“Drugs of abuse like cocaine and methamphetamine elevate dopamine levels to extremely high levels. In doing so, the high amounts of dopamine need to find somewhere to go. The dopamine ends up docking itself at receptors that cause secondary effects in the brain, such as euphoria or heightened awareness.”
Those secondary effects, he explains, are what motivate a person to crave those particular drugs again and again.
Nader’s office, a modest space on the Wake Forest School of Medicine campus, has just enough space for an L-shaped desk and a lateral file cabinet which neatly houses a proliferation of published journal articles.
This office, with its simple furniture and modest view, tucked away in a quiet corner of one of the Southeast’s most prestigious academic medical centers and top-ranked schools of medicine, is the ideal setting to support Nader’s inquisitive mind and his extensive quest to understand what exactly happens to brains when they are on and off drugs.
Nader shows me a slide on his monitor of two PET scans. Each scan is a map of a different monkey’s brain. He points out the glowing sections: two dots and a crescent. The image to the right is much brighter than its counterpart.
“Those glowing sections,” Nader says, “are images of the dopamine receptors at work.”
“We know that addiction is an illness of the brain. If we are going to solve, or at least mitigate, drug abuse, we need to better understand and develop therapies that will address the long-term physiologic causes of substance abuse.”
“Cocaine elevates dopamine levels and the dopamine binds to two kinds of receptors,” Nader says, “those that stimulate and those that inhibit. Animals with naturally low levels of inhibitory receptors, termed D2/D3 receptors – they’re the ones with the duller spots in these scans – will be more vulnerable to cocaine abuse. That’s true in humans as well. People with fewer receptors have a greater chance for excitation and consequently a greater vulnerability to drug abuse.”
This vulnerability to drug abuse is estimated to cost the U.S. taxpayer $500 billion a year, according to the National Institute on Drug Abuse. The solution, Nader says, is better treatment options.
Today, there are treatments on the market for alcohol, narcotics and nicotine abuse, but none are available for cocaine, amphetamines and other drugs of abuse. For the pharmaceutical industry and providers of health care, this will become increasingly relevant because of the Affordable Care Act and the requirement for insurers to cover addiction treatment. Further, existing treatments are not customized to abuser phenotype and, as Nader explains, when it comes to drug abuse, one size does not fit all. These factors emphasize the importance of preclinical models of drug addiction.
Nader shows another slide: two sets of three scans at various intervals – baseline, one-year self-administration and abstinence – of two monkeys with histories of cocaine use.
In subject R-1241, receptor levels are robustly diminished at one year of self-administration. After abstinence, the levels stay diminished. Subject R-1247’s receptor measures, however, return to near baseline levels after abstinence.
“If we could figure out why there is complete recovery in this animal and not in the other that would give us more signals as to what we can do to develop novel treatments of addiction,” says Nader.
But drug taking does not occur in a vacuum. It generally occurs in a social environment for humans and this is the focus of Nader’s second and most novel arm of research.
“Just like humans, monkeys create social hierarchies.” In Nader’s research, dominance and subordinance represent two ends of a continuum from environmental enrichment in dominant monkeys to chronic social stress in subordinate animals.
“Dominant monkeys have high levels of the inhibitory D2/D3 receptors and subordinate monkeys have lower levels, making the subordinate more vulnerable. Both categories of monkeys are susceptible to addiction, but overall brain functions affected by addiction manifest in a significantly different way. For example, if these same monkeys are moved into new social groups, the dominant monkey’s brain activity will increase while the subordinate’s will decrease, elevating its vulnerability.”
Nader believes there’s much work to be done to develop novel therapeutics to treat substance abuse. The most effective therapeutics, he says, will address both the physiological and the social dynamics of addiction. “The brain is way too complicated for us to come up with one medication that is going to work in everybody,” he says. “We need a tool chest of possibilities.”
Nader believes this model of addiction – nonhuman primates that self-administer cocaine, methamphetamine and other drugs of abuse – is the best predictive model of human drug taking. By studying drug self-administration within these animal models, he has made a series of breakthrough findings that offer promise for the development of future therapeutics and treatments. Key findings include:
- Environmental, social and pharmacological variables can impact dopamine D2/D3 receptor availability and impact vulnerability in subjects.
- The behavioral effects of compounds that bind to D2/D3 receptors are modified when nonhuman primates have a history of cocaine use, so the best way to study treatments for drug addiction are in animals with a long history of exposure to drugs of abuse.
- Dominant male and female monkeys have high levels of D2/D3 receptors while subordinate male and female monkeys have lower levels; this makes the subordinate male monkeys more vulnerable to cocaine abuse than dominant male monkeys.
- Dominant female monkeys are more vulnerable to cocaine reinforcement than subordinate females, an effect opposite to that observed in males. These findings support the strategy for sex-specific treatment options for drug addiction.
Nader sees an essential next step in the development of effective treatments: building partnerships with drug developers to test the effectiveness of their therapeutics in his animal models. Pharmaceutical companies developing new treatments for drug abuse need access to preclinical models of drug addiction with strong predictive validity. In addition, the FDA requires abuse liability assessments for all novel drugs and Nader believes nonhuman primates can provide invaluable data on abuse potential for emerging drugs.
An active investigator with a state-of-the-art research laboratory, Nader has spent the majority of his 30-year career investigating the physiological, social and environmental characteristics of drug abuse in his male and female rhesus and cynomolgus monkey models of drug self-administration. He now offers this expertise and his unique models and investigative methods to industry partners to help develop and assess the liability of the next generation of therapeutics.
Contact Wake Forest Innovations to schedule a meeting with Dr. Nader to discuss how Wake Forest’s preclinical models of addiction can be used to address abuse liability and help your organization discover new treatments for drugs of abuse.