Circadian gene mutations linked to increased risk for substance abuse in study with mice

Dec. 2 (UPI) — Mice trained to self-administer cocaine went on more benders when they carried a mutation in the NPAS2 gene, a gene that regulates circadian rhythms.

The research, published Wednesday in the Journal of Neuroscience, suggests a link between the disruption of wake-sleep cycles and substance abuse.

Circadian genes are found in nearly every cell in the brain and body, but some circadian genes are unique to specific parts of the brain.

NPAS2 is highly expressed in the forebrain, specifically the striatum and nucleus accumbens, which helps operate the brain’s reward system.

“This suggests that NPAS2 might play a particularly important role in regulating rhythms in these brains regions, which is part of the appeal of studying NPAS2 and rewards,” lead study author Lauren DePoy told UPI in an email.

For the study, DePoy and her research partners trained them to self-administer a dose of cocaine.

The mice were implanted with a jugular intravenous catheter. When the mice stepped on a lever inside an experimental chamber, the catheter released a dose of cocaine into their bloodstream. Researchers synced light and sound cues with cocaine usage, or lever-pressing.

The experiment revealed differences in the way mice with and without NPAS2 gene mutations used cocaine.

“We found that mutant mice, particularly females and during the active phase, which is the dark phase for nocturnal mice, had a higher propensity to take cocaine, were impaired in their ability to stop seeking cocaine, and were more likely to show relapse-like behavior,” said DePoy, a postdoctoral fellow at the Center for Neuroscience at the University of Pittsburgh.

“More specifically, mutants took more cocaine, were more motivated to take cocaine, were slower to extinguish their drug seeking behavior — lever pressing — and showed more cue-induced reinstatement, which we use to model relapse to drug associated cues,” he said.

In addition to behavioral changes, researchers found females with NPAS2 gene mutations hosted heighten neural activity in the striatum, which helps control the brain’s reward system.

Though the NPAS2 gene mutation studied in mice is absent in the human genome, previous studies have identified links between other types of circadian gene mutations and a variety of psychiatric disorders.

In followup studies, researchers plan to investigate the neural mechanisms that underpin the connection between circadian gene mutations and cocaine use.

“We found that these results are likely mediated by neurons expressing the dopamine D1 receptor in certain subregions of the striatum, so we are interested in investigating how gene expression changes in these neurons in particular in mice with an NPAS2 mutation,” DePoy said.

Interestingly, researchers found when they silenced hormones of female mice with NPAS2, the rodents were less likely to use cocaine.

“There is clearly an interplay between hormones, rhythms and drug taking, but the mechanisms underlying these relationships are unknown,” DePoy said.

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