Physicists at Lancaster University have been investigating the potential impact methamphetamine can have on behavioural rhythms in mice, exploring the potential implications the drug may have for conditions such as sleep disorders and ADHD.

Members of Lancaster’s Nonlinear and Biomedical Physics research group – including Professor Aneta Stefanovska, and PhD students Sam Barnes and Mansour Alanazi – recently collaborated with Professor Shin Yamazaki of the University of Texas to publish a paper in PNAS Nexus delving into the impact methamphetamine administration has on mice’s ability to regulate their “body clock” – also known as their circadian rhythms. Circadian rhythms are roughly 24 hours in length, and are primarily dictated by the Earth’s natural day-night cycle and genetics. The circadian clock acts like a conductor in an orchestra, and allows mammals to coordinate the timing of processes throughout the body such as hormone levels, digestive processes and sleep-wake cycles.

Disruption to an animal’s circadian rhythms can have serious health implications, including short-term impacts (such as tiredness, fatigue, and behavioural changes), to more serious chronic conditions, including increased risk of cardiovascular disease, mental ill health, and autoimmune dysfunction. Circadian rhythms – and any disruption to them – can also have an effect on the body’s ultradian rhythms, which are shorter biological processes which take place during a circadian cycle.

Methamphetamines are a stimulant-type drug, used both illicitly as a performance enhancement and recreational substance, as well as medically to treat conditions such as Attention Deficit Hyperactivity Disorder (ADHD). However, those using methamphetamines have long reported disruption to their sleep cycles as a side effect of taking the drug, suggesting that methamphetamines may have an impact upon the circadian and ultradian rhythms of mammals. The researchers within Lancaster, therefore, decided to explore the potential side effects of methamphetamines in mammals through a series of controlled tests on mice, using time-localized multiscale analysis to determine whether the drugs had any impact on the mice’s behaviours and activity patterns. Time-localized multiscale analysis involves examining rhythmic patterns across different scales, and tracking them across time, often using techniques such as wavelet transforms.

In order to study the impact these drugs had upon the mice, the team conducted their experiment on modified mice that had the genes that typically regulate circadian rhythms removed (meaning that their bodies had no innate timekeeping abilities) as well as ensuring that the mice were kept in complete darkness over the course of the experiment to eliminate the influence of external cues on these cycles.

After administering methamphetamines to the mice, the team then logged the mice’s activity on their running wheel. Within these genetically-modified mice, they found that methamphetamines restored the mice’s circadian-like rhythms, although the frequencies of these cycles were far more variable, switching between periods greater and less than 24 hours over time. The changes to the circadian rhythms that the mice underwent also altered the behaviour of mice over faster timescales, via phase couplings. Additionally, they found that the drugs had a tendency to induce a 48-hour (circabidian) cycle in the mice. Medically, the ramifications of these findings could be significant; the restoration of a time-varying circadian rhythm may explain the sleep-wake cycle disturbances reported in individuals treated with stimulants, especially those with attention-deficit/hyperactivity disorder (ADHD).

On the results of the experiment, Sam Barnes commented: “By applying the time-localised, multiscale analysis approaches developed at Lancaster University, we’ve uncovered dynamic features of circadian, ultradian, and infradian rhythms that traditional methods overlook. This research sheds light upon behavioural rhythms in varying experimental conditions — with a particular focus upon the understudied methamphetamine-sensitive circadian oscillator.”

DOI: https://doi.org/10.1093/pnasnexus/pgaf070