Published October 28, 2016
A new preclinical study by researchers in the Department of Pharmacology and Toxicology finds exercise, coupled with methamphetamine, may help recovery of those addicted to the drug and increase their odds of avoiding relapse.
The study, published in the Federation of American Societies for Experimental Biology (FASEB) Journal, reports a potential treatment to normalize disturbances in the circadian rhythms of addicts.
The researchers based their hypothesis on the fact that both methamphetamine and running wheel activity target the same reward centers in the brain, which are also involved in daily synchronization of physiological rhythms.
“Our experiments show that it might be possible to use methamphetamine to treat meth addiction itself, by associating drug usage with a stimuli that’s not harmful — exercise,” explains co-first author Oliver Rawashdeh, PhD, formerly a postdoctoral researcher in the Jacobs School of Medicine and Biomedical Sciences.
“Since various aspects of circadian rhythms are conserved among mammals, these findings may be directly translatable to humans,” says Margarita L. Dubocovich, PhD, SUNY Distinguished Professor and chair of pharmacology and toxicology, who is senior author.
The goal of the research was to find a treatment for disrupted circadian rhythms, which are likely to increase craving for the drug and relapse after treatment.
“The circadian system is negatively impacted by drugs of addiction, and it doesn’t necessarily recover,” says Rawashdeh, now a lecturer and head of the chronobiology lab in the School of Biomedical Sciences at the University of Queensland in Australia.
“We also know that the success of rehabilitation and prevention of relapse is linked to the degree of circadian disturbance in addicts.”
To better understand the relationship between addiction and circadian rhythms, the researchers studied mice that had the suprachiasmatic nucleus (SCN) — a small region in the brain’s hypothalamus that acts as the master circadian clock — removed.
“Metabolism and sleep cycles are all off kilter when someone is addicted, just like an animal whose master circadian clock has been removed,” Rawashdeh explains.
“It’s like being in a constant state of jet lag,” Dubocovich says. “You are in a constant transition state, and the same goes for these animals.”
That’s what happens when the SCN, the master circadian driver, becomes decoupled from the so-called “slave” oscillators that it controls, one of which is the methamphetamine-sensitive circadian oscillator (MASCO).
The researchers found that access to a running wheel and methamphetamine reinstate circadian rhythms in animals with no SCN, providing periodic feedback to a newly activated circadian brain clock, which could be the MASCO.
“Our idea was that if you pair a reward, in this case access to the running wheel, along with methamphetamine in 24-hour intervals over a period of time, the animal’s fragmented sleep/wake cycles would acclimatize to the 24-hour cycles, a process we call entrainment and consolidation,” Rawashdeh says.
Even more fascinating is the fact that the re-established circadian rhythm persists even after removing methamphetamine, he adds.
“We created a new homeostatic state,” Rawashdeh says. “By using the principles of learning and memory, we may have rewired the brain’s circuitry, activating a new clock — a form of plasticity — using the same stimulus that caused addiction in the first place, methamphetamine.”
“This was necessary in order to transfer the euphoric and pleasurable characteristics associated with the drug over to a healthy stimulus — exercise.”
Exercise stimulates the growth of new neurons, which may also play a role in the successful brain rewiring that takes place, the researchers say.
If this association can be duplicated in people, it might be possible to accelerate the efficiency of drug rehabilitation, decreasing the chances for relapse and re-establishing healthy circadian rhythms after withdrawal, according to Rawashdeh.
The team’s next step is to understand how the pairing of exercise with methamphetamine activates this circadian clock to induce robust rhythms and drug withdrawal and to localize the brain structure that hosts it, says Dubocovich, who is also senior associate dean for inclusion and cultural enhancement.
She notes that future research on the pairing of exercise and methamphetamine in humans will be facilitated by the clinical and translational science research infrastructure provided by the UB Clinical and Translational Science Award Hub.
Shannon J. Clough, PhD, a postdoctoral researcher in the Department of Pharmacology and Toxicology, is co-first author with Rawashdeh.
This work is supported by grants from the National Institutes of Health under awards from the National Institute on Drug Abuse and from the National Center for Advancing Translational Sciences and by funds from the Jacobs School of Medicine and Biomedical Sciences.