Addiction often upsets circadian rhythms, increasing craving for the drug and making relapse after treatment more likely. A new study with mice suggests combining exercise with a regimen of methamphetamine could help addicts get clean—and increase the likelihood they’ll stay clean.
The reason lies in the mechanism through which exercise and methamphetamine affect circadian rhythms, the roughly 24-hour cycles that drive all organisms.
“Metabolism and sleep cycles are all off kilter when someone is addicted.”
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,” says Oliver Rawashdeh, a lecturer at the University of Queensland and co-first author of the study published in the FASEB Journal. Rawashdeh conducted the research as a postdoctoral researcher at the University at Buffalo with colleague Shannon J. Clough, the study’s co-first author
“Since various aspects of circadian rhythms are conserved among mammals, these findings may be directly translatable to humans,” says Margarita Dubocovich, the study’s senior author and chair of pharmacology and toxicology at Buffalo.
Off-kilter sleep cycles
“The circadian system is negatively impacted by drugs of addiction and it doesn’t necessarily recover,” says Rawashdeh. “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 from whom the suprachiasmatic nucleus (SCN), a small region in the brain’s hypothalamus that acts as the master circadian clock, was removed.
“Metabolism and sleep cycles are all off kilter when someone is addicted,” Rawashdeh says, “just like an animal whose master circadian clock has been removed.”
“It’s like being in a constant state of jet lag,” says Dubocovich. “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.
A new brain clock
The researchers found that running wheel access and methamphetamine reinstate circadian rhythmicity 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,” says Rawashdeh.
Even more fascinating, he adds, is the fact that the re-established circadian rhythm in sleep/wake cycles persists even after removing methamphetamine.
“We created a new homeostatic state,” he 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,” says Rawashdeh. “This was necessary in order to transfer the euphoric and pleasurable characteristics associated with the drug over to a healthy stimulus – exercise.”
Can it be duplicated in people?
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, Rawashdeh adds, it might be very possible to accelerate the efficiency of drug rehabilitation, decreasing the chances for relapse, and re-establishing healthy circadian rhythms after withdrawal.
The team’s immediate 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, says Dubocovich.
The National Institute of Drug Abuse of the National Institutes of Health, the National Center for Advancing Translational Sciences, and funds from the Jacobs School of Medicine and Biomedical Science at the University at Buffalo supported the work.
Source: University at Buffalo