The discovery of increased levels of dopamine (DA) in the basolateral amygdala (BLA) of the brain at the transition from non-rapid eye movement (NREM) to REM sleep in mice suggests a druggable sleep disorder target, according to a Japanese study.

"This study has for the first time implicated the involvement of dopamine in the BLA in the regulation of REM sleep," said study leader Takeshi Sakurai, a professor in the Faculty of Medicine/WPI-IIIS at the University of Tsukuba.

Mammalian sleep is characterized by alternating periods of NREM and REM sleep, with REM sleep, the stage in which vivid dreams usually happen, occurring after stages of NREM sleep in a cycle that occurs repeatedly until waking.

However, to date, how the brain regulates sleep and cycles between sleep states has been poorly understood.

While pharmacological studies have indicated that DA can modulate REM sleep, the neurotransmitter, which is most commonly associated with pleasure and addiction, is absent in most commonly used REM sleep models.

In their new study reported in the March 3, 2022, edition of Science, Sakurai and colleagues used fiber photometry in the brains of mice to study the role of DA in sleep.

"Fiber photometry assesses fluorescent intensity in particular brain regions," said Sakurai, noting, "we used fluorescent DA sensors to monitor extracellular DA levels in several brain regions during each sleep stage and in the transitions between each state."

They observed increases in DA activation in the brain's BLA, but not in other regions, just before the transition from NREM to REM sleep, suggesting that transient DA in this brain region triggers initiation of REM sleep.

The researchers then used optogenetic manipulation in mice to excite DA fibers in the BLA during NREM sleep, which caused a transition to REM sleep.

"Likewise, the inhibition of DA release in the BLA markedly decreased REM sleep," Sakurai told BioWorld Science.

Sakurai and colleagues also examined whether DA signaling in the BLA is implicated in cataplexy, which occurs in narcoleptics and manifests as a crippling pathologic intrusion of REM sleep into wakefulness resulting in loss of postural motor control.

The investigators found that DA levels in the BLA while eating chocolate were increased in narcoleptic mice, but not in wild-type mice. The increased DA levels were followed by cataplexy, "while mimicking DA increase in the BLA by optogenetic manipulation also triggered cataplexy," said Sakurai.

"A transient increase of DA in the BLA put mice into REM sleep, but during wakefulness, orexin neurons are active, and they inhibit the DA increase," he said.

"However, in narcoleptics, orexin is absent, so the DA increase is not blocked, which results in cataplexy," Sakurai told BioWorld Science.

These findings provide new insights into control of both REM sleep and cataplexy by DA, suggesting that DA D2 receptor-expressing BLA neurons could be a selective druggable target for treating debilitating symptoms in REM sleep disorders, including cataplexy in narcolepsy.

These findings further suggest that "DA D2 receptor agonists/antagonists might be effective to regulate the REM sleep amount," said Sakurai.

Intriguingly, the findings may also have implications for the management of other disorders in which DA signaling is disrupted, such as Parkinson's disease (PD).

"Sleep disorders are very common in PD patients, in whom they have an immense negative impact on their quality of life, with insomnia, restless leg syndrome, and REM-sleep behavior disorder being the most frequent," said Sakurai.

"Our study's findings may prove to be important in an improved understanding of the pathophysiology of these sleep disorders found in PD," he said.

In the future, "we are considering the investigation of the downstream pathways of BLA, some preliminary results of which we have included in supplementary materials of this study," said Sakurai. "Simultaneous to the further study of this pathway, we would also like to know the mechanisms whereby DA neurons are regulated during sleep."