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Published on: September 22, 2020
Monoaminergic neuronal changes in orexin deficient mice
Tomohisa Mori1, Shinobu Ito, Tomoyuki Kuwaki
1Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute of Drug Abuse, National Institute of Health, Baltimore, MD 21224, USA.
Abstract:
Orexin knockout (KO) mice and orexin/ataxin-3 mice (which have a different pathophysiological background in orexin deficiency) exhibit a phenotype that is similar to human narcolepsy. Although the interactions between the monoaminergic and orexinergic systems are not entirely clear, indirect monoamine-receptor agonists (especially psychostimulants) may contribute to the treatment of narcolepsy. The present study was designed to investigate the interaction between brain orexinergic and monoaminergic neurons as measured by the status of monoaminergic systems and monoamine-related behaviors using orexin-deficient mice. Previous studies have shown that a reduction of monoaminergic tone is related to wakefulness. In the present study, locomotor activity in a novel environment and dopamine turnover was significantly decreased in orexin-deficient mice compared to WT mice, which suggests that psychostimulants may be useful for maintaining wakefulness in orexin deficiency. We also examined the effects of orexin deficiency on psychostimulant-induced hyperlocomotion. The hyperlocomotion induced by methamphetamine and methylphenidate was lower, whereas that induced by MDMA was higher in orexin KO mice compared to WT mice. The sensitivities against psychostimulants in orexin/ataxin-3 mice differed from those in orexin KO mice. These results indicate that the effectiveness of each psychostimulant, which is closely related to its monoaminergic function, was influenced by orexin deficiency itself as well as by the different pathophysiological background in orexin deficiency.
Insights
Orexin deficiency in mice reduces wakefulness and dopamine activity, suggesting psychostimulants could treat narcolepsy. However, their effectiveness varies based on the specific drug and the cause of orexin deficiency.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Orexin deficiency in mice mimics human narcolepsy.
- The interplay between orexinergic and monoaminergic systems in wakefulness regulation is not fully understood.
- Monoamine-receptor agonists, particularly psychostimulants, show potential for narcolepsy treatment.
Purpose of the Study:
- To investigate the interaction between orexinergic and monoaminergic neurons.
- To assess monoaminergic system status and behaviors in orexin-deficient mice.
- To evaluate the impact of orexin deficiency on psychostimulant-induced behaviors.
Main Methods:
- Utilized orexin knockout (KO) mice and orexin/ataxin-3 mice.
- Measured locomotor activity in novel environments.
- Assessed dopamine turnover.
- Examined responses to psychostimulants like methamphetamine, methylphenidate, and MDMA.
Main Results:
- Orexin-deficient mice showed decreased locomotor activity and dopamine turnover compared to wild-type (WT) mice.
- Methamphetamine and methylphenidate-induced hyperlocomotion were reduced in orexin KO mice.
- MDMA-induced hyperlocomotion was increased in orexin KO mice.
- Responses to psychostimulants differed between orexin KO and orexin/ataxin-3 mice.
Conclusions:
- Orexin deficiency impacts monoaminergic systems and wakefulness.
- Psychostimulants may help maintain wakefulness in orexin deficiency, but their efficacy is drug- and condition-specific.
- The pathophysiological background of orexin deficiency influences psychostimulant effectiveness.
