ABSTRACT
BACKGROUND: Modafinil (MOD) is a waking-promoting compound that is used for the treatment of sleep disorders such as sleepiness and narcolepsy. Despite its efficiency, there are missing pieces of evidence regarding the mechanism of action of MOD at molecular level. For example, current data have demonstrated that MOD induces alertness by activating several wake-related neurotransmitter receptors, including dopamine 1 (D1) receptor. Nevertheless, an intriguing point highlights that MOD might be activating intracellular elements bounded to D1 receptor, such as cAMP response element-binding (CREB) or mitogen-activated protein kinase (MAP-K) expression. OBJECTIVE: We tested whether administrations of MOD induce phosphorylation of either CREB or MAPK in wake-related brain areas, such as dorsomedial hypothalamic nucleus (DM) and tuberomammillary nucleus (TMN) in rats. METHODS: Rats that received a systemic injection of MOD (30 or 150 mg/Kg) were sacrificed and brains were processed for immunohistochemical analysis of phospho-CREB or phospho-MAP-K staining. RESULTS: MOD dose-dependently enhanced phospho-CREB and phospho-MAP-K immunoreactivity in DM and TMN. Moreover, the statistical analysis revealed that MOD increased the number of phospho- CREB and phospho-MAP-K immunoreactive neurons in these brain areas studied. CONCLUSION: These findings provide significative insights regarding the possible molecular mechanism of action of MOD engaging the activation of phospho-CREB and phospho-MAP-K in wake-linked brain areas. Indeed, further studies are required to fully understand the molecular mechanism of action of MOD.
Subject(s)
Brain/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Mitogen-Activated Protein Kinases/metabolism , Modafinil/pharmacology , Wakefulness/physiology , Animals , Brain/drug effects , Hypothalamic Area, Lateral/drug effects , Hypothalamic Area, Lateral/physiology , Male , Phosphorylation/drug effects , Rats, Wistar , Wakefulness/drug effectsABSTRACT
The peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily that has been suggested as a modulator of several physiological functions. The PPARα recognizes as an endogenous ligand the anorexic lipid mediator oleoylethanolamide (OEA) which displays wake-inducing properties. Despite that recent evidence indicates that activation of PPARα by synthetic agonists such as Wy14643 enhances waking as well as the extracellular contents of wake-related neurotransmitters, the role of PPARα in sleep recovery after prolonged waking has not been fully described. Thus, the aim of this study was to characterize if PPARα regulates sleep rebound after total sleep deprivation (TSD). We report that after 6h of TSD activation of PPARα by pharmacological systemic administration of OEA (10, 20 or 30mg/Kg, i.p.) promoted alertness by blocking the sleep rebound after TSD. Besides, wake-linked compounds such as dopamine, norepinephrine, serotonin, or adenosine collected from nucleus accumbens were enhanced after TSD in OEA-treated animals. These sleep and neurochemical results were mimicked after injection of PPARα agonist Wy14643 (10, 20, 30mg/Kg, i.p.). However, similar findings from the sham of vehicle groups were observed if PPARα antagonist MK-886 was administered to rats (10, 20, 30mg/Kg, i.p.). Our results strengthened the hypothesis that PPARα might modulate sleep and neurochemical homeostasis after sleep deprivation.
Subject(s)
Homeostasis/drug effects , PPAR alpha/metabolism , Peroxisome Proliferators/pharmacology , Sleep/drug effects , Wakefulness-Promoting Agents/pharmacology , Adenosine/metabolism , Animals , Biogenic Monoamines/metabolism , Brain/drug effects , Brain/metabolism , Dose-Response Relationship, Drug , Endocannabinoids/pharmacology , Homeostasis/physiology , Indoles/pharmacology , Male , Oleic Acids/pharmacology , PPAR alpha/agonists , PPAR alpha/antagonists & inhibitors , Pyrimidines/pharmacology , Rats, Wistar , Sleep/physiology , Sleep Deprivation/metabolism , Wakefulness/drug effects , Wakefulness/physiologyABSTRACT
Modafinil (MOD) it has to be considered as a wake-inducing drug to treat sleep disorders such as excessive sleepiness in narcolepsy, shift-work disorder, and obstructive/sleep apnea syndrome. Current evidence suggests that MOD induces waking involving the dopamine D1 receptor. However, little is known regarding the molecular elements linked in the wake-promoting actions of MOD. Since the D1 receptor activates the mitogen-activated protein kinase (MAP-K) cascade, it raises the interesting possibility that effects of MOD would depend upon the activation of MAP-K. Here we tested the expression of MAP-K in hypothalamus as well as pons after the microinjection of MOD (10 or 20 µg/1 µL) in rats into anterior hypothalamus, a wake-inducing brain area. Intrahypothalamic injections of MOD promoted MAP-K phosphorylation in hypothalamus and pons. Taken together, these results suggest that the wake-inducing compound MOD promotes the MAP-K phosphorylation.
