A new study with mice finds that a combination of exercise and methamphetamine could be a new way to treat addiction.
The reason lies in the mechanism through which exercise and methamphetamine affect circadian rhythms, according to the researchers.
“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,” said co-first author Oliver Rawashdeh, Ph.D., formerly a postdoctoral researcher in the Jacobs School of Medicine and Biomedical Sciences at the University of Buffalo.
Researchers based their hypothesis on the fact that both methamphetamine and running on a wheel target the same reward centers in the brain, which are also involved in the daily synchronization of physiological rhythms.
The researchers said they were interested in circadian rhythms because addiction upsets them, increasing craving for the drug and making relapse after treatment more likely.
“The circadian system is negatively impacted by drugs of addiction and it doesn’t necessarily recover,” said 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 said.
“It’s like being in a constant state of jet lag,” added Margarita L. Dubocovich, Ph.D., senior author and SUNY Distinguished Professor and chair of the Department of Pharmacology and Toxicology in the Jacobs School of Medicine and Biomedical Sciences. “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 or MASCO, the researchers noted.
The scientists found that having access to a running wheel and methamphetamine reinstate circadian rhythms in mice 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 said.
Even more fascinating is the fact that the re-established circadian rhythm persists even after removing methamphetamine, he noted.
“We created a new homeostatic state,” he said. “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,” said Rawashdeh.
“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 brain rewiring that takes place, the researchers said.
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 researchers’ next step is to understand how the pairing of exercise with methamphetamine activates a new circadian clock in the brain to induce robust rhythms and drug withdrawal, Dubocovich said.
The study was published in The FASEB Journal.
Source: University of Buffalo