Molecular Insights of CREB and MAP-K Phosphorylation by Modafinil in Wake-Related Brain Areas

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.