Monoaminergic neuronal changes in orexin deficient mice
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 ."
ABSTRACT: Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. To help determine how these neurons promote wakefulness, we generated transgenic mice in which orexin neurons expressed halorhodopsin (orexin/Halo mice), an orange light-activated neuronal silencer. Slice patch-clamp recordings of orexin neurons that expressed halorhodopsin demonstrated that orange light photic illumination immediately hyperpolarized membrane potential and inhibited orexin neuron discharge in proportion to illumination intensity. Acute silencing of orexin neurons in vivo during the day (the inactive period) induced synchronization of the electroencephalogram and a reduction in amplitude of the electromyogram that is characteristic of slow-wave sleep (SWS). In contrast, orexin neuron photoinhibition was ineffective during the night (active period). Acute photoinhibition of orexin neurons during the day in orexin/Halo mice also reduced discharge of neurons in an orexin terminal field, the dorsal raphe (DR) nucleus. However, serotonergic DR neurons exhibited normal discharge rates in mice lacking orexin neurons. Thus, although usually highly dependent on orexin neuronal activity, serotonergic DR neuronal activity can be regulated appropriately in the chronic absence of orexin input. Together, these results demonstrate that acute inhibition of orexin neurons results in time-of-day-dependent induction of SWS and in reduced firing rate of neurons in an efferent projection site thought to be involved in arousal state regulation. The results presented here advance our understanding of the role of orexin neurons in the regulation of sleep/wakefulness and may be relevant to the mechanisms that underlie symptom progression in narcolepsy.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2011; 31(29):10529-39. DOI:10.1523/JNEUROSCI.0784-11.2011 · 6.75 Impact Factor
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ABSTRACT: The relationship between genes and behavior, and particularly the hyperactive behavior, is clearly not linear nor monotonic. To address this problem, a database of the locomotor behavior obtained from thousands of mutant mice has been previously retrieved from the literature. Data showed that the percent of genes in the genome related to locomotor hyperactivity is probably more than 1.56%. These genes do not belong to a single neurotransmitter system or biochemical pathway. Indeed, they are probably required for the correct development of a specific neuronal network necessary to decrease locomotor activity. The present paper analyzes the brain expression pattern of the genes whose deletion is accompanied by changes in locomotor behavior. Using literature data concerning knockout mice, 46 genes whose deletion was accompanied by increased locomotor behavior, 24 genes related to decreased locomotor behavior and 23 genes not involved in locomotor behavior (but important for other brain functions) have been identified. These three groups of genes belonged to overlapping neurotransmitter systems or cellular functions. Therefore, we postulated that a better predictor of the locomotor behavior resulting from gene deletion might be the brain expression pattern. To this aim we correlated the brain expression of the genes and the locomotor activity resulting from the deletion of the same genes, using two databases (Allen Brain Atlas and SymAtlas). The results showed that the deletion of genes with higher expression level in the brain had higher probability to be accompanied by increased behavioral activity. Moreover the genes that were accompanied by locomotor hyperactivity when deleted, were more expressed in the cerebral cortex, amygdala and hippocampus compared to the genes unrelated to locomotor activity. Therefore, the prediction of the behavioral effect of a gene should take into consideration its brain distribution. Moreover, data confirmed that genes highly expressed in the brain are more likely to induce hyperactivity when deleted. Finally, it is suggested that gene mutations linked to specific behavioral abnormalities (e.g. inattention) might probably be associated to hyperactivity if the same gene has elevated brain expression.Physiology & Behavior 02/2010; 99(5):618-26. DOI:10.1016/j.physbeh.2010.01.026 · 3.03 Impact Factor
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ABSTRACT: The party drug 3,4-methylenedioxymethamphetamine -better known as MDMA or ecstasy- has numerous effects on the human body, characterized by a rush of energy, euphoria and empathy. However, also a multitude of toxic/neurotoxic effects have been ascribed to MDMA, based upon case reports and studies in animals. Given the intrinsic difficulties associated with controlled studies in human beings, most of our insights into the biology of MDMA have been gained through animal studies. The vast majority of these studies utilizes a pharmacological approach to elucidate the mechanisms by which MDMA exerts its effects. Advances in genetics during the last decade have led to the development of several mouse models (transgenic or knockout) that have greatly contributed to our understanding of MDMA biology. This review provides an overview of these genetically modified animal models, in the light of some characteristic effects of MDMA, e.g. hyperlocomotion, neurotoxicity, hyperthermia, behaviour or rewarding. Without a shadow of a doubt, the next decade will bring many more advanced animal models, such as mice with site-specific deletion or rescue of genes and more genetically modified rat models. These models will further improve our knowledge on the pharmacology and toxicity of MDMA and, possibly, may assist in developing therapies coping with potential damage in abusers of MDMA and other drugs, as well as in patients suffering from specific neuronal pathologies.Current pharmaceutical biotechnology 08/2010; 11(5):421-33. DOI:10.2174/1389210204205762010 · 2.51 Impact Factor