Modafinil enhances thalamocortical activity through electrotonic coupling

F. J. URBANO, E. LEZNIK, R. R. LLINAS.

San Diego, USA.

Conferencia; San Diego Convention Center: Halls B-H; 2007

Modafinil, a (diphenylmethyl)sulphinyl-2 acetamide derivative (also known as Provigil®, Modiodal®) has been used for the treatment of excessive sleepiness associated with narcolepsy for over a decade. However, its precise mechanism of action remains unknown. Here we characterized the effects of modafinil on both thalamocortical and inferior olivary systems in rodents in vitro, using voltage sensitive dye imaging in combination with single and dual neuron recordings. In our study, modafinil was applied indistinctively either with a fast exchange perfusion system or by local pressure injection. We found that modafinil (1-200 µM) was able to equally facilitate high- and low frequency-induced imaging responses in thalamocortical slices, by increasing both the activated cortical area and the rising slopes of the imaging responses. Modafinil effects on the thalamocortical system were not directly related to either a facilitation of excitatory synapses or an inhibition of inhibitory synapses. Nevertheless, an increase in membrane conductance observed after modafinil application for both pyramidal cells and interneurons in the cortex pointed toward the involvement of this drug in changing the passive properties of neurons. Indeed, a wide range of gap junction blockers (18β-glycyrretinic, carbenoxolone and mefloquine) were able to prevent modafinil effects in the thalamocortical system suggesting the involvement of modafinil in regulating electrotonical coupling. The direct demonstration that modafinil increased electrotonical coupling came from dual patch recording of electrically coupled neurons in both the cortex and the inferior olive. In the cortex, the coupling coefficient between pairs of cortical interneurons was, on average, 170% larger after modafinil (100 µM) application. While in the inferior olive, an average increment of 240% in the coupling coefficient was observed after modafinil (150 µM) superfusion. In conclusion, modafinil increases the electrical coupling in the thalamocortical and the inferior olivary systems.