Monoaminergic neuronal changes in orexin deficient mice

Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute of Drug Abuse, National Institute of Health, Baltimore, MD 21224, USA.
Neuropharmacology (Impact Factor: 4.82). 09/2009; 58(4-5):826-32. DOI: 10.1016/j.neuropharm.2009.08.009
Source: PubMed

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.

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    • "ergic neurons in orexin / ataxin - 3 mice would be reduced during wakefulness rela - tive to wild - type mice . Surprisingly , however , serotonergic DR neurons in orexin / ataxin - 3 mice showed no differences in firing frequency in any state compared with wild - type mice . Orexin / ataxin - 3 mice have normal serotonin levels in the forebrain ( Mori et al . , 2010 ) . These results indicate that the activity of se - rotonergic DR neurons is normally highly influenced by orexin neuronal activity but , in the chronic absence of orexin input , compensation can occur ."
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