology that’s involved in the transitions – what are those genes; what are those late targets that become semi-permanently altered as you transition from a normal brain to an addicted brain is only starting to be elucidated. Some of our earlier work on cocaine abuse shows that sigma receptor antagonists can block the immediate effects of the drug, and have the ability to block aspects of the transition from a normal functioning brain to an addicted brain.

However, when we treat those already addicted, we may need to use a different type of strategy. While there is no FDA approved treatment for methamphetamine, there are approved treatments for opioids and nicotine. For opioids the medications that are in use are like a weaker version of the opioid so that the patients are getting a small, partial effect but not the strong effect of the addictive drug. If the treatment completely lacks the drug like effects, then the patients don’t want to take their medications and this is problematic. To ensure the patients take the medication, there needs to be some mimicking of the drug’s effects to make the treatment tolerable and to prevent withdrawal. Animal studies indicate that sigma receptor agonists may be promising for addiction treatment because they can reduce self-administration behavior.

Meth Mouse Rae Interview

An example of a self-administering device, the mouse presses a button to gain access to the drug from the feeding unit. Image credit: Barbara Bailus

Q: What is self-administration behavior?

One way that we assess whether a drug might have potential abuse liability is if an animal will work to get the drug. In evaluating self-administration, a common experiment features a lever that an animal can press to receive (self-administer) the drug; if the animal is pressing the lever a lot, then the drug is potentially addictive. What’s interesting is these animal experiments show a high correlation to commonly addictive drugs in humans. Also, the animals are able to titrate the dosage received. If you adjust the dose that is delivered with the bar press, and if you give smaller doses, the animals will press the bar more, but with higher doses they’ll press the bar less. This behavior makes sense, because if one takes too much of a drug then one passes out. Animals are very good at adjusting their dosage to an optimal level. One can’t ask a lab animal “how good a high are you getting with this drug?” but one can evaluate “how hard will the subject work to get this drug?” For cocaine or methamphetamine, animals will work really hard to self-administer the drug.

Since these drugs interact with the sigma receptor it is interesting that animals will not work as hard to get a sigma receptor activator, when compared to a known drug of abuse. They will press the bar more than for saline but much less than for an addictive drug like cocaine. It also makes a difference whether the animal has experienced and abused a known addictive drug or if this is their first experience self-administering a drug. If the animal is self-administering for the first time, it’s likely they don’t show much self-administrative behavior to a sigma receptor activator.  In contrast, if an animal has experience with a drug like cocaine or MDMA (Ecstasy), when they experience the sigma receptor activator they self-administer more presumably because they are seeking the high based on their previous drug associations.

It suggests that an addicted person would take a sigma receptor activator but regular people would have less affinity for it. This makes sigma activators good treatment candidates as regular individuals are less likely to become addicted to it, but addicts might find it an acceptable substitute for their preferred drug.

Q: What are the other potential treatments besides sigma receptors?

It is very difficult to convert the addictive brain back to a normal brain. One avenue of research being pursued is the development of addiction vaccines. In theory these would enable individuals to develop antibodies, including catalytic antibodies in some cases. The mechanism involves immunization so when someone takes the addictive drug the person’s antibodies, developed in response to the vaccine, would protect them from the drug, and in the case of catalytic antibodies attack and destroy the drug before the drug’s effects could be felt. The hope is that when addicts have been given the vaccine and the drug no longer has the desired effect, they would stop taking the drug. Unfortunately although the vaccine was very promising in animal studies there were some complications in the human clinical trials.  Perhaps due to human’s excellent long term memory and association with the drugs, the addicts would take excessive amounts of the drug to try and overcome the vaccine’s effect. The antibodies were very effective at preventing drug over-dosing, which should have occurred in the patients who were taking excessive amounts of the drugs to try and overcome the vaccine’s effectiveness. Although the antibodies were very effective in eliminating the high, they were far less effective at modulating addictive drug seeking behavior. This study showed that it is not just sufficient to treat the primary targets in the normal brain you have to treat the addicted brain, which has an ingrained memory of the high and associated drug-taking cues. The vaccine is an example of how one can design the perfect treatment based on science but it can fail if the “human behavior” element is not factored into the treatment.